Publications by authors named "David A Lewis"

449 Publications

Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder.

Biol Psychiatry 2021 Jun 12. Epub 2021 Jun 12.

Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; Center for Systems Neuroscience, Boston University, Boston, Massachusetts. Electronic address:

Background: Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on the dorsolateral prefrontal cortex and nucleus accumbens, regions heavily implicated in OUD, from postmortem brains in subjects with OUD.

Methods: We performed RNA sequencing on the dorsolateral prefrontal cortex and nucleus accumbens from unaffected comparison subjects (n = 20) and subjects diagnosed with OUD (n = 20). Our transcriptomic analyses identified differentially expressed transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric orderlap. Weighted gene coexpression analyses identified OUD-specific modules and gene networks. Integrative analyses between differentially expressed transcripts and genome-wide association study datasets using linkage disequilibrium scores assessed the genetic liability of psychiatric-related phenotypes in OUD.

Results: Rank-rank hypergeometric overlap analyses revealed extensive overlap in transcripts between the dorsolateral prefrontal cortex and nucleus accumbens in OUD, related to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control proinflammatory cytokine, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. Linkage disequilibrium score analysis suggested genetic liabilities for risky behavior, attention-deficit/hyperactivity disorder, and depression in subjects with OUD.

Conclusions: Overall, our findings suggest connections between the brain's immune system and opioid dependence in the human brain.
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http://dx.doi.org/10.1016/j.biopsych.2021.06.007DOI Listing
June 2021

Demographic and behavioural risk factors associated with reduced susceptibility of to first-line antimicrobials in South African men with gonococcal urethral discharge.

Antimicrob Agents Chemother 2021 Aug 2:AAC0038921. Epub 2021 Aug 2.

Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

is the predominant cause of male urethral discharge in South Africa, and escalating prevalence of gonococcal antimicrobial resistance (AMR) is a major health concern, both in-country and globally. We analysed the demographic, behavioural and clinical characteristics of 685 men presenting with gonococcal urethral discharge to sentinel surveillance clinics over a three-year period (2017 - 2019), to determine the burden of factors that are known to be associated with AMR to first-line therapy (defined as Group 1 isolates exhibiting resistance or reduced susceptibility to extended-spectrum cephalosporins or azithromycin). Among 685 men with gonococcal urethral discharge, median age was 28 years (IQR 24-32). Only two men (2/632; 0.3%) self-identified as homosexual; however, on further enquiry, another 16 (2%) confirmed that they had sex with men only. Almost 30% practised oral sex, and were at risk for pharyngeal gonococcal infection. In univariate analysis, male circumcision (OR 0.69; 95%CI 0.49-0.99), and recent sex outside the country (OR 1.83; 95%CI 1.21-2.76) were significantly associated with having a Category 1 isolate. In a multivariable model, only sex outside South Africa increased the odds of being infected with a decreased susceptible/resistant isolate (aOR 1.64; 95%CI 1.05-2.55). These findings warrant the intensification of AMR surveillance among recently-arrived migrant and overseas traveler populations, as well as the inclusion of extragenital specimens for AMR surveillance purposes.
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http://dx.doi.org/10.1128/AAC.00389-21DOI Listing
August 2021

Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia.

Neuropsychopharmacology 2021 Jul 20. Epub 2021 Jul 20.

Department of Psychiatry and Behavioral Sciences, University of California Davis Medical Center, Sacramento, CA, USA.

Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having "an orchestra without a conductor." Kraepelin further speculated that this "conductor" was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
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http://dx.doi.org/10.1038/s41386-021-01089-0DOI Listing
July 2021

Barriers to HIV testing in hospital settings within a culturally diverse urban district of Sydney, Australia.

Sex Health 2021 Sep;18(4):340-343

Western Sydney Sexual Health Centre, 162 Marsden Street, Parramatta, NSW 2150, Australia; and Sexual Health and HIV, Brighton and Sussex Medical School, Brighton, UK; and Corresponding author. Email:

Background Eleven percent of people living with HIV in Australia remain unaware of their diagnosis, and there are missed opportunities for HIV testing in priority settings in New South Wales. HIV testing remains low outside of sexual health clinics with the exception of antenatal settings where HIV testing is routine. To understand why HIV testing rates are low, we sought to identify health worker-related barriers to HIV testing.

Methods: We conducted an anonymous online survey to health workers in Western Sydney Local Health District (WSLHD) in September 2019. Tick-box, Likert scale responses were analysed using Chi-square and Kruskal-Wallis statistical tests, and free text responses were analysed with thematic analysis.

Results: Three percent (n = 420) of WSLHD's estimated 14 000 health workers responded. These included 317 clinicians (171 nurses, 65 doctors, 56 allied health professionals (AHPs), 25 midwives, and 103 health workers in non-clinical roles). Health workers were from a variety of in-patient/out-patient settings. Many health workers (291/420, 69%; 95%CI = 64.9-73.7%) were unaware that HIV testing is offered in their areas; doctors (82%) and midwives (80%) were more aware than nurses (23%) and AHPs (11%) (P < 0.0001). Doctors (Likert score = 3.62; 3.45/5) and midwives (2.84; 2.76) were significantly more comfortable discussing and confidently offering HIV testing than nurses (2.42; 1.81) or AHPs (1.83; 0.91) (P < 0.0001 for both). The top five barriers to HIV testing were (1) procedural knowledge, (2) identification of at-risk patients, (3) HIV knowledge, (4) positive result management, and (5) privacy concerns. Free text responses highlighted perceived stigma, testing/result responsibilities and resource challenges as barriers to HIV testing.

Conclusions: Clinicians working in priority settings and with priority populations require more education and support to increase targeted HIV testing.
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http://dx.doi.org/10.1071/SH20189DOI Listing
September 2021

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.

J Neurosci 2021 Aug 14;41(31):6596-6616. Epub 2021 Jul 14.

Departments of Cell Biology

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders. The balance between cytoplasmic protein synthesis and degradation, or cytoplasmic proteostasis, is required for normal synapse function and neurodevelopment. Cytoplasmic and mitochondrial ribosomes are necessary for two compartmentalized, yet interdependent, forms of proteostasis. Proteostasis dependent on cytoplasmic ribosomes is a well-established target of genetic defects that cause neurodevelopmental disorders, such as autism. Here we show that the mitochondrial ribosome is a neurodevelopmentally regulated organelle whose function is required for synapse development and function. We propose that defective mitochondrial proteostasis is a mechanism with the potential to contribute to neurodevelopmental disease.
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http://dx.doi.org/10.1523/JNEUROSCI.2197-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336702PMC
August 2021

Long-term protection from HIV infection with oral HIV pre-exposure prophylaxis in gay and bisexual men: findings from the expanded and extended EPIC-NSW prospective implementation study.

Lancet HIV 2021 08 1;8(8):e486-e494. Epub 2021 Jul 1.

Clinic 16, St Leonards, NSW, Australia.

Background: Daily pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but few long-term data are available on effectiveness and adherence in real-world settings. Here, we report trends in HIV incidence over 3 years in individuals at high risk who were prescribed PrEP in New South Wales (NSW), as well as adherence before the transition to subsidised PrEP.

Methods: Expanded PrEP Implementation in Communities-New South Wales (EPIC-NSW) was a pragmatic, prospective, single-arm, implementation study of daily, oral PrEP in 31 sites (sexual health clinics, general practices, and a hospital) in NSW, Australia. Eligible participants were HIV-negative adults (aged ≥18 years) who were at high risk of HIV infection as defined in local PrEP guidelines. Participants were prescribed coformulated (once-daily, oral tablet) tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) as HIV PrEP and were followed up with HIV testing, sexually transmitted infection testing, and PrEP dispensing. Originally planned for 3700 participants followed for 1 year, the study was expanded so that all eligible participants in the state could obtain PrEP and extended until publicly subsidised PrEP became available in Australia. The primary outcome was new HIV infection among all participants who were dispensed PrEP at least once and had at least one follow-up HIV test result. Adherence was estimated by medication possession ratio (MPR), defined as the proportion of PrEP pills dispensed in 90 days, assuming daily dosing. This study is registered with ClinicalTrials.gov, NCT02870790.

Findings: Between March 1, 2016, and April 30, 2018, we enrolled 9709 participants. 9596 participants were dispensed PrEP, of whom 9448 (98·3%) were gay or bisexual men. Participants were followed up until March 31, 2019, with at least one follow-up HIV test available in 9520 (99·2%) participants. Mean MPR declined from 0·93 to 0·64 from the first to the ninth quarter. There were 30 HIV seroconversions over 18 628 person-years, an incidence of 1·61 per 1000 person-years (95% CI 1·13-2·30). Being younger, living in a postcode with fewer gay men, reporting more risk behaviours at baseline, and having an MPR of less than 0·6 were each univariately associated with increased HIV incidence. In the final year of follow-up, when PrEP was mostly purchased rather than provided free by the study, HIV incidence remained low at 2·24 per 1000 person-years (1·46-3·44).

Interpretation: HIV incidence remained low over up to 3 years of follow-up, including during a transition from study-provided to publicly subsidised PrEP. In a setting of affordable PrEP and associated health-care services, very low HIV incidence of 1 to 2 per 1000 person-years can be maintained in gay and bisexual men who were previously at high risk.

Funding: New South Wales Ministry of Health, Australian Capital Territory Health Directorate, Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(21)00074-6DOI Listing
August 2021

Ongoing evolution of lymphogranuloma venereum: exploring the genomic diversity of circulating strains.

Microb Genom 2021 06;7(6)

Clinical Bacteriology & Mycology, University Hospital Basel, University of Basel, Switzerland.

Lymphogranuloma venereum (LGV), the invasive infection of the sexually transmissible infection (STI) , is caused by strains from the LGV biovar, most commonly represented by -genotypes L2b and L2. We investigated the diversity in LGV samples across an international collection over seven years using typing and genome sequencing. LGV-positive samples (=321) from eight countries collected between 2011 and 2017 (Spain =97, Netherlands =67, Switzerland =64, Australia =53, Sweden =37, Hungary =31, Czechia =30, Slovenia =10) were genotyped for and variants. All were found to contain the 9 bp insertion in the gene, previously associated with -genotype L2b. However, analysis of the gene shows -genotype L2b (=83), -genotype L2 (=180) and several variants of these (=52; 12 variant types), as well as other/mixed -genotypes (=6). To elucidate the genomic diversity, whole genome sequencing (WGS) was performed from selected samples using SureSelect target enrichment, resulting in 42 genomes, covering a diversity of -genotypes and representing most of the countries sampled. A phylogeny of these data clearly shows that these -genotypes derive from an -genotype L2b ancestor, carrying up to eight SNPs per isolate. SNPs within are overrepresented among genomic changes in these samples, each of which results in an amino acid change in the variable domains of OmpA (major outer membrane protein, MOMP). A reversion to -genotype L2 with the L2b genomic backbone is commonly seen. The wide diversity of -genotypes found in these recent LGV samples indicates that this gene is under immunological selection. Our results suggest that the -genotype L2b genomic backbone is the dominant strain circulating and evolving particularly in men who have sex with men (MSM) populations.
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http://dx.doi.org/10.1099/mgen.0.000599DOI Listing
June 2021

Azithromycin or Doxycycline for Asymptomatic Rectal .

N Engl J Med 2021 06;384(25):2418-2427

From the University of Melbourne (A.L., F.Y.S.K., S.P., E.P.F.C., N.C., J.S.H.), the Melbourne Sexual Health Centre (C.K.F., M.Y.C., C.S.B., E.P.F.C., J.S.H.), and Monash University (C.K.F., M.Y.C., C.S.B., E.P.F.C.), Melbourne, VIC, Macquarie University, Macquarie, NSW (J.A.), Central Clinical School, Faculty of Medicine and Health, University of Sydney (D.J.T.), Sydney Sexual Health Centre (A.M., B.D.), and the School of Population Health (A.M.) and the Kirby Institute (D.J.T., M.L., B.D., D.G.R., J.K., J.A.), University of New South Wales, Sydney, the Department of Sexual Health Medicine and Sexual Assault Medicine, Sydney Local Health District, Camperdown, NSW (D.J.T.), Western Sydney Sexual Health Centre, Parramatta, NSW, and Westmead Clinical School, University of Sydney, Westmead, NSW (D.A.L.), the Adelaide Sexual Health Centre (C.K., M.R.) and the University of Adelaide (M.A.B.), Adelaide, SA, and the University of the Sunshine Coast, Sippy Downs, QLD (P.T.) - all in Australia.

Background: Rectal chlamydia is a common bacterial sexually transmissible infection among men who have sex with men. Data from randomized, controlled trials are needed to guide treatment.

Methods: In this double-blind trial conducted at five sexual health clinics in Australia, we randomly assigned men who have sex with men and who had asymptomatic rectal chlamydia to receive doxycycline (100 mg twice daily for 7 days) or azithromycin (1-g single dose). Asymptomatic chlamydia was selected as the trial focus because more than 85% of men with rectal chlamydia infection are asymptomatic, and clinical guidelines recommend a longer treatment course for symptomatic infection. The primary outcome was a negative nucleic acid amplification test for rectal chlamydia (microbiologic cure) at 4 weeks.

Results: From August 2016 through August 2019, we enrolled 625 men (314 in the doxycycline group and 311 in the azithromycin group). Primary outcome data were available for 290 men (92.4%) in the doxycycline group and 297 (95.5%) in the azithromycin group. In the modified intention-to-treat population, a microbiologic cure occurred in 281 of 290 men (96.9%; 95% confidence interval [CI], 94.9 to 98.9) in the doxycycline group and in 227 of 297 (76.4%; 95% CI, 73.8 to 79.1) in the azithromycin group, for an adjusted risk difference of 19.9 percentage points (95% CI, 14.6 to 25.3; P<0.001). Adverse events that included nausea, diarrhea, and vomiting were reported in 98 men (33.8%) in the doxycycline group and in 134 (45.1%) in the azithromycin group (risk difference, -11.3 percentage points; 95% CI, -19.5 to -3.2).

Conclusions: A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men. (Funded by the National Health and Medical Research Council; RTS Australian New Zealand Clinical Trials Registry number, ACTRN12614001125617.).
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http://dx.doi.org/10.1056/NEJMoa2031631DOI Listing
June 2021

Cross-sectional study of sexual behaviour and health of gay and bisexual men in suburban Sydney, New South Wales, Australia: contrasts between sex venue and clinic attendees.

Sex Health 2021 Jul;18(3):248-253

Western Sydney Sexual Health Centre, Western Sydney Local Health District, Parramatta, NSW, Australia; and Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Westmead, NSW, Australia.

Background In Australia, men-who-have-sex-with-men (MSM) have higher rates of sexually transmissible infections (STIs) and HIV compared with heterosexual men. We compared demographics, behaviour and HIV/STI prevalence for MSM attending a sex-on-premises-venue (SOPV) or the local sexual health clinic (SHC) to determine key differences.

Methods: Men attending a SOPV during onsite HIV/STI screening from November 2015 for 12 months were compared with MSM attending a local SHC for screening. Each group completed a self-administered questionnaire and STI/HIV testing. Data analysis was performed using SPSS.

Results: Compared with SHC participants (n = 108), SOPV participants (n = 84) had a higher median age (47 years [range, 22-88] vs 33 years [range, 19-71]; P < 0.001) and less likely to report previous HIV testing (73% vs 89%; P < 0.01), STI testing (60% vs 90%; P < 0.001) or be vaccinated for hepatitis A (32% vs 65%; P < 0.001) or hepatitis B (35% vs 73%; P < 0.001). SOPV participants were more likely to be married, widowed or have a long-term female partner (39% vs 7%; P < 0.001) and have a higher prevalence of urethral and rectal chlamydia (7% vs 1%; P = 0.02 and 8% vs 2%; P = 0.03, respectively). There was no significant difference between the groups for detection of syphilis (4% vs 9%), gonorrhoea (5% vs 9%) or HIV (1% vs 0%).

Conclusion: MSM attending the SOPV had higher anogenital chlamydial prevalence compared with those attending the SHC. They reported higher rates of sex with female partners, which may facilitate STI/HIV transmission to heterosexual populations. Our findings have implications for HIV/STI service provision, contact tracing and local health promotion initiatives.
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http://dx.doi.org/10.1071/SH20196DOI Listing
July 2021

Enabling culturally safe sexual health services in western Sydney: a protocol to improve STI treatment outcomes for Aboriginal young people.

Pilot Feasibility Stud 2021 May 13;7(1):106. Epub 2021 May 13.

Western Sydney Sexual Health Centre, Western Sydney Local Health District, Parramatta, NSW, Australia.

Background: Aboriginal people face challenges on several fronts when it comes to the health and wellbeing of their community, compared to the rest of the Australian population. This is no different in urban areas such as Australia's largest urban Aboriginal community located in Blacktown, NSW, where sexually transmitted infections (STIs) remain an issue of concern. Across Australia, rates of infectious syphilis, human immunodeficiency virus (HIV), and hepatitis C infection have increased by 400, 260, and 15% respectively while gonorrhoea decreased 12% in the 5-year period from 2013 to 2017. This study explores how to address the barriers that prevent young Aboriginal people under 30 years of age from accessing STI treatment through Government Sexual Health Services.

Methods: This qualitative study will use purposeful sampling to recruit 20 male and 20 female health consumers, 10 Aboriginal elders and 10 sexual health clinicians. This recruitment will be undertaken with the assistance of the local Government Health Services and local Aboriginal organisations. One-on-one semi-structured interviews will be undertaken by someone of the same gender in order to address cultural preferences. Data will be entered into NVivo and thematically analysed.

Discussion: This study will seek to add to the literature that explores why young Aboriginal people do not access sexual health services. This study seeks to understand the experience of clinicians, Aboriginal elders and Aboriginal young people to provide practical policy and clinical redesign evidence that can be used to improve the experience and cultural safety of sexual health services in urban areas of Australia. The results of the qualitative research will be disseminated with the assistance of participating local Aboriginal organisations, and the findings will be published through peer-reviewed scientific journals and conference presentations.

Trial Registration: The study is approved by the Western Sydney Local Health District Human Research Ethics Committee (HREC/16/WMEAD/449) and the New South Wales Aboriginal Health and Medical Research Council's Human Research Ethics Committee (1220/16).
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http://dx.doi.org/10.1186/s40814-021-00847-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117628PMC
May 2021

Kcns3 deficiency disrupts Parvalbumin neuron physiology in mouse prefrontal cortex: Implications for the pathophysiology of schizophrenia.

Neurobiol Dis 2021 07 30;155:105382. Epub 2021 Apr 30.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address:

The unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on the expression of multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively express Kcns3, the gene encoding Kv9.3 subunits, suggesting that Kcns3 expression is critical for the FS phenotype. KCNS3 expression is lower in PV neurons in the neocortex of subjects with schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. Therefore, to assess the role of Kv9.3 subunits in PV neuron function, we combined gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex of Kcns3-deficient mice. Kcns3 mRNA levels were ~ 50% lower in cortical PV neurons from Kcns3-deficient relative to wildtype mice. While silent per se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na channel inactivation. As in the computational model, PV basket cells (PVBCs) from Kcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing. Moreover, Kcns3 deficiency impaired the recruitment of PVBC firing at gamma frequency by stimuli mimicking synaptic input observed during cortical UP states. Our data indicate that Kv9.3 subunits are critical for PVBC physiology and suggest that KCNS3 deficiency in schizophrenia could impair PV neuron firing, possibly contributing to deficits in cortical gamma oscillations in the illness.
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http://dx.doi.org/10.1016/j.nbd.2021.105382DOI Listing
July 2021

Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age-related neurodegeneration.

Aging Cell 2021 05 28;20(5):e13365. Epub 2021 Apr 28.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Age is the greatest risk factor for Parkinson's disease (PD) which causes progressive loss of dopamine (DA) neurons, with males at greater risk than females. Intriguingly, some DA neurons are more resilient to degeneration than others. Increasing evidence suggests that vesicular glutamate transporter (VGLUT) expression in DA neurons plays a role in this selective vulnerability. We investigated the role of DA neuron VGLUT in sex- and age-related differences in DA neuron vulnerability using the genetically tractable Drosophila model. We found sex differences in age-related DA neurodegeneration and its associated locomotor behavior, where males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. We discovered that dynamic changes in DA neuron VGLUT expression mediate these age- and sex-related differences, as a potential compensatory mechanism for diminished DA neurotransmission during aging. Importantly, female Drosophila possess higher levels of VGLUT expression in DA neurons compared with males, and this finding is conserved across flies, rodents, and humans. Moreover, we showed that diminishing VGLUT expression in DA neurons eliminates females' greater resilience to DA neuron loss across aging. This offers a new mechanism for sex differences in selective DA neuron vulnerability to age-related DA neurodegeneration. Finally, in mice, we showed that the ability of DA neurons to achieve optimal control over VGLUT expression is essential for DA neuron survival. These findings lay the groundwork for the manipulation of DA neuron VGLUT expression as a novel therapeutic strategy to boost DA neuron resilience to age- and PD-related neurodegeneration.
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http://dx.doi.org/10.1111/acel.13365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135008PMC
May 2021

Altered Parvalbumin Basket Cell Terminals in the Cortical Visuospatial Working Memory Network in Schizophrenia.

Biol Psychiatry 2021 07 19;90(1):47-57. Epub 2021 Feb 19.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Visuospatial working memory (vsWM), which is commonly impaired in schizophrenia, involves information processing across the primary visual cortex, association visual cortex, posterior parietal cortex, and dorsolateral prefrontal cortex (DLPFC). Within these regions, vsWM requires inhibition from parvalbumin-expressing basket cells (PVBCs). Here, we analyzed indices of PVBC axon terminals across regions of the vsWM network in schizophrenia.

Methods: For 20 matched pairs of subjects with schizophrenia and unaffected comparison subjects, tissue sections from the primary visual cortex, association visual cortex, posterior parietal cortex, and DLPFC were immunolabeled for PV, the 65- and 67-kDa isoforms of glutamic acid decarboxylase (GAD65 and GAD67) that synthesize GABA (gamma-aminobutyric acid), and the vesicular GABA transporter. The density of PVBC terminals and of protein levels per terminal was quantified in layer 3 of each cortical region using fluorescence confocal microscopy.

Results: In comparison subjects, all measures, except for GAD65 levels, exhibited a caudal-to-rostral decline across the vsWM network. In subjects with schizophrenia, the density of detectable PVBC terminals was significantly lower in all regions except the DLPFC, whereas PVBC terminal levels of PV, GAD67, and GAD65 proteins were lower in all regions. A composite measure of inhibitory strength was lower in subjects with schizophrenia, although the magnitude of the diagnosis effect was greater in the primary visual, association visual, and posterior parietal cortices than in the DLPFC.

Conclusions: In schizophrenia, alterations in PVBC terminals across the vsWM network suggest the presence of a shared substrate for cortical dysfunction during vsWM tasks. However, regional differences in the magnitude of the disease effect on an index of PVBC inhibitory strength suggest region-specific alterations in information processing during vsWM tasks.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243491PMC
July 2021

Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder.

Transl Psychiatry 2021 03 15;11(1):171. Epub 2021 Mar 15.

Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.

Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.
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http://dx.doi.org/10.1038/s41398-021-01290-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961029PMC
March 2021

Antiseptic mouthwash for gonorrhoea prevention (OMEGA): a randomised, double-blind, parallel-group, multicentre trial.

Lancet Infect Dis 2021 05 4;21(5):647-656. Epub 2021 Mar 4.

Melbourne Sexual Health Centre, Alfred Health, Melbourne, VIC, Australia; Central Clinical School, Monash University, Melbourne, VIC, Australia; China-Australia Joint Research Centre for Infectious Diseases, School of Public Health, Xi'an Jiaotong University, Xi'an, China.

Background: To address the increasing incidence of gonorrhoea and antimicrobial resistance, we compared the efficacy of Listerine and Biotène mouthwashes for preventing gonorrhoea among men who have sex with men (MSM).

Methods: The OMEGA trial was a multicentre, parallel-group, double-blind randomised controlled trial among MSM, done at three urban sexual health clinics and one general practice clinic in Australia. Men were eligible if they were diagnosed with oropharyngeal gonorrhoea by nucleic acid amplification test (NAAT) in the previous 30 days or were aged 16-24 years. They were randomly assigned to receive Listerine (intervention) or Biotène (control) via a computer-generated sequence (1:1 ratio, block size of four). Participants, clinicians, data collectors, data analysts, and outcome adjudicators were masked to the interventions after assignment. Participants were instructed to rinse and gargle with 20 mL of mouthwash for 60 s at least once daily for 12 weeks. Oropharyngeal swabs were collected by research nurses every 6 weeks, and participants provided saliva samples every 3 weeks, to be tested for Neisseria gonorrhoeae with NAAT and quantitative PCR. The primary outcome was proportion of MSM diagnosed with oropharyngeal N gonorrhoeae infection at any point over the 12-week period, defined as a positive result for either oropharyngeal swabs or saliva samples by NAAT, and the cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit. A modified intention-to-treat analysis for the primary outcome was done that included men who provided at least one follow-up specimen over the 12-week study period. The trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12616000247471).

Findings: Between March 30, 2016, and Oct 26, 2018, 786 MSM were screened and 256 were excluded. 264 MSM were randomly assigned to the Biotène group and 266 to the Listerine group. The analysis population included 227 (86%) men in the Biotène group and 219 (82%) in the Listerine group. Oropharyngeal gonorrhoea was detected in ten (4%) of 227 of MSM in the Biotène group and in 15 (7%) of 219 in the Listerine group (adjusted risk difference 2·5%, 95% CI -1·8 to 6·8). The cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit did not differ between the two mouthwash groups (adjusted risk difference 3·1%, 95% CI -1·4 to 7·7).

Interpretation: Listerine did not reduce the incidence of oropharyngeal gonorrhoea compared with Biotène. However, previous research suggests that mouthwash might reduce the infectivity of oropharyngeal gonorrhoea; therefore, further studies of mouthwash examining its inhibitory effect on N gonorrhoeae are warranted to determine if it has a potential role for the prevention of transmission.

Funding: Australian National Health and Medical Research Council.
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http://dx.doi.org/10.1016/S1473-3099(20)30704-0DOI Listing
May 2021

Insulating Composites Made from Sulfur, Canola Oil, and Wool*.

ChemSusChem 2021 Jun 10;14(11):2352-2359. Epub 2021 Mar 10.

Institute for Nanoscale Science and Technology, College of Science and Engineering, Flinders University, Bedford Park, South Australia, 5042, Australia.

An insulating composite was made from the sustainable building blocks wool, sulfur, and canola oil. In the first stage of the synthesis, inverse vulcanization was used to make a polysulfide polymer from the canola oil triglyceride and sulfur. This polymerization benefits from complete atom economy. In the second stage, the powdered polymer was mixed with wool, coating the fibers through electrostatic attraction. The polymer and wool mixture were then compressed with mild heating to provoke S-S metathesis in the polymer, which locks the wool in the polymer matrix. The wool fibers imparted tensile strength, insulating properties, and reduced the flammability of the composite. All building blocks are sustainable or derived from waste and the composite is a promising lead on next-generation insulation for energy conservation.
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http://dx.doi.org/10.1002/cssc.202100187DOI Listing
June 2021

Is gentamicin a viable therapeutic option for treating resistant Neisseria gonorrhoeae in New South Wales?

Commun Dis Intell (2018) 2021 Feb 26;45. Epub 2021 Feb 26.

Neisseria Reference Laboratory and World Health Organization Collaborating Centre for STI and AMR, Sydney; New South Wales Health Pathology, Microbiology, The Prince of Wales Hospital, Randwick, NSW 2031, Australia.

Abstract: The key issues with Neisseria gonorrhoeae infections, in Australia and elsewhere, are coincident increases in disease rates and in antimicrobial resistance (AMR), although these factors have not been shown to be correlated. Despite advances in diagnosis, control of this disease remains elusive, and incidence in Australia continues to increase. Of the Australian jurisdictions, New South Wales (NSW) has the highest N. gonorrhoeae notifications, and over the five-year period 2015-2019, notifications in NSW have increased above the national average (by 116% versus 85%, respectively). Gonococcal disease control is reliant on effective antibiotic regimens. However, escalating AMR in N. gonorrhoeae is a global health priority, as the collateral injury of untreated infections has substantive impacts on sexual and newborn health. Currently, our first-line therapy for gonorrhoea is also our last line, with no ideal alternative identified. Despite some limitations, gentamicin is licensed and readily available in Australia, and is proposed for treatment of resistant N. gonorrhoeae in national guidelines; however, supportive published microbiological data are lacking. Analysis of gonococcal resistance patterns within Australia for the period 1991-2019, including 35,000 clinical isolates from NSW, illustrates the establishment and spread of population-level resistance to all contemporaneous therapies. An analysis of gentamicin susceptibility on 2,768 N. gonorrhoeae clinical isolates from NSW, for the period 2015-2020, demonstrates that the median minimum inhibitory concentration (MIC) for gentamicin in NSW has remained low, at 4.0 mg/L, and resistance was not detected in any isolate. There has been no demonstration of MIC drift over time (p = 0.91, Kruskal-Wallis test), nor differences in MIC distributions according to patients' sex or site of specimen collection. This is the first large-scale evaluation of gentamicin susceptibility in N. gonorrhoeae in Australia. No gentamicin resistance was detected in clinical isolates, 2015-2020, hence this is likely to be an available treatment option for resistant gonococcal infections in NSW.
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http://dx.doi.org/10.33321/cdi.2021.45.12DOI Listing
February 2021

Potential and demonstrated impacts of the COVID-19 pandemic on sexually transmissible infections: Republication.

Curr Opin HIV AIDS 2021 03;16(2):115-120

Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Westmead.

Purpose Of Review: This review considers the potential and demonstrated impacts of SARS-CoV-2 on the sexually transmissible infection (STI)/HIV transmission.

Recent Findings: COVID-19 increases the vulnerability of those at highest risk of acquiring STI/HIV. Altered health-seeking behaviour, reductions in STI/HIV clinic capacity, service disruptions and redeployment of human resources to assist COVID-19 control efforts have impacted on STI/HIV control programmes. Reports of reduced STI incidence are emerging, but it is hard to determine whether this is real or due to decreased testing during COVID-19 lockdown periods. Fear of COVID-19 and implemented control measures have altered STI/HIV transmission dynamics. Sexual health services adapted to the pandemic by reducing face-to-face patient encounters in favour of telehealth and mail-based initiatives as well as more stringent triage practice. Many sexual health and HIV treatment services now operate at reduced capacity and experience ongoing service disruptions, which necessarily translates into poorer outcomes for patients and their communities.

Summary: In the short-term, COVID-19 related sexual behaviour change is driving STI/HIV transmission downwards. However, the impacts of the global COVID-19 response on sexual health-seeking behaviour and STI/HIV services threaten to drive STI/HIV transmission upwards. Ultimately, the expected rebound in STI/HIV incidence will require an appropriate and timely public health response.

Video Abstract: http://links.lww.com/COID/A31.
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http://dx.doi.org/10.1097/COH.0000000000000672DOI Listing
March 2021

Similarities in Cortical Transcriptome Alterations Between Schizophrenia and Bipolar Disorder Are Related to the Presence of Psychosis.

Schizophr Bull 2021 Aug;47(5):1442-1451

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Schizophrenia (SCZ) and bipolar disorder (BP) share a number of features. For example, multiple transcriptome analyses have reported molecular alterations common to both diagnoses, findings supported by the considerable overlap in the genetic risk for each disorder. These molecular similarities may underlie certain clinical features that are frequently present in both disorders. Indeed, many individuals with BP exhibit psychosis, and some individuals with SCZ have prominent mood symptoms that warrant the diagnosis of schizoaffective disorder (SA). To explore the potential relationships between molecular alterations and certain clinical features among subjects with these diagnoses, we analyzed RNA sequencing data from the dorsolateral prefrontal and anterior cingulate cortices, provided by the CommonMind Consortium, in subjects from the University of Pittsburgh Brain Tissue Donation Program. Relative to unaffected comparison subjects, in each brain region, robust differential gene expression was present only in SCZ, including a lower expression of genes involved in mitochondrial function and an elevated expression of immune-related genes. However, correlation analyses showed that BP subjects had similar, although less pronounced, gene expression alterations. Comparisons across subgroups of subjects revealed that the similarities between SCZ and BP subjects were principally due to the BP subjects with psychosis. Moreover, the gene expression profile in BP subjects with psychosis was more similar to "pure" SCZ and SA subjects than to BP subjects without psychosis. Together, these analyses suggest that similarities in gene expression between SCZ and BP are at least partially related to the presence of psychosis in some BP subjects.
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http://dx.doi.org/10.1093/schbul/sbaa195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379536PMC
August 2021

Involvement of the nuclear factor-κB transcriptional complex in prefrontal cortex immune activation in bipolar disorder.

Transl Psychiatry 2021 01 12;11(1):40. Epub 2021 Jan 12.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.
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http://dx.doi.org/10.1038/s41398-020-01092-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804457PMC
January 2021

Involvement of the nuclear factor-κB transcriptional complex in prefrontal cortex immune activation in bipolar disorder.

Transl Psychiatry 2021 01 12;11(1):40. Epub 2021 Jan 12.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Bipolar disorder and schizophrenia have multiple clinical and genetic features in common, including shared risk associated with overlapping susceptibility loci in immune-related genes. Higher activity of the nuclear factor-κB (NF-κB) transcription factor complex, which regulates the transcription of multiple immune markers, has been reported to contribute to immune activation in the prefrontal cortex in schizophrenia. These findings suggest the hypothesis that elevated NF-κB activity is present in the prefrontal cortex in bipolar disorder in a manner similar to that seen in schizophrenia. Therefore, we quantified levels of NF-κB-related mRNAs in the prefrontal cortex of 35 matched pairs of bipolar disorder and unaffected comparison subjects using quantitative PCR. We found that transcript levels were higher in the prefrontal cortex of bipolar disorder subjects for several NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs, and were lower for an NF-κB inhibitor. Transcript levels for NF-κB family members, NF-κB activation receptors, and NF-κB-regulated mRNAs levels were also highly correlated with each other. This pattern of elevated transcript levels for NF-κB-related markers in bipolar disorder is similar to that previously reported in schizophrenia, suggesting that cortical immune activation is a shared pathophysiological feature between the two disorders.
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http://dx.doi.org/10.1038/s41398-020-01092-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804457PMC
January 2021

Diurnal rhythms across the human dorsal and ventral striatum.

Proc Natl Acad Sci U S A 2021 01;118(2)

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219;

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology.
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http://dx.doi.org/10.1073/pnas.2016150118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812799PMC
January 2021

Distinct Laminar and Cellular Patterns of GABA Neuron Transcript Expression in Monkey Prefrontal and Visual Cortices.

Cereb Cortex 2021 Mar;31(5):2345-2363

Translational Neuroscience Program, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

The functional output of a cortical region is shaped by its complement of GABA neuron subtypes. GABA-related transcript expression differs substantially between the primate dorsolateral prefrontal cortex (DLPFC) and primary visual (V1) cortices in gray matter homogenates, but the laminar and cellular bases for these differences are unknown. Quantification of levels of GABA-related transcripts in layers 2 and 4 of monkey DLPFC and V1 revealed three distinct expression patterns: 1) transcripts with higher levels in DLPFC and layer 2 [e.g., somatostatin (SST)]; 2) transcripts with higher levels in V1 and layer 4 [e.g., parvalbumin (PV)], and 3) transcripts with similar levels across layers and regions [e.g., glutamic acid decarboxylase (GAD67)]. At the cellular level, these patterns reflected transcript- and cell type-specific differences: the SST pattern primarily reflected differences in the relative proportions of SST mRNA-positive neurons, the PV pattern primarily reflected differences in PV mRNA expression per neuron, and the GAD67 pattern reflected opposed patterns in the relative proportions of GAD67 mRNA-positive neurons and in GAD67 mRNA expression per neuron. These findings suggest that differences in the complement of GABA neuron subtypes and in gene expression levels per neuron contribute to the specialization of inhibitory neurotransmission across cortical circuits.
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http://dx.doi.org/10.1093/cercor/bhaa341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023857PMC
March 2021

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits.

Front Neuroanat 2020 20;14:578483. Epub 2020 Nov 20.

Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, United States.

cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.
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http://dx.doi.org/10.3389/fnana.2020.578483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714912PMC
November 2020

Potential and demonstrated impacts of the COVID-19 pandemic on sexually transmissible infections.

Curr Opin Infect Dis 2021 02;34(1):56-61

Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Westmead.

Purpose Of Review: This review considers the potential and demonstrated impacts of SARS-CoV-2 on the sexually transmissible infection (STI)/HIV transmission.

Recent Findings: COVID-19 increases the vulnerability of those at highest risk of acquiring STI/HIV. Altered health-seeking behaviour, reductions in STI/HIV clinic capacity, service disruptions and redeployment of human resources to assist COVID-19 control efforts have impacted on STI/HIV control programmes. Reports of reduced STI incidence are emerging, but it is hard to determine whether this is real or due to decreased testing during COVID-19 lockdown periods. Fear of COVID-19 and implemented control measures have altered STI/HIV transmission dynamics. Sexual health services adapted to the pandemic by reducing face-to-face patient encounters in favour of telehealth and mail-based initiatives as well as more stringent triage practice. Many sexual health and HIV treatment services now operate at reduced capacity and experience ongoing service disruptions, which necessarily translates into poorer outcomes for patients and their communities.

Summary: In the short-term, COVID-19 related sexual behaviour change is driving STI/HIV transmission downwards. However, the impacts of the global COVID-19 response on sexual health-seeking behaviour and STI/HIV services threaten to drive STI/HIV transmission upwards. Ultimately, the expected rebound in STI/HIV incidence will require an appropriate and timely public health response.

Video Abstract: http://links.lww.com/COID/A31.
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http://dx.doi.org/10.1097/QCO.0000000000000699DOI Listing
February 2021

Postnatal Development of Glutamate and GABA Transcript Expression in Monkey Visual, Parietal, and Prefrontal Cortices.

Cereb Cortex 2021 03;31(4):2026-2037

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Visuospatial working memory (vsWM) requires information transfer among multiple cortical regions, from primary visual (V1) to prefrontal (PFC) cortices. This information is conveyed via layer 3 glutamatergic neurons whose activity is regulated by gamma-aminobutyric acid (GABA)ergic interneurons. In layer 3 of adult human neocortex, molecular markers of glutamate neurotransmission were lowest in V1 and highest in PFC, whereas GABA markers had the reverse pattern. Here, we asked if these opposite V1-visual association cortex (V2)-posterior parietal cortex (PPC)-PFC gradients across the vsWM network are present in layer 3 of monkey neocortex, when they are established during postnatal development, and if they are specific to this layer. We quantified transcript levels of glutamate and GABA markers in layers 3 and 6 of four vsWM cortical regions in a postnatal developmental series of 30 macaque monkeys. In adult monkeys, glutamate transcript levels in layer 3 increased across V1-V2-PPC-PFC regions, whereas GABA transcripts showed the opposite V1-V2-PPC-PFC gradient. Glutamate transcripts established adult-like expression patterns earlier during postnatal development than GABA transcripts. These V1-V2-PPC-PFC gradients and developmental patterns were less evident in layer 6. These findings demonstrate that expression of glutamate and GABA transcripts differs across cortical regions and layers during postnatal development, revealing potential molecular substrates for vsWM functional maturation.
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http://dx.doi.org/10.1093/cercor/bhaa342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248841PMC
March 2021

Laminar Differences in the Targeting of Dendritic Spines by Cortical Pyramidal Neurons and Interneurons in Human Dorsolateral Prefrontal Cortex.

Neuroscience 2021 01 16;452:181-191. Epub 2020 Nov 16.

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Biomedical Science Tower W1654, 3811 O'Hara Street, Pittsburgh, PA 15213, USA; Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, USA. Electronic address:

Activation of specific neural circuits in different layers of the primate dorsolateral prefrontal cortex (DLPFC) is essential for working memory, a core cognitive function. Recurrent excitation between pyramidal neurons in middle and deep layers of the DLPFC contributes to the laminar-specific activity associated with different working memory subprocesses. Excitation between cortical pyramidal neurons is mediated by glutamatergic synapses on dendritic spines, but whether the relative abundance of spines receiving cortical inputs differs between middle and deep cortical layers in human DLPFC is unknown. Additionally, GABAergic inputs to spines sculpt pyramidal neuron activity. Whether dendritic spines that receive a glutamatergic input from a cortical pyramidal neuron are targeted by GABAergic interneurons in the human DLPFC is unknown. Using triple-label fluorescence confocal microscopy, we found that 1) the density of spines receiving an input from a cortical pyramidal neuron is greater in the middle than in the deep laminar zone, 2) dendritic spines dually innervated by a cortical pyramidal neuron and an interneuron are present in the human DLPFC, and 3) the density of spines dually innervated by a cortical pyramidal neuron and an interneuron is also greater in the middle than in the deep laminar zone. Ultrastructural analyses support the presence of spines that receive a cortical pyramidal neuron synapse and an interneuron synapse in human and monkey DLPFC. These data support the notion that the DLPFC middle laminar zone is particularly endowed with a microcircuit structure that supports the gating, integrating and fine-tuning of synaptic information in recurrent excitatory microcircuits.
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http://dx.doi.org/10.1016/j.neuroscience.2020.10.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770119PMC
January 2021

Diagnosis- and Cell Type-Specific Mitochondrial Functional Pathway Signatures in Schizophrenia and Bipolar Disorder.

Am J Psychiatry 2020 12 29;177(12):1140-1150. Epub 2020 Oct 29.

Department of Psychiatry, University of Pittsburgh (all authors).

Objective: The shared risk factors and clinical features in schizophrenia and bipolar disorder may be linked via mitochondrial dysfunction. However, the severity of mitochondrial dysfunction, and/or the specific mitochondrial functional pathways affected, may differ between diagnoses, especially at the level of individual cell types.

Methods: Transcriptomic profiling data for a gene set indexing mitochondrial functional pathways were obtained for dorsolateral prefrontal cortex (DLPFC) gray matter and layer 3 and layer 5 pyramidal neurons of subjects with schizophrenia or bipolar disorder. Analyses were conducted using a dual strategy: identification of differentially expressed genes (DEGs) and their functional pathway enrichment, and application of weighted gene coexpression network analysis. These analyses were repeated in monkeys chronically exposed to antipsychotic drugs to determine their effect on mitochondrial-related gene expression.

Results: In DLPFC gray matter, 41% of mitochondrial-related genes were differentially expressed in the schizophrenia group, whereas 8% were differentially expressed in the bipolar group. In the schizophrenia group, 83% of DEGs showed lower expression, and these were significantly enriched for three functional pathways, each indexing energy production. DEGs in the bipolar disorder group were not enriched for functional pathways. This disease-related pattern of findings was also identified in pyramidal neurons. None of the gene expression alterations disrupted coexpression modules, and DEGs were not attributable to antipsychotic medications.

Conclusions: Schizophrenia and bipolar disorder do not appear to share similar mitochondrial alterations in the DLPFC. The selective and coordinated down-regulation of energy production genes in schizophrenia is consistent with the effects of chronic reductions in pyramidal neuron firing, and enhancement of this activity may serve as a therapeutic target.
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http://dx.doi.org/10.1176/appi.ajp.2020.19111210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195258PMC
December 2020
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