Publications by authors named "Albert Lee"

334 Publications

Impact of COVID-19 on Life of Students: Case Study in Hong Kong.

Int J Environ Res Public Health 2021 10 6;18(19). Epub 2021 Oct 6.

Centre for Health Education and Health Promotion, The Chinese University of Hong Kong, 4/Floor, Lek Yuen Health Centre, Shatin, Hong Kong, China.

COVID-19 has an impact on the day-to-day life of students, with school closure and detrimental effects on health and well-being that cannot be underestimated. A study collected data reflecting the health and well-being of secondary school students entering a programme entitled "Healthy Life Planning: Assist Students to Acquire and Practice Health Knowledge and Skills" (ASAP study) in September and October 2019 before the outbreak of COVID-19. Follow-up data were collected in June and July 2020, over half a year since the spread of COVID-19, which facilitated analyses of its impact on the health behaviours and well-being of young people. Comparative analyses between baseline and the follow-up period were conducted on weight status, sleep pattern and quality, pattern of sedentary lifestyle, pattern of physical activity, attitudes and perceived barriers for exercise, and hand hygiene. Attitudes toward precautionary measures and influenza vaccination, self-reported changes in hygiene practices, exercise habits and eating habits were analysed. Although hygiene habits and risk perceptions among young people have improved in many aspects, the level of physical activity has declined as well as the beliefs and attitudes on increasing time on electronic media and change in sleep hygiene. Attitudes and beliefs towards influenza vaccination have declined, which would reflect the slow increase in the uptake rate of COVID-19 vaccination. Health education should equip students with the knowledge and skills to cultivate beliefs and attitudes to face health challenges.
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http://dx.doi.org/10.3390/ijerph181910483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508172PMC
October 2021

Age Differences in Leadership Positions Across Cultures.

Front Psychol 2021 17;12:703831. Epub 2021 Sep 17.

Department of Psychology, Queen's University, Kingston, ON, Canada.

In most countries around the world, the population is rapidly aging. A by-product of these demographic shifts is that older adults will likely occupy more positions of power and influence in our societies than ever before. Further, cultural differences might shape how these transitions unfold around the globe. Across two studies, we investigated whether business and political leaders differed in age across various cultures. Study 1 ( = 1,034) showed that business leaders were significantly older in Eastern (e.g., China, India, and Japan) cultures than Western (e.g., United States, Sweden, and United Kingdom) cultures, even while controlling for population structure (e.g., percentage of elderly in the society), gross domestic product (GDP), and wealth distribution across the population (GINI). Study 2 ( = 1,268) conceptually replicated these findings by showing that political leaders were once again older in Eastern vs. Western cultures. Furthermore, cultural tightness mediated the relationship between culture and older leadership. These findings highlight how cultural differences impact not only our preferences, but also important outcomes in consequential domains such as business and politics. Potential explanations for why cultural tightness may be related to differences in leader age across cultures are discussed. To build on these findings, future research should assess the potential causal mechanisms underlying the cultural effect on leader age, and explore the various practical implications of this effect.
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http://dx.doi.org/10.3389/fpsyg.2021.703831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484309PMC
September 2021

A cross-cultural study of the effect of parental bonding on the perception and response to criticism in Singapore, Italy and USA.

PLoS One 2021 30;16(9):e0257888. Epub 2021 Sep 30.

Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore.

Parents play a primary and crucial role in emotional socialisation processes in children where individuals learn the expression, understanding and regulation of emotions. Parenting practices and dimensions of the parent-child relationship have been associated with social and emotional processes in children. As criticism involves negative emotional reactions and emotion regulation, the parent-child relationship is likely to influence an individual's perception and response to criticism. Hence, the present study investigated the relationship of parental bonding and the perception and response to criticism in three different countries-Singapore, Italy and USA. Adult participants (n = 444) completed the Parental Bonding Inventory (PBI) and measures of criticism. Parental care, overprotection and country were found to be significant predictors of a tendency to perceive criticism as destructive. Higher levels of parental care predicted a lower tendency to perceive criticism as destructive while higher levels of parental overprotection predicted a higher tendency to perceive criticism as destructive. US American participants were found to have a significantly higher tendency to perceive criticism as destructive compared to Italian and Singaporean participants. The findings align with past research on the role of the parent-child relationship in the socio-emotional development of children as well as providing insight into a specific aspect in social interaction; perception and response to criticism, being affected. Future studies can look to investigate this relationship further in different countries in light of cultural variation in parenting styles and emotion experience, expression and regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257888PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483350PMC
September 2021

Expanding the family of extracellular chaperones: Identification of human plasma proteins with chaperone activity.

Protein Sci 2021 Nov 4;30(11):2272-2286. Epub 2021 Oct 4.

Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, Australia.

Proteostasis, the balance of protein synthesis, folding and degradation, is essential to maintain cellular function and viability, and the many known intracellular chaperones are recognized as playing key roles in sustaining life. In contrast, the identity of constitutively secreted extracellular chaperones (ECs) and their physiological roles in extracellular proteostasis is less completely understood. We designed and implemented a novel strategy, based on the well-known propensity of chaperones to bind to regions of hydrophobicity exposed on misfolding proteins, to discover new ECs present in human blood. We used a destabilized protein that misfolds at 37°C as "bait" to bind to potential ECs in human serum and captured the complexes formed on magnetic beads. Proteins eluted from the beads were identified by mass spectrometry and a group of seven abundant serum proteins was selected for in vitro analysis of chaperone activity. Five of these proteins were shown to specifically inhibit protein aggregation. Vitronectin and plasminogen activator-3 inhibited both the in vitro aggregation of the Alzheimer's β peptide (Aβ ) to form fibrillar amyloid, and the aggregation of citrate synthase (CS) to form unstructured (amorphous) aggregates. In contrast, prothrombin, C1r, and C1s inhibited the aggregation of Aβ but did not inhibit CS aggregation. This study thus identified five novel and abundant putative ECs which may play important roles in the maintenance of extracellular proteostasis, and which apparently have differing abilities to inhibit the amorphous and amyloid-forming protein aggregation pathways.
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http://dx.doi.org/10.1002/pro.4189DOI Listing
November 2021

Correction: SERS-based nanostrategy for rapid anemia diagnosis.

Nanoscale 2021 Oct 1;13(37):15981. Epub 2021 Oct 1.

Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences Henan University Kaifeng, Henan 475004, China.

Correction for 'SERS-based nanostrategy for rapid anemia diagnosis' by Pir Muhammad , , 2020, , 1948-1957, DOI: 10.1039/C9NR09152A.
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http://dx.doi.org/10.1039/d1nr90196fDOI Listing
October 2021

Development of an In Vitro Hemorrhagic Hydrocephalus Model for Functional Evaluation of Magnetic Microactuators Against Shunt Obstructions.

World Neurosurg 2021 Aug 18. Epub 2021 Aug 18.

Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.

Objective: Occlusion of ventriculoperitoneal shunts placed after intraventricular hemorrhage occurs frequently. The objective of this study was to develop a hemorrhagic hydrocephalus model to assess the ability of an oscillating microactuator within the ventricular catheter (VC) to prevent shunt obstruction.

Methods: An in vitro hydrocephalus model with extreme risk of shunt obstruction was created. Phosphate-buffered saline, blood, and thrombin were driven through ventriculoperitoneal shunts for 8 hours. Five VCs were fitted with a microactuator and compared with 5 control VCs. The microactuator was actuated by an external magnetic field for 30 minutes. Pressure within the imitation lateral ventricle was measured.

Results: In the 5 control shunts, 6 obstructions developed (3 VC, 3 valve-distal catheter) compared with 1 obstruction (VC) in the 5 microactuator shunts. In the control and microactuator groups, the median volume exiting the shunts in 8 hours was 30 mL versus 256 mL. Median time to reach an intraventricular pressure of 40 mm Hg (13.8 minutes vs. >8 hours), median total time >40 mm Hg (6.2 hours vs. 0.0 hours), and median maximum pressure (192 mm Hg vs. 36 mm Hg) were significantly improved in the microactuator group (P < 0.01).

Conclusions: In addition to protecting the VC, the microactuator appeared to prevent hematoma obstructing the valve or distal catheter, resulting in a much longer duration of low intraventricular pressures. A microactuator activated by placing the patient's head in an external magnetic field could reduce shunt obstructions in hemorrhagic hydrocephalus.
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http://dx.doi.org/10.1016/j.wneu.2021.08.048DOI Listing
August 2021

Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo.

Mol Brain 2021 08 20;14(1):128. Epub 2021 Aug 20.

Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Level 1, 2 Technology Place, Sydney, NSW 2109, Australia.

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.
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http://dx.doi.org/10.1186/s13041-021-00839-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377983PMC
August 2021

Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis.

Eur J Neurosci 2021 09 26;54(6):6237-6255. Epub 2021 Aug 26.

Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, 'rNLS8', mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.
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http://dx.doi.org/10.1111/ejn.15422DOI Listing
September 2021

Impact of COVID-19 pandemic on the presentation, management and outcome of testicular torsion in the pediatric population - an analysis of a large pediatric center.

Can J Urol 2021 08;28(4):10750-10755

Division of Pediatric Urology, Children's National Hospital, Washington, DC, USA.

INTRODUCTION To examine the impact of COVID-19 pandemic on the presentation, management and outcome of testicular torsion at our institution.

Materials And Methods: A retrospective review of a prospectively maintained testicular torsion database was performed. Patients ≤ 18 years of age evaluated in our emergency room between 3/11/2020 to 10/1/2020 (during-COVID-19) and the same period in 2018 and 2019 (pre-COVID-19) with US diagnosed and OR confirmed testicular torsion were included. Basic demographics, timing of presentation, referral rate, time to OR and orchiectomy rate were extracted and compared. P < 0.05 was considered statistically significant.

Results: A total of 82 torsions were included in the study; 55 pre-COVID-19 and 27 during-COVID-19. The incidence of testicular torsion remained the same; 3.93 cases/month pre-COVID-19 versus 3.86 cases/month during-COVID-19 (p = 0.791). However, there were significantly fewer delayed (> 24 hours) presentations (11.1% versus 45.5% , p = 0.003), shorter time from onset of symptoms to presentation (median 15.5 hours versus 8 hours, p = 0.001), and a lower but not statistically significant overall orchiectomy rate (33.3% versus 50.9% p = 0.1608) during-COVID-19. Among those presenting acutely with torsion (< 24 hours from onset), no statistical differences were found in the median time from US diagnosis to OR, from ED to OR, referral rate, or orchiectomy rate between the two groups. Lastly, SARS-CoV2 testing did not delay median time from ED to OR.

Conclusions: There was a notably less delayed presentation of testicular torsion and shorter ischemia time on presentation during-COVID, however, no significant change of time to OR or orchiectomy rate in those with acute testicular torsion were observed.
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August 2021

Cultural Differences in People's Psychological Response to COVID-19.

Front Psychol 2021 12;12:636062. Epub 2021 Jul 12.

Faculty of Education, Central China Normal University, Wuhan, China.

The present research studied Chinese and Euro-Canadian students during the COVID-19 pandemic, focusing on their affect, optimism, well-being, and meaning in life. The results revealed both differences and similarities across cultures. As predicted, Chinese participants reported more positive affect and less negative affect, higher optimism, higher state psychological well-being, and higher meaning presence, compared to Euro-Canadian participants. The findings were replicated after a week's delay. Analyses on longitudinal data showed that state optimism, state well-being, and meaning presence influenced one another over time. These variables also mediated the cultural differences in one another. These results are consistent with cultural work on naïve dialecticism and non-linear lay theory of change. Results also demonstrate underlying relationships among the constructs that are common to both cultural groups. Broadly, the present research highlights the impact of culture on people's response to challenging life situations and the mechanisms underlying these cultural differences.
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http://dx.doi.org/10.3389/fpsyg.2021.636062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312224PMC
July 2021

Splicing factor proline and glutamine rich intron retention, reduced expression and aggregate formation are pathological features of amyotrophic lateral sclerosis.

Neuropathol Appl Neurobiol 2021 Jul 20. Epub 2021 Jul 20.

Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.

Aim: Splicing factor proline and glutamine rich (SFPQ) is an RNA-DNA binding protein that is dysregulated in Alzheimer's disease and frontotemporal dementia. Dysregulation of SFPQ, specifically increased intron retention and nuclear depletion, has been linked to several genetic subtypes of amyotrophic lateral sclerosis (ALS), suggesting that SFPQ pathology may be a common feature of this heterogeneous disease. Our study aimed to investigate this hypothesis by providing the first comprehensive assessment of SFPQ pathology in large ALS case-control cohorts.

Methods: We examined SFPQ at the RNA, protein and DNA levels. SFPQ RNA expression and intron retention were examined using RNA-sequencing and quantitative PCR. SFPQ protein expression was assessed by immunoblotting and immunofluorescent staining. At the DNA level, SFPQ was examined for genetic variation novel to ALS patients.

Results: At the RNA level, retention of SFPQ intron nine was significantly increased in ALS patients' motor cortex. In addition, SFPQ RNA expression was significantly reduced in the central nervous system, but not blood, of patients. At the protein level, neither nuclear depletion nor reduced expression of SFPQ was found to be a consistent feature of spinal motor neurons. However, SFPQ-positive ubiquitinated protein aggregates were observed in patients' spinal motor neurons. At the DNA level, our genetic screen identified two novel and two rare SFPQ sequence variants not previously reported in the literature.

Conclusions: Our findings confirm dysregulation of SFPQ as a pathological feature of the central nervous system of ALS patients and indicate that investigation of the functional consequences of this pathology will provide insight into ALS biology.
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http://dx.doi.org/10.1111/nan.12749DOI Listing
July 2021

Engaging Diverse Community Groups to Promote Population Health through Healthy City Approach: Analysis of Successful Cases in Western Pacific Region.

Int J Environ Res Public Health 2021 06 19;18(12). Epub 2021 Jun 19.

Secretariat, Alliance for Healthy Cities, Tokyo 101-0062, Japan.

Background: A substantial global burden of health can be attributed to unhealthy lifestyles and an unhealthy living environment. The concept of a Healthy City is continually creating and improving physical and social environments to enable healthy living. The aim of this paper is to investigate how the Healthy City concept would tackle the complexity of health by addressing the socio-economic and political determinants of health in the Western Pacific Region.

Methods: The SPIRIT model adopted by the Alliance for Healthy Cities can provide a framework for an integrated and holistic approach to enable policy, environment, social matters, behaviours, and bio-medical interventions to take their rightful place side by side. The performance of cities awarded by the AFHC was analysed under each domain of the SPIRIT model to show the efforts striving to acquire the qualities of a healthy city.

Findings: Two cities have incorporated the Healthy City concept in most of their policies outside the health sector, with a high level of commitment from city leaders and citizens, so the Health City activities were recognised as part of the means to advance the cityies' general planning. One city has made use of its strong network of key stakeholders from different sectors and disciplines to establish a "Medical-Social-Community' model. All three cities have collected health information to reflect health status, determinants of health and issues reflecting health promotion to enable the creation of a city health profile and show positive changes in health. The cities have engaged key stakeholders to launch a variety of health-promoting programmes according to the needs of the population.

Conclusion: The AFHC can play an important role in linking the cities with strong action in Healthy City activities to support other cities in Healthy City development.
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http://dx.doi.org/10.3390/ijerph18126617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296388PMC
June 2021

In Reply: Prepontine Shunting for Pseudotumor Cerebri in Previously Failed Shunt Patients: A 5-Year Analysis.

Neurosurgery 2021 07;89(2):E142

Department of Neurological Surgery Indiana University School of Medicine Indianapolis, Indiana, USA.

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http://dx.doi.org/10.1093/neuros/nyab171DOI Listing
July 2021

Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.

Front Mol Neurosci 2021 27;14:627740. Epub 2021 Apr 27.

Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia.

The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g., SOD1), regulation of RNA homeostasis (e.g., TDP-43 and FUS), and protein degradation through the ubiquitin-proteasome system (e.g., ubiquilin-2 and cyclin F) and autophagy (TBK1 and sequestosome-1/p62). It is likely that the various initial triggers of disease (either genetic, environmental and/or gene-environment interaction) must converge upon a common set of molecular pathways that underlie ALS pathogenesis. Given the complexity, it is not surprising that a catalog of molecular pathways and proteostasis dysfunctions have been linked to ALS. One of the challenges in ALS research is determining, at the early stage of discovery, whether a new gene mutation is indeed disease-specific, and if it is linked to signaling pathways that trigger neuronal cell death. We have established a proof-of-concept proteogenomic workflow to assess new gene mutations, using CCNF (cyclin F) as an example, in cell culture models to screen whether potential gene candidates fit the criteria of activating apoptosis. This can provide an informative and time-efficient output that can be extended further for validation in a variety of and models and/or for mechanistic studies. As a proof-of-concept, we expressed cyclin F mutations (K97R, S195R, S509P, R574Q, S621G) in HEK293 cells for label-free quantitative proteomics that bioinformatically predicted activation of the neuronal cell death pathways, which was validated by immunoblot analysis. Proteomic analysis of induced pluripotent stem cells (iPSCs) derived from patient fibroblasts bearing the S621G mutation showed the same activation of these pathways providing compelling evidence for these candidate gene mutations to be strong candidates for further validation and mechanistic studies (such as E3 enzymatic activity assays, protein-protein and protein-substrate studies, and neuronal apoptosis and aberrant branching measurements in zebrafish). Our proteogenomics approach has great utility and provides a relatively high-throughput screening platform to explore candidate gene mutations for their propensity to cause neuronal cell death, which will guide a researcher for further experimental studies.
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http://dx.doi.org/10.3389/fnmol.2021.627740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111008PMC
April 2021

Engineered red blood cells as an off-the-shelf allogeneic anti-tumor therapeutic.

Nat Commun 2021 05 11;12(1):2637. Epub 2021 May 11.

Rubius Therapeutics, Inc., Cambridge, MA, USA.

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E7, 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.
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http://dx.doi.org/10.1038/s41467-021-22898-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113241PMC
May 2021

Striated muscle activator of Rho signalling (STARS) overexpression in the mdx mouse enhances muscle functional capacity and regulates the actin cytoskeleton and oxidative phosphorylation pathways.

Exp Physiol 2021 Jul 27;106(7):1597-1611. Epub 2021 May 27.

Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia.

New Findings: What is the central question of this study? Striated muscle activator of rho signalling (STARS) is an actin-binding protein that regulates transcriptional pathways controlling muscle function, growth and myogenesis, processes that are impaired in dystrophic muscle: what is the regulation of the STARS pathway in Duchenne muscular dystrophy (DMD)? What is the main finding and its importance? Members of the STARS signalling pathway are reduced in the quadriceps of patients with DMD and in mouse models of muscular dystrophy. Overexpression of STARS in the dystrophic deficient mdx mouse model increased maximal isometric specific force and upregulated members of the actin cytoskeleton and oxidative phosphorylation pathways. Regulating STARS may be a therapeutic approach to enhance muscle health.

Abstract: Duchenne muscular dystrophy (DMD) is characterised by impaired cytoskeleton organisation, cytosolic calcium handling, oxidative stress and mitochondrial dysfunction. This results in progressive muscle damage, wasting and weakness and premature death. The striated muscle activator of rho signalling (STARS) is an actin-binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway, a pathway regulating cytoskeletal structure and muscle function, growth and repair. We investigated the regulation of the STARS pathway in the quadriceps muscle from patients with DMD and in the tibialis anterior (TA) muscle from the dystrophin-deficient mdx and dko (utrophin and dystrophin null) mice. Protein levels of STARS, SRF and RHOA were reduced in patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in the mdx mice and Srf and Mrtfa mRNAs decreased in the dko mice. Overexpressing human STARS (hSTARS) in the TA muscles of mdx mice increased maximal isometric specific force by 13% (P < 0.05). This was not associated with changes in muscle mass, fibre cross-sectional area, fibre type, centralised nuclei or collagen deposition. Proteomics screening followed by pathway enrichment analysis identified that hSTARS overexpression resulted in 31 upregulated and 22 downregulated proteins belonging to the actin cytoskeleton and oxidative phosphorylation pathways. These pathways are impaired in dystrophic muscle and regulate processes that are vital for muscle function. Increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via synergistic regulation of cytoskeletal structure and energy production.
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http://dx.doi.org/10.1113/EP089253DOI Listing
July 2021

Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings.

Science 2021 04;372(6539)

UCL Queen Square Institute of Neurology, University College London, London, UK.

Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.
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http://dx.doi.org/10.1126/science.abf4588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244810PMC
April 2021

An Analysis of the Generalizability and Stability of the Halo Effect During the COVID-19 Pandemic Outbreak.

Front Psychol 2021 24;12:631871. Epub 2021 Mar 24.

Psychology Program, School of Social Sciences, Nanyang Technological University, Singapore, Singapore.

The influence on the global evaluation of a person based on the perception of a single trait is a phenomenon widely investigated in social psychology. Widely regarded as , this phenomenon has been studied for more than 100 years now, and findings such as the relationship between aesthetic perception and other personality traits-such as competence and trustworthiness-have since been uncovered. Trustworthiness plays an especially crucial role in individuals' social interactions. Despite the large body of literature published on the Halo effect, and especially on the relationship between aesthetic appearance and perceived trustworthiness, little is known about the overall generalizability of the effect, as almost all of the studies have been conducted on adult participants from Western countries. Moreover, little is known about the stability of the effect over time, in the event of major destabilization, such as the outbreak of a pandemic. In this work, the cross-cultural generalizability of the is investigated before and during the first few months of the COVID-19 pandemic. An analysis of the generalizability and stability over time of the is presented. Participants ( = 380, = 145 Asians, = 235 Caucasians) have been asked to rate the aesthetic appearance and perceived trustworthiness of a set of human faces of different ages, gender, and ethnicity. Result of our analysis demonstrated that the (Aesthetic × trustworthiness) is influenced by the age of presented faces, but not by their gender or ethnicity. Moreover, our results show that the strength of the effect can be affected by external events and that the volatility is higher for adults' than children's faces.
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http://dx.doi.org/10.3389/fpsyg.2021.631871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024691PMC
March 2021

ALS/FTD-causing mutation in cyclin F causes the dysregulation of SFPQ.

Hum Mol Genet 2021 May;30(11):971-984

Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Centre for Motor Neuron Disease Research, Macquarie University, 2 Technology Place, North Ryde, NSW 2109, Australia.

Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Hallmark features of these diseases include the build-up of insoluble protein aggregates as well as the mislocalization of proteins such as transactive response DNA binding protein 43 kDa (TDP-43). In recent years, the dysregulation of SFPQ (splicing factor proline and glutamine rich) has also emerged as a pathological hallmark of ALS/FTD. CCNF encodes for the protein cyclin F, a substrate recognition component of an E3 ubiquitin ligase. We have previously shown that ALS/FTD-linked mutations in CCNF cause disruptions to overall protein homeostasis that leads to a build-up of K48-linked ubiquitylated proteins as well as defects in autophagic machinery. To investigate further processes that may be affected by cyclin F, we used a protein-proximity ligation method, known as Biotin Identification (BioID), standard immunoprecipitations and mass spectrometry to identify novel interaction partners of cyclin F and infer further process that may be affected by the ALS/FTD-causing mutation. Results demonstrate that cyclin F closely associates with proteins involved with RNA metabolism as well as a number of RNA-binding proteins previously linked to ALS/FTD, including SFPQ. Notably, the overexpression of cyclin F(S621G) led to the aggregation and altered subcellular distribution of SFPQ in human embryonic kidney (HEK293) cells, while leading to altered degradation in primary neurons. Overall, our data links ALS/FTD-causing mutations in CCNF to converging pathological features of ALS/FTD and provides a link between defective protein degradation systems and the pathological accumulation of a protein involved in RNA processing and metabolism.
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http://dx.doi.org/10.1093/hmg/ddab073DOI Listing
May 2021

A thermodynamic core using voltage-controlled spin-orbit-torque magnetic tunnel junctions.

Nanotechnology 2021 Oct 11;32(50). Epub 2021 Oct 11.

Department of Electrical and Computer Engineering, UCLA, Los Angeles, CA, 90095, United States of America.

We present a magnetic implementation of a thermodynamic computing fabric. Magnetic devices within computing cores harness thermodynamics through its voltage-controlled thermal stability; while the evolution of network states is guided by the spin-orbit-torque effect. We theoretically derive the dynamics of the cores and show that the computing fabric can successfully compute ground states of a Boltzmann Machine. Subsequently, we demonstrate the physical realization of these devices based on a CoFeB-MgO magnetic tunnel junction structure. The results of this work pave the path towards the realization of highly efficient, high-performance thermodynamic computing hardware. Finally, this paper will also give a perspective of computing beyond thermodynamic computing.
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http://dx.doi.org/10.1088/1361-6528/abeb9bDOI Listing
October 2021

Bio-culturally grounded: why separation and connection may not be the same around the world.

Behav Brain Sci 2021 02 18;44:e14. Epub 2021 Feb 18.

School of Social Sciences, Nanyang Technological University, Singapore639818,

Central to the account of grounded procedures is the premise that mental experiences are grounded in physical actions. We complement this account by incorporating frameworks in cultural psychology and developmental neuroscience, with new predictions. Through the examples of vicarious experiences and demerit transfer, we discuss why, and how, separation and connection may operate somewhat differently across cultures.
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http://dx.doi.org/10.1017/S0140525X2000045XDOI Listing
February 2021

Culture, assumptions about the world, and interpretations of children's disabilities.

Res Dev Disabil 2021 Apr 29;111:103877. Epub 2021 Jan 29.

Program of Psychology, School of Social Sciences, Nanyang Technological University, Singapore. Electronic address:

Sim et al. (2021) examined the interplay between parental caretakers and children with health disabilities in East Asian cultures. Their analyses suggested that the way East Asian mothers responded to their disabled children may have to do with the culture in which they were embedded. Complementing their work, we aim to integrate their findings with the cultural psychology literature, focusing on styles of thought and supernatural beliefs. Doing so allows us to forge theoretical links between Sim et al. (2021) and frameworks that delineate the distinct ways of thought in East Asian cultures, recommend promising directions for future research, and motivate interdisciplinary readership.
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http://dx.doi.org/10.1016/j.ridd.2021.103877DOI Listing
April 2021

Pre-low raising in Cantonese and Thai: Effects of speech rate and vowel quantity.

J Acoust Soc Am 2021 01;149(1):179

University College London, London, United Kingdom.

Although pre-low raising (PLR) has been extensively studied as a type of contextual tonal variation, its underlying mechanism is barely understood. This paper explored the effects of phonetic vs phonological duration on PLR in Cantonese and Thai and examined how speech rate and vowel quantity interact with its realization in these languages, respectively. The results for Cantonese revealed that PLR always occurred before a large falling excursion (i.e., high-low); in other tonal contexts, it was observed more often in faster speech. In the Thai corpus, PLR also occurred before large falling excursions, and there was more PLR in short vowels. These results are discussed in terms of possible accounts of the underlying mechanism of PLR.
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http://dx.doi.org/10.1121/10.0002976DOI Listing
January 2021

In vivo Validation of Bimolecular Fluorescence Complementation (BiFC) to Investigate Aggregate Formation in Amyotrophic Lateral Sclerosis (ALS).

Mol Neurobiol 2021 May 7;58(5):2061-2074. Epub 2021 Jan 7.

Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, NSW, 2109, Australia.

Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that is characterized by the progressive loss of motor neurons within the spinal cord, brainstem, and motor cortex. Although ALS clinically manifests as a heterogeneous disease, with varying disease onset and survival, a unifying feature is the presence of ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, the precise mechanisms linking protein inclusions and aggregation to neuronal loss are currently poorly understood. Bimolecular fluorescence complementation (BiFC) takes advantage of the association of fluorophore fragments (non-fluorescent on their own) that are attached to an aggregation-prone protein of interest. Interaction of the proteins of interest allows for the fluorescent reporter protein to fold into its native state and emit a fluorescent signal. Here, we combined the power of BiFC with the advantages of the zebrafish system to validate, optimize, and visualize the formation of ALS-linked aggregates in real time in a vertebrate model. We further provide in vivo validation of the selectivity of this technique and demonstrate reduced spontaneous self-assembly of the non-fluorescent fragments in vivo by introducing a fluorophore mutation. Additionally, we report preliminary findings on the dynamic aggregation of the ALS-linked hallmark proteins Fus and TDP-43 in their corresponding nuclear and cytoplasmic compartments using BiFC. Overall, our data demonstrates the suitability of this BiFC approach to study and characterize ALS-linked aggregate formation in vivo. Importantly, the same principle can be applied in the context of other neurodegenerative diseases and has therefore critical implications to advance our understanding of pathologies that underlie aberrant protein aggregation.
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http://dx.doi.org/10.1007/s12035-020-02238-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018926PMC
May 2021

Canonical goal-selective representations are absent from prefrontal cortex in a spatial working memory task requiring behavioral flexibility.

Elife 2020 12 24;9. Epub 2020 Dec 24.

Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, United States.

The prefrontal cortex (PFC)'s functions are thought to include working memory, as its activity can reflect information that must be temporarily maintained to realize the current goal. We designed a flexible spatial working memory task that required rats to navigate - after distractions and a delay - to multiple possible goal locations from different starting points and via multiple routes. This made the current goal location the key variable to remember, instead of a particular direction or route to the goal. However, across a broad population of PFC neurons, we found no evidence of current-goal-specific memory in any previously reported form - that is differences in the rate, sequence, phase, or covariance of firing. This suggests that such patterns do not hold working memory in the PFC when information must be employed flexibly. Instead, the PFC grouped locations representing behaviorally equivalent task features together, consistent with a role in encoding long-term knowledge of task structure.
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http://dx.doi.org/10.7554/eLife.63035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781596PMC
December 2020

The claustrum.

Curr Biol 2020 12;30(23):R1401-R1406

Department of Physiology and Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Electronic address:

The claustrum is a brain region that has been investigated for over 200 years, yet its precise function remains unknown. In the final posthumously released article of Francis Crick, written with Christof Koch, the claustrum was suggested to be critically linked to consciousness. Though the claustrum remained relatively obscure throughout the last half century, it has enjoyed a renewed interest in the last 15 years since Crick and Koch's article. During this time, the claustrum, like many other brain regions, has been studied with the myriad of modern systems neuroscience tools that have been made available by the intersection of genetic and viral technologies. This has uncovered new information about its anatomical connectivity and physiological properties and begun to reveal aspects of its function. From these studies, one clear consensus has emerged which supports Crick and Koch's primary interest in the claustrum: the claustrum has widespread extensive connectivity with the entire cerebral cortex, suggesting a prominent role in 'higher order processes'.
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http://dx.doi.org/10.1016/j.cub.2020.09.069DOI Listing
December 2020

Synergistically integrated phosphonated poly(pentafluorostyrene) for fuel cells.

Nat Mater 2021 Mar 7;20(3):370-377. Epub 2020 Dec 7.

MPA-11: Materials Synthesis and Integrated Devices, Los Alamos National Laboratory, Los Alamos, NM, USA.

Modern electrochemical energy conversion devices require more advanced proton conductors for their broad applications. Phosphonated polymers have been proposed as anhydrous proton conductors for fuel cells. However, the anhydride formation of phosphonic acid functional groups lowers proton conductivity and this prevents the use of phosphonated polymers in fuel cell applications. Here, we report a poly(2,3,5,6-tetrafluorostyrene-4-phosphonic acid) that does not undergo anhydride formation and thus maintains protonic conductivity above 200 °C. We use the phosphonated polymer in fuel cell electrodes with an ion-pair coordinated membrane in a membrane electrode assembly. This synergistically integrated fuel cell reached peak power densities of 1,130 mW cm at 160 °C and 1,740 mW cm at 240 °C under H/O conditions, substantially outperforming polybenzimidazole- and metal phosphate-based fuel cells. Our result indicates a pathway towards using phosphonated polymers in high-performance fuel cells under hot and dry operating conditions.
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http://dx.doi.org/10.1038/s41563-020-00841-zDOI Listing
March 2021

High-throughput fetal fraction amplification increases analytical performance of noninvasive prenatal screening.

Genet Med 2021 03 15;23(3):443-450. Epub 2020 Nov 15.

Myriad Women's Health, South San Francisco, CA, USA.

Purpose: The percentage of a maternal cell-free DNA (cfDNA) sample that is fetal-derived (the fetal fraction; FF) is a key driver of the sensitivity and specificity of noninvasive prenatal screening (NIPS). On certain NIPS platforms, >20% of women with high body mass index (and >5% overall) receive a test failure due to low FF (<4%).

Methods: A scalable fetal fraction amplification (FFA) technology was analytically validated on 1264 samples undergoing whole-genome sequencing (WGS)-based NIPS. All samples were tested with and without FFA.

Results: Zero samples had FF < 4% when screened with FFA, whereas 1 in 25 of these same patients had FF < 4% without FFA. The average increase in FF was 3.9-fold for samples with low FF (2.3-fold overall) and 99.8% had higher FF with FFA. For all abnormalities screened on NIPS, z-scores increased 2.2-fold on average in positive samples and remained unchanged in negative samples, powering an increase in NIPS sensitivity and specificity.

Conclusion: FFA transforms low-FF samples into high-FF samples. By combining FFA with WGS-based NIPS, a single round of NIPS can provide nearly all women with confident results about the broad range of potential fetal chromosomal abnormalities across the genome.
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http://dx.doi.org/10.1038/s41436-020-01009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935715PMC
March 2021

Are Nomograms Useful in Predicting Upstage From Ductal Carcinoma In Situ to Invasive Carcinoma Requiring Sentinel Lymph Node Biopsy?

Am Surg 2020 Oct 2;86(10):1238-1242. Epub 2020 Nov 2.

Department of Surgery, Harbor-UCLA Medical Center, Torrance, CA, USA.

The upstage rate from ductal carcinoma in situ (DCIS) on core biopsy to invasive carcinoma at definitive excision ranges from 20 to 30%. Nomograms have been developed to aid in the prediction of upstaging so as to guide surgical planning with respect to performance of sentinel lymph node biopsy (SLNB). The aim of this study was to evaluate the ability of these nomograms to predict upstaging within our public hospital population. A retrospective review of patients with DCIS from 2013 to 2018 at a single institution was performed. Individualized probability of upstage was calculated using the Samsung Medical Center (SMC) and (ASO) nomograms. Areas under the receiver operating characteristic curves were calculated to assess the discriminative power of each. Of 105 patients with DCIS, 31 (29.5%) were upstaged to invasive disease. The SMC and ASO nomograms demonstrated area under the curves (AUCs) of .65 (OR = 1.023, 95% CI 1.004-1.042, = .02) and .60 (OR = 1.035, 95% CI 1.003-1.068, = .03), respectively. While SMC provided greater discrimination in our cohort, the performance of these nomograms as reliable clinical adjuncts to guide SLNB decision-making in this cohort was less than optimal and thus should not be the sole factor in determining individual upstage risk.
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http://dx.doi.org/10.1177/0003134820964192DOI Listing
October 2020

Implementation of a geriatric emergency department program using a novel workforce.

Am J Emerg Med 2021 08 24;46:703-707. Epub 2020 Oct 24.

Medicine Service, Louis Stokes Cleveland Veterans Affairs Medical Center, 10701 East Blvd, Cleveland, OH 44106, USA; Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, OH 44106, USA.

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http://dx.doi.org/10.1016/j.ajem.2020.10.039DOI Listing
August 2021
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