Publications by authors named "Andrew Fry"

228 Publications

Periodization and Block Periodization in Sports: Emphasis on Strength-Power Training-A Provocative and Challenging Narrative.

J Strength Cond Res 2021 Jun 15. Epub 2021 Jun 15.

Center of Excellence for Sport Science and Coach Education, SERK, East Tennessee State University, Johnson City, Tennessee; College of Physical Activity and Sport Sciences, West Virginia University, Morgantown, West Virginia; Center for Exercise and Sport Sciences Research, Edith Cowan University, Joondalup, Washington, Australia; Jayhawk Athletic Performance Laboratory, University of Kansas, Lawrence, Kansas; Institute of Human Factors and Ergonomics, Shenzhen University, Shenzhen, China; Sports Training Laboratory, Faculty of Sport Sciences, University of Castilla la Mancha, Spain; and Department of Kinesiology and Health Science, Louisiana State University Shreveport, Shreveport, Louisiana.

Abstract: Stone, MH, Hornsby, WG, Haff, GG, Fry, AC, Suarez, DG, Liu, J, Gonzalez-Rave, JM, and Pierce, KC. Periodization and block periodization in sports: emphasis on strength-power training-a provocative and challenging narrative. J Strength Cond Res XX(X): 000-000, 2021-Periodization can be defined as a logical sequential, phasic method of manipulating fitness and recovery phases to increase the potential for achieving specific performance goals while minimizing the potential for nonfunctional over-reaching, overtraining, and injury. Periodization deals with the micromanagement of timelines and fitness phases and is cyclic in nature. On the other hand, programming deals with the micromanagement of the training process and deals with exercise selection, volume, intensity, etc. Evidence indicates that a periodized training process coupled with appropriate programming can produce superior athletic enhancement compared with nonperiodized process. There are 2 models of periodization, traditional and block. Traditional can take different forms (i.e., reverse). Block periodization has 2 subtypes, single goal or factor (individual sports) and multiple goals or factors (team sports). Both models have strengths and weaknesses but can be "tailored" through creative programming to produce excellent results for specific sports.
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http://dx.doi.org/10.1519/JSC.0000000000004050DOI Listing
June 2021

T2*-weighted MRI produces viable fetal "Black-Bone" contrast with significant benefits when compared to current sequences.

Br J Radiol 2021 Jul 21;94(1123):20200940. Epub 2021 May 21.

Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.

Objectives: Fetal "black bone" MRI could be useful in the diagnosis of various skeletal conditions during pregnancy without exposure to ionizing radiation. Previously suggested susceptibility-weighted imaging (SWI) is not available in the suggested form on all scanners leading to long imaging times that are susceptible to motion artefacts. We aimed to assess if an optimized T2*-weighted GRE sequence can provide viable "black bone" contrast and compared it to other sequences in the literature.

Methods: A retrospective study was conducted on 17 patients who underwent fetal MRI. Patients were imaged with an optimized T2*-weighted GRE sequence, as well as at least one other "black-bone" sequence. Image quality was scored by four blinded observers on a five-point scale.

Results: The T2*-weighted GRE sequence offered adequate to excellent image quality in 63% of cases and scored consistently higher than the three other comparison sequences when comparing images from the same patient. Image quality was found to be dependent on gestational age with good image quality achieved on almost all patients after 26 weeks.

Conclusions: T2*-weighted GRE imaging can provide adequate fetal "black bone" contrast and performs at least as well as other sequences in the literature due to good bone to soft tissue contrast and minimal motion artefacts.

Advances In Knowledge: T2*-weighted fetal "black-bone" imaging can provide excellent bone to soft tissue contrast without using ionizing radiation. It is as good as other "black bone" sequences and may be simpler and more widely implemented, with less motion artefacts.
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http://dx.doi.org/10.1259/bjr.20200940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248208PMC
July 2021

Androgen and glucocorticoid receptor phosphorylation following resistance exercise and pre-workout supplementation.

Steroids 2021 Aug 8;172:108859. Epub 2021 May 8.

Northwest Missouri State University, School of Health Science and Wellness, Maryville, MO, USA. Electronic address:

Purpose: Consumption of caffeine or caffeine containing pre-workout supplements (SUPP) augments steroid hormone responses to resistance exercise (RE). However, the activation of glucocorticoid (GR) and androgen receptors (AR) following RE SUPP has not been investigated. The purpose of this study was to determine the influence of a pre-workout supplement on AR and GR phosphorylation following RE.

Methods: In a randomized, counter-balanced, double-blind, placebo-controlled, within-subject crossover study, ten resistance-trained males ((X¯±SD, age = 22 ± 2.4 yrs, hgt = 175 ± 7 cm, body mass = 84.1 ± 11.8 kg) performed four sets of 8 repetitions of barbell back squats at 75% of their 1-repetition maximum (1-RM) with two minutes of rest between sets and a fifth set of barbell back squats at 60% of 1-RM until concentric failure. A SUPP or flavor and color matched placebo (PL) was consumed 60-minutes prior to RE. Vastus lateralis muscle biopsies were obtained prior to supplementation at rest (BL), and ten minutes post-exercise (POST). Biopsies were analyzed for phosphorylated GR (ser134, ser211, and ser226) and phosphorylated AR (ser81, ser213, ser515, ser650) via western blotting.

Results: pGRser134 decreased, and pGRser226 increased following RE (p < 0.05) with no difference between conditions (p > 0.05). pGRser211 was unchanged after RE (p > 0.05). pARser515 increased, and total AR expression decreased after RE (p < 0.05) in SUPP only. Testosterone and cortisol were not different between SUPP and PL at POST (p > 0.05).

Conclusion: RE influences AR and GR phosphorylation, and SUPP minimally influences this response in the early recovery period.
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http://dx.doi.org/10.1016/j.steroids.2021.108859DOI Listing
August 2021

Lean Body Mass and Muscle Cross-Sectional Area Adaptations Among College Age Males with Different Strength Levels across 11 Weeks of Block Periodized Programmed Resistance Training.

Int J Environ Res Public Health 2021 04 29;18(9). Epub 2021 Apr 29.

Center of Excellence for Sport Science and Coach Education, Department of Sport, Exercise, Recreation and Kinesiology, East Tennessee State University, Johnson City, TN 37614, USA.

The block periodization training paradigm has been shown to produce enhanced gains in strength and power. The purpose of this study is to assess resistance training induced alterations in lean body mass and cross-sectional area using a block periodization training model among individuals (n = 15) of three differing strength levels (high, moderate and low) based on one repetition maximum back squat relative to body weight. A 3 × 5 mixed-design ANOVA was used to examine within-and between-subject changes in cross-sectional area (CSA), lean body mass (LBM), lean body mass adjusted (LBM) and total body water (TBW) over an 11-week resistance training program. LBM is total body water subtracted from lean body mass. The ANOVA revealed no statistically significant between-group differences in any independent variable ( > 0.05). Within-group effects showed statistically significant increases in cross-sectional area ( < 0.001), lean body mass ( < 0.001), lean body mass adjusted ( ˂ 0.001) and total body water ( < 0.001) from baseline to post intervention: CSA: 32.7 cm ± 8.6; 36.3 cm ± 7.2, LBM: 68.0 kg ± 9.5; 70.6 kg ± 9.4, LBM: 20.4 kg ± 3.1; 21.0 kg ± 3.3 and TBW: 49.8 kg ± 6.9; 51.7 kg ± 6.9. In conclusion, the results of this study suggest subjects experienced an increase in both lean body mass and total body water, regardless of strength level, over the course of the 11-week block periodized program. Gains in lean body mass and cross-sectional area may be due to edema at the early onset of training.
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http://dx.doi.org/10.3390/ijerph18094735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124523PMC
April 2021

Supplemental Creatine Modified With Polyethylene Glycol Effectively Loads Skeletal Muscle With Lower Doses.

J Strength Cond Res 2021 May;35(5):1256-1261

Jayhawk Athletic Performance Laboratory, Department of Health, Sport, and Exercise Sciences, University of Kansas, Lawrence, Kansas.

Abstract: Fry, AC, Parra, ME, and Cabarkapa, D. Supplemental creatine modified with polyethylene glycol effectively loads skeletal muscle with lower doses. J Strength Cond Res 35(5): 1256-1261, 2021-The purpose of this study was to compare the efficacy of skeletal muscle uptake of creatine monohydrate (Cr H2O) with that of creatine bound to polyethylene glycol (Cr PEG). Healthy men (X ± SE; age = 23.5 ± 1.0 years) were divided into control (Con, n = 9, 20 g·d-1 of Cr H2O) and experimental (Exp, n = 8, 10 g·d-1 of Cr PEG) groups. Blood samples and muscle biopsies were used to determine acute gastrointestinal absorption over 5 hours and muscle cellular uptake over 5 days. Both groups exhibited significantly (p < 0.05) elevated concentrations of muscle-free Cr (M·gdw-1; Con, pre = 23.0 ± 4.2, post = 39.2 ± 2.7; Exp pre = 22.1 ± 2.9, post = 33.6 ± 3.2), total Cr (M·gdw-1, Con pre = 94.7 ± 5.4, post = 114.8 ± 7.4; Exp pre = 92.6 ± 5.4, post = 106.6 ± 8.4), which were also elevated when these values were normalized for adenosine triphosphate using molar ratios. Circulatory uptake of Cr was significantly different between the groups, with blood concentrations (mg·dL-1) for the Con group peaking at 2 hours post-ingestion (25.99 ± 2.96), whereas the concentrations for the Exp group were lower and were still rising at 5 hours (4.05 ± 0.87). The integrated area under the curve for the 5-hour postingestion period was 7-fold greater for the Con group. Although total Cr ingested over the 5 days supplementation period was less for the Cr PEG group, skeletal muscle uptake of Cr PEG was similar to Cr H2O. Based on circulating Cr concentrations, it seems that Cr PEG is cleared more slowly from the gastrointestinal tract. Thus, lower dosages of Cr may be ingested while maintaining optimal loading kinetics.
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http://dx.doi.org/10.1519/JSC.0000000000003906DOI Listing
May 2021

Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.

Genet Med 2021 Jul 5;23(7):1202-1210. Epub 2021 Mar 5.

Genetic Health Queensland c/-Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed.

Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID.

Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
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http://dx.doi.org/10.1038/s41436-021-01119-8DOI Listing
July 2021

Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine.

Nat Commun 2021 02 5;12(1):833. Epub 2021 Feb 5.

Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.
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http://dx.doi.org/10.1038/s41467-021-21053-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864902PMC
February 2021

2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase.

RSC Med Chem 2020 Jun 22;11(6):707-731. Epub 2020 May 22.

Cancer Research UK Newcastle Drug Discovery Unit , Chemistry, School of Natural and Environmental Sciences , Newcastle University , Newcastle upon Tyne , UK . Email: ; Tel: +44 (0)191 208 7060.

Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl--phenyl-7-purin-2-amine [IC 0.15 μM (Nek2)] and 4-((6-ethynyl-7-purin-2-yl)amino)benzenesulfonamide (IC 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the -phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9-purin-2-yl)amino)phenyl)acetamide [IC 0.06 μM (Nek2); GI (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2.
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http://dx.doi.org/10.1039/d0md00074dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649933PMC
June 2020

Emphasizing Task-Specific Hypertrophy to Enhance Sequential Strength and Power Performance.

J Funct Morphol Kinesiol 2020 Oct 27;5(4). Epub 2020 Oct 27.

Center of Excellence for Sport Science and Coach Education, Department of Sport, Exercise, Recreation, and Kinesiology, East Tennessee State University, Johnson City, TN 37604, USA.

While strength is indeed a skill, most discussions have primarily considered structural adaptations rather than ultrastructural augmentation to improve performance. Altering the structural component of the muscle is often the aim of hypertrophic training, yet not all hypertrophy is equal; such alterations are dependent upon how the muscle adapts to the training stimuli and overall training stress. When comparing bodybuilders to strength and power athletes such as powerlifters, weightlifters, and throwers, while muscle size may be similar, the ability to produce force and power is often inequivalent. Thus, performance differences go beyond structural changes and may be due to the muscle's ultrastructural constituents and training induced adaptations. Relative to potentiating strength and power performances, eliciting specific ultrastructural changes should be a variable of interest during hypertrophic training phases. By focusing on task-specific hypertrophy, it may be possible to achieve an optimal amount of hypertrophy while deemphasizing metabolic and aerobic components that are often associated with high-volume training. Therefore, the purpose of this article is to briefly address different types of hypertrophy and provide directions for practitioners who are aiming to achieve optimal rather than maximal hypertrophy, as it relates to altering ultrastructural muscular components, to potentiate strength and power performance.
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http://dx.doi.org/10.3390/jfmk5040076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739346PMC
October 2020

Addressing the Confusion within Periodization Research.

J Funct Morphol Kinesiol 2020 Aug 28;5(3). Epub 2020 Aug 28.

Center of Excellence for Sport Science and Coach Education, SERK, East Tennessee State University, Johnson City, TN 37614, USA.

In this editorial, we focus on recent problematic developments in sport science, and more specifically, problems related to periodization research. Primary areas discussed are (1) appreciation of history, (2) considerations for training studies, (3) the development of concepts, and (4) programming-driven training models.
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http://dx.doi.org/10.3390/jfmk5030068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739353PMC
August 2020

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Eur J Hum Genet 2021 Apr 12;29(4):625-636. Epub 2021 Jan 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
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http://dx.doi.org/10.1038/s41431-020-00769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115148PMC
April 2021

Acute Systemic Response Of BDNF, Lactate and Cortisol to Strenuous Exercise Modalities in Healthy Untrained Women.

Dose Response 2020 Oct-Dec;18(4):1559325820970818. Epub 2020 Dec 10.

Facultad de Deportes Campus Ensenada, Universidad Autónoma de Baja California, Ensenada, México.

Acute bouts of intense exercise increase lactate concentration, which in turn stimulates brain-derived neurotrophic factor (BDNF) production. Cortisol released during intense exercise might inhibit BDNF synthesis. This study examined the acute effects of 2 protocols of strenuous exercise on serum BDNF. Seventeen physically-active healthy females (Age = 20.0 ± 0.9 yr., BMI = 23.0 ± 2.6 kg/m) performed a strenuous cycle-ergometer graded exercise test (GXT) and a high-intensity interval training session (HIIT). Serum BDNF, serum cortisol, cortisol: BDNF ratio and blood lactate (BLa) were recorded at baseline and immediately following exercise. Although non-statistically significant, the HIIT session elicited a higher magnitude of change from baseline for BDNF ( = 0.17) and cortisol ( = 1.18) than after the GXT ( = -0.26, and = 0.82, respectively). An interaction was found between GXT and HIIT trials and measurements on BLa levels, with higher post-exertion values after HIIT than after GXT (p < 0.0001, η = 0.650, 95%CI = 2.2, 5.2). The higher BLa levels did not raise circulating BDNF. The elevated cortisol levels may have overcome the effects of lactate on BDNF. However, the higher BLa induced by HIIT suggest that interval exercise modality on the long-term could be a feasible intervention to increase circulating peripheral BDNF, at least in untrained healthy women.
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http://dx.doi.org/10.1177/1559325820970818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734519PMC
December 2020

Effects of Transspinal Direct Current Stimulation on Cycling Perception of Effort and Time to Exhaustion.

J Strength Cond Res 2021 Feb;35(2):347-352

Osness Human Performance Laboratories, Department of Health, Sport, and Exercise Sciences, University of Kansas, Lawrence, Kansas.

Abstract: Ciccone, AB, Fry, AC, Emerson, DM, Gallagher, PM, Herda, TJ, and Weir, JP. Effects of transspinal direct current stimulation on cycling perception of effort and time to exhaustion. J Strength Cond Res 35(2): 347-352, 2021-In the past decade, researchers have investigated the efficacy of transspinal direct current stimulation (tsDCS) on the central nervous system and afferent neuron function in humans. Recently, data have suggested it may be possible for such tsDCS-induced changes in neuromuscular function to enhance performance. This study used noninvasive thoracic spine tsDCS to determine if cycling performance and perception of effort could be modulated by tsDCS. In 3 different stimulation conditions, anodal, cathodal, and sham, subjects cycled at 80% of their maximal aerobic capacity until exhaustion and reported their rating of perceived exertion (RPE) every minute. From this period, we compared the RPE responses over the first 3 minutes and time to exhaustion. There was no significant difference in time to exhaustion between anodal (408 ± 121 seconds), cathodal (413 ± 168 seconds), and sham (440 ± 189 seconds) conditions (p = 0.58). There was no significant difference in RPE from minutes 1-3 (collapsed across time) between anodal (12.9 ± 2.4 arbitrary units (AUs)), cathodal (13.3 ± 2.2 AUs), and sham (12.9 ± 2.1 AUs) conditions (p = 0.51). These data suggest tsDCS condition did not influence cycling performance or perception of effort during high-intensity cycling. Therefore, thoracic spine and lower abdominal montage delivering a current density of 0.071 mA·cm-2 for 20 minutes likely does not substantially improve high-intensity cycling work capacity. Therefore, more research is needed to investigate the efficacy of tsDCS and which stimulation methods may and may not enhance human performance.
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http://dx.doi.org/10.1519/JSC.0000000000003876DOI Listing
February 2021

Visualisation of fetal meconium on post-mortem magnetic resonance imaging scans: a retrospective observational study.

Acta Radiol Open 2020 Nov 19;9(11):2058460120970541. Epub 2020 Nov 19.

Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Sheffield, UK.

Background: Less invasive techniques for fetal post-mortems are increasingly used to correlate with parental wishes. With the use of post-mortem magnetic resonance imaging (MRI), normal appearance of the organs must be established.

Purpose: To investigate the after death appearance of the fetal meconium throughout gestation using the hyperintense appearance of meconium on T1 weighted MRI.

Material And Methods: This was a retrospective study that took place in a tertiary referral centre radiology department. Sixty-two fetal body post-mortem MRI scans (January 2014 to May 2018) between 12 and 41 weeks gestation were reviewed. Signal intensity of meconium at the rectum, sigmoid colon, splenic flexure and hepatic flexure was evaluated and correlated with gestational age. Interrater reliability was calculated.

Results: Meconium did not consistently have high signal intensity on T1 scans and was not always obvious. Rectal meconium had the highest intensity, and the more proximal the bowel the lower the intensity. The meconium had higher intensity at earlier gestations. Interrater reliability for rectal meconium gradings was excellent.

Conclusion: This study provides the first published primary research on the appearance of fetal meconium on post-mortem MRI. Overall, results were variable and suggest an alteration of bowel contents after death, but further investigation is needed to effectively inform practice.
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http://dx.doi.org/10.1177/2058460120970541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683848PMC
November 2020

Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy.

Am J Hum Genet 2021 01 26;108(1):176-185. Epub 2020 Nov 26.

Neurology and Molecular Neuroscience Research, Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK; Kids Neuroscience Centre, Kids Research, Children Hospital at Westmead, Sydney, NSW 2145, Australia; Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, NSW 2050, Australia.

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na channel function.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820623PMC
January 2021

Biometric analysis of the foetal meconium pattern using T1 weighted 2D gradient echo MRI.

BJR Open 2020 5;2(1):20200032. Epub 2020 Aug 5.

Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield, Jessop Wing, Tree Root Walk, Sheffield, S10 2SF, United Kingdom.

Objectives: Foetal MRI is used to assess abnormalities after ultrasonography. Bowel anomalies are a significant cause of neonatal morbidity, however there are little data concerning its normal appearance on antenatal MRI. This study aims to investigate the pattern of meconium accumulation throughout gestation using its hyperintense appearance on weighted scans and add to the current published data.

Methods: This was a retrospective cohort study in a tertiary referral clinical MRI centre. Foetal body MRI scans of varying gestational ages were obtained dating between October 2011 and March 2018. The bowel was visualised on weighted images. The length of the meconium and the width of the meconium at the rectum, sigmoid colon, splenic flexure and hepatic flexure was measured. Presence or absence of meconium in the small bowel was noted. Inter- and intrarater reliability was assessed.

Results: 181 foetal body scans were reviewed. 52 were excluded and 129 analysed. Visualisation of the meconium in the large bowel became increasingly proximal with later gestations, and small bowel visualisation was greater at earlier gestations. There was statistically significant strong ( = 0.6-0.8) or very strong ( = 0.8-1.0) positive correlation of length and width with increasing gestation. Interrater reliability was moderate to excellent ( = 0.4-1.0).

Conclusion: This study provides new information regarding the pattern of meconium accumulation throughout gestation. With care, the results can be used in clinical practice to aid diagnosis of bowel pathology.

Advances In Knowledge: The findings of this study provide further information concerning the normal accumulation of foetal meconium on MR imaging, an area where current research is limited.
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http://dx.doi.org/10.1259/bjro.20200032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594886PMC
August 2020

BRCA1/MAD2L1 Deficiency Disrupts the Spindle Assembly Checkpoint to Confer Vinorelbine Resistance in Mesothelioma.

Mol Cancer Ther 2021 02 6;20(2):379-388. Epub 2020 Nov 6.

Leicester Cancer Research Centre, University of Leicester, Leicester, United Kingdom.

Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. silencing led to codepletion of at the mRNA and protein levels consistent with its status as a transcriptional target of Silencing of phenocopied and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both and expression. Following vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in -positive explants compared with 0% in -negative explants. In 48 patients, and/or loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking expression compared with double-positive patients (5.9 vs. 36.7 months, = 0.03). Our data implicate loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0363DOI Listing
February 2021

The Effect of Training Status on Adaptations to 11 Weeks of Block Periodization Training.

Sports (Basel) 2020 Oct 31;8(11). Epub 2020 Oct 31.

Center of Excellence for Sport Science and Coach Education, Department of Sport, Exercise, Recreation and Kinesiology, East Tennessee State University, Johnson City, TN 37614, USA.

Some controversy exists as to the most efficacious method of training to achieve enhanced levels of sport performance. Controversy concerning the efficacy of periodization and especially block periodization (BP) likely stems from the use of poorly or untrained subjects versus trained who may differ in their responses to a stimulus. The purpose of this study was to investigate the effect of training status on performance outcomes resulting from 11 weeks of BP training. Fifteen males were recruited for this study and placed into strong (age = 24.3 ± 1.9 years., body mass (BM) = 87.7 ± 8.7 kg, squat: body mass = 1.96 ± 0.16), moderate (age = 25.3 ± 2.7 years., body mass = 100.2 ± 15.5 kg, squat: body mass = 1.46 ± 0.14), or weak (age = 23.2 ± 3.9 yrs., body mass = 83.5 ± 17.1 kg, squat: body mass = 1.17 ± 0.07) groups based on relative strength. Testing was completed at baseline, and after each block which consisted of 1 repetition maximum (1RM) squat, 0 kg static jump (SJ), 0 kg countermovement jump (CMJ), 20 kg SJ, and 20 kg CMJ. Absolute and relative strength were strongly correlated with rates of improvement for absolute strength, relative strength, 0 kg, and 20 kg vertical jumps. All subjects substantially improved back squat ( < 0.001), relative back squat ( < 0.001) with large-very large effect sizes between groups for percent change favoring the weak group over the moderate and strong group for all performance variables. All subjects showed statistically significant improvements in 0 kg SJ ( < 0.001), 0 kg CMJ ( < 0.001), 20 kg SJ ( = 0.002), and 20 kg CMJ ( < 0.001). Statistically significant between group differences were noted for both 20 kg SJ ( = 0.01) and 20 kg CMJ ( = 0.043) with the strong group statistically greater jump heights than the weak group. The results of this study indicate BP training is effective in improving strength and explosive ability. Additionally, training status may substantially alter the response to a resistance training program.
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http://dx.doi.org/10.3390/sports8110145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693826PMC
October 2020

Myosin heavy chain expression relationships to power-load and velocity-load curves.

J Sports Med Phys Fitness 2021 Jan 22;61(1):2-9. Epub 2020 Oct 22.

Osness Human Performance Laboratories, University of Kansas, Lawrence, KS, USA.

Background: Velocity- and power-based training are popular methods of determining training session loads and volumes. One factor that may influence load-velocity and load-power properties of an individual is the myosin heavy chain (MHC) composition of the muscle. The aim of this study was to examine the relationship between MHC composition and both load-velocity and load-power properties of muscle performance.

Methods: Forty-two men with a variety of training backgrounds took part in this study (mean±SD; age=22.4±3.5 yrs, hgt=1.78±0.07 m, BW=78.7±13.3 kg). After testing leg extension one repetition maximum (1 RM), subjects performed maximal effort leg extensions at loads from 30% to 90% 1 RM. Muscle biopsies from the vastus lateralis were analyzed via SDS-PAGE electrophoresis technique for MHC content (IIx=13.8±12.9%, IIa=49.4±10.3%, I=36.8±11.3%). Leg extension rotational velocity and power were plotted against relative loads for all subjects.

Results: Significant correlations (P<0.05) were observed for MHC IIa with all performance variables (i.e. slopes, intercepts, peaks and relative loads). Relationships indicated that greater %MHC IIa was associated with greater velocity intercepts, more negative load-velocity slopes, greater maximal power, and with maximal power occurring at a lower relative intensity (% 1 RM).

Conclusions: These data indicate that muscle velocity and power characteristics appear to be partially influenced by MHC content in a manner consistent with single muscle fiber contractile properties.
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http://dx.doi.org/10.23736/S0022-4707.20.10469-9DOI Listing
January 2021

International consensus recommendations on the diagnostic work-up for malformations of cortical development.

Nat Rev Neurol 2020 Nov 7;16(11):618-635. Epub 2020 Sep 7.

Institute for Clinical Genetics, TU Dresden, Dresden, Germany.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.
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http://dx.doi.org/10.1038/s41582-020-0395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790753PMC
November 2020

Promoting Alzheimer's Risk-Reduction through Community-Based Lifestyle Education and Exercise in Rural America: A Pilot Intervention.

Kans J Med 2020 10;13:179-185. Epub 2020 Jul 10.

University of Kansas, Alzheimer's Disease Center, Fairway, KS.

Introduction: Rural Americans (RA) have poorer vascular health and physical activity levels than their urban counterparts; all are dementia risk factors. Dementia risk reduction among rural individuals requires a tailored approach. The purpose of this project was to examine preliminary efficacy of a community-based physical exercise and/or dementia risk factor-reduction curriculum among rural adults 50 and older.

Methods: Seventy-five rural dwelling adults 50 and older were randomized to one of three groups: 1) 10 weeks of Alzheimer's disease risk-reduction education (ED), 2) risk-reduction education and supervised exercise (EDEX) or 3) control group (CON). Outcomes included baseline to 10-week follow-up difference in dementia knowledge (primary outcome) and physical activity, muscular endurance, healthy lifestyle engagement, and anthropometrics (secondary outcomes).

Results: Sixty-nine adults successfully completed the 10-week study. Dementia knowledge increased in a Treatment Arm-dependent manner (χ = 6.95 (2), p = 0.03), being ED and EDEX superior to CON. Engagement in healthy lifestyle behaviors did not change statistically. However, participation specifically in physical activity increased over time (χ = 11.47 (2), p = 0.003) with EDEX reporting the greatest increases. No significant change in average daily steps was observed for any group.

Conclusion: The results suggested dementia risk-reduction education, both with and without structured exercise, leads to improvements in dementia knowledge. When coupled with regular, supervised exercise, this education intervention also helped participants increase engagement in physical activity over 10 weeks. Tailored interventions that combine Alzheimer's disease education and regular, supervised exercise may help reduce dementia risk in rural communities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363174PMC
July 2020

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.

Proc Natl Acad Sci U S A 2020 07 30;117(29):17195-17203. Epub 2020 Jun 30.

Warp Drive Bio, Inc., Redwood City, CA 94063;

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.
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http://dx.doi.org/10.1073/pnas.2006560117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382241PMC
July 2020

The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure.

Nat Commun 2020 06 26;11(1):3252. Epub 2020 Jun 26.

Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, LE1 7RH, UK.

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
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http://dx.doi.org/10.1038/s41467-020-17078-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319964PMC
June 2020

Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation.

Eur J Med Genet 2020 Sep 10;63(9):103972. Epub 2020 Jun 10.

Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; Institute of Medical Genetics, University Hospital of Wales, Heath Park, Cardiff, CF14 4XW, UK. Electronic address:

Mutations in the TRIM8 gene have been described in patients with severe developmental delay, intellectual disability and epilepsy. Only six patients have been described to date. All the previous mutations were truncating variants clustered in the C-terminus of the protein. A previous patient with TRIM8-related epileptic encephalopathy was reported to have nephrotic syndrome. Here we describe the clinical, radiological and histological features of an 8-year-old male patient with a TRIM8 mutation who, in contrast to previous patients, had only mild intellectual disability and well-controlled epilepsy. The patient was found to have proteinuria at 2 years of age. Renal biopsy findings were suggestive of focal segmental glomerulosclerosis. His kidney function declined and peritoneal dialysis was started at 5 years of age. He underwent renal transplant at 7 years of age. Trio-based whole genome sequencing identified a novel de novo heterozygous frameshift mutation in TRIM8 (NM_030912.2) c.1198_1220del, p.(Tyr400ArgfsTer2). This patient is further evidence that TRIM8 mutations cause a syndrome with both neurological and renal features. Our findings suggest the spectrum of TRIM8-related disease may be wider than previously thought with the possibility of milder neurodevelopmental problems and/or a more severe, progressive renal phenotype. We highlight the need for proteinuria screening in patients with TRIM8 mutations.
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http://dx.doi.org/10.1016/j.ejmg.2020.103972DOI Listing
September 2020

SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.

Ann Neurol 2020 08 9;88(2):348-362. Epub 2020 Jul 9.

West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, United Kingdom.

Objective: Pathogenic variants in SCN3A, encoding the voltage-gated sodium channel subunit Nav1.3, cause severe childhood onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A-related neurodevelopmental disorder.

Methods: Patients were ascertained via an international collaborative network. We compared sodium channels containing wild-type versus variant Nav1.3 subunits coexpressed with β1 and β2 subunits using whole-cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK-293T cells).

Results: Of 22 patients with pathogenic SCN3A variants, most had treatment-resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20, 75%). Many, but not all (15/19, 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4 to 6 of domains II to IV. Most pathogenic missense variants tested (10/11, 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function.

Interpretation: Our study defines SCN3A-related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in >75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis. ANN NEUROL 2020;88:348-362.
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http://dx.doi.org/10.1002/ana.25809DOI Listing
August 2020

Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review.

Am J Med Genet A 2020 07 22;182(7):1637-1654. Epub 2020 Apr 22.

Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.

With advances in genetic testing and improved access to such advances, whole exome sequencing is becoming a first-line investigation in clinical work-up of children with developmental delay/intellectual disability (ID). As a result, the need to understand the importance of genetic variants and its effect on the clinical phenotype is increasing. Here, we report on the largest cohort of patients with HNRNPU variants. These 21 patients follow on from the previous study published by Yates et al. in 2017 from our group predominantly identified from the Deciphering Developmental Disorders study that reported seven patients with HNRNPU variants. All the probands reported here have a de novo loss-of-function variant. These probands have craniofacial dysmorphic features, in the majority including widely spaced teeth, microcephaly, high arched eyebrows, and palpebral fissure abnormalities. Many of the patients in the group also have moderate to severe ID and seizures that tend to start in early childhood. This series has allowed us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency, and expand substantially on already published literature on HNRNPU-related neurodevelopmental syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61599DOI Listing
July 2020

EML4-ALK V3 oncogenic fusion proteins promote microtubule stabilization and accelerated migration through NEK9 and NEK7.

J Cell Sci 2020 05 11;133(9). Epub 2020 May 11.

Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK

EML4-ALK is an oncogenic fusion present in ∼5% of non-small cell lung cancers. However, alternative breakpoints in the gene lead to distinct variants of EML4-ALK with different patient outcomes. Here, we show that, in cell models, EML4-ALK variant 3 (V3), which is linked to accelerated metastatic spread, causes microtubule stabilization, formation of extended cytoplasmic protrusions and increased cell migration. EML4-ALK V3 also recruits the NEK9 and NEK7 kinases to microtubules via the N-terminal EML4 microtubule-binding region. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates migration in a microtubule-dependent manner that requires the downstream kinase NEK7 but does not require ALK activity. Strikingly, elevated NEK9 expression is associated with reduced progression-free survival in EML4-ALK patients. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through NEK9 and NEK7, leading to increased cell migration. This represents a novel actionable pathway that could drive metastatic disease progression in EML4-ALK lung cancer.
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http://dx.doi.org/10.1242/jcs.241505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240300PMC
May 2020

A new 1p36.13-1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis.

Clin Genet 2020 06 1;97(6):927-932. Epub 2020 Apr 1.

Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.

Two 1p36 contiguous gene deletion syndromes are known so far: the terminal 1p36 deletion syndrome and a 1p36 deletion syndrome with a critical region located more proximal at 1p36.23-1p36.22. We present even more proximally located overlapping deletions from seven individuals, with the smallest region of overlap comprising 1 Mb at 1p36.13-1p36.12 (chr1:19077793-20081292 (GRCh37/hg19)) defining a new contiguous gene deletion syndrome. The characteristic features of this new syndrome are learning disability or mild intellectual disability, speech delay, behavioral abnormalities, and ptosis. The genes UBR4 and CAPZB are considered the most likely candidate genes for the features of this new syndrome.
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http://dx.doi.org/10.1111/cge.13739DOI Listing
June 2020