bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ovarian insufficiency and secondary amenorrhea in a patient with a novel variant within GDF9 gene
Authors: Marinakis Nikolaos M. , Tsoutsou Eirini , Sofocleous Christalena , Veltra Danai , Papaefthimiou Petros , Lytras Aristides , Traeger-Synodinos Joanne , Kanaka-Gantenbein Christina 
Published: January 2022

Abstract

Objective:
Premature ovarian insufficiency is a heterogeneous condition that can be caused by several factors, such as genetic, environmental, etc. and represents one of the main causes of female infertility. One of the genes implicated is GDF9, which encodes a member of the transforming growth factor-beta superfamily that participates in the coordination of somatic cell activity, female fertility, including folliculogenesis, and oocyte maturation. Damaging variants in GDF9-encoded growth factors can cause the production of inhibin, perturb oocyte granulosa cell microenvironments, and obstruct follicle development. A novel GDF9 variant is herein reported to consolidate the role of GDF9 in ovarian function and female fertility.

Methods:
A 38-year-old female was referred for the investigation of secondary amenorrhea. Eventually, she was referred for genetic evaluation whereby conventional karyotyping and Fragile-X molecular testing were normal. Whole Exome Sequencing was performed, followed by targeted Sanger sequencing in all family members for variant confirmation and evaluation.

Results:
In this study we report a patient presenting with secondary amenorrhea due to premature ovarian failure and a pituitary lesion with radiological characteristics compatible with a Rathke cyst or a macroadenoma, residing between the adenohypophysis and neurohypophysis. Whole Exome Sequencing revealed a novel heterozygous stoploss variant c.1364A>C, p.(*455Serext*8) in the GDF9 gene.

Conclusions:
Should the predicted elongated GDF9 protein and differentially configurated GDF9 mature protein molecule form unstable dimers, rapid proteolytic degradation may take place and inhibit homo/heterodimer formation.
Time series proteome profile analysis reveals a protective role of citrate synthase in angiotensin II-induced atrial fibrillation
Authors: Teng Fei , Han Xiao , Yu Peng , Li Pang-Bo , Li Hui-Hua , Zhang Yun-Long 
Published: January 2022

Background:
Angiotensin (Ang) II and elevated blood pressure are considered to be the main risk factors for atrial fibrillation. However, the proteome profiles and key mediators/signaling pathways involved in the development of Ang II-induced atrial fibrillation remain unclear.

Methods:
Male wild-type C57BL/6 mice (10-week old) were infused with Ang II (2000 ng/kg per min) for 1, 2, or 3 weeks, respectively. Time series proteome profiling of atrial tissues was performed using isobaric tags for relative and absolute quantitation and liquid chromatography coupled with tandem mass spectrometry.

Results:
We identified a total of 1566 differentially expressed proteins (DEPs) in the atrial tissues at weeks 1, 2, and 3 after Ang II infusion. These DEPs were predominantly involved in mitochondrial oxidation-reduction and tricarboxylic acid cycle in Ang II-infused atria. Moreover, coexpression network analysis revealed that citrate synthase, a rate-limiting enzyme in the tricarboxylic acid cycle, was localized at the center of the mitochondrial oxidation-reduction process, and its expression was significantly downreguated in Ang II-infused atria at different time points. Cardiomyocyte-specific overexpresion of citrate synthase markedly reduced atrial fibrillation susceptibility and atrial remodeling in mice. These beneficial effects were associated with increased ATP production and mitochondrial oxidative phosphorylation system complexes I–V expression and inhibition of oxidative stress.

Conclusion:
The current study defines the dynamic changes of the DEPs involved in Ang II-induced atrial fibrillation, and identifies that citrate synthase plays a protective role in regulating atrial fibrillation development, and increased citrate synthase expression may represent a potential therapeutic option for atrial fibrillation treatment.
Chimeric antigen receptor T-cell therapy in acute myeloid leukemia
Authors: Koedam Jan , Wermke Martin , Ehninger Armin , Cartellieri Marc , Ehninger Gerhard 
Published: January 2022

Purpose of review
Treatment outcome of relapsed or refractory AML patients remains dismal and new treatment options are needed. Adoptive cell therapy using CAR-T cells is a potentially interesting approach in this.

Recent findings
Several potentially interesting AML targets are being investigated with CAR-T therapy with over 60 clinical trials listed on clinicaltrials.gov. The first clinical data are only just emerging with mixed results, once more proving that further research is needed.

Summary
Adoptive cell therapy using chimeric antigen receptor T cells is being investigated in AML through many clinical trials. So far, no AML-specific antigen has been identified, requiring additional strategies to mitigate on-target off-tumor toxicity and to increase efficacy. Focus point is to acquire control over the CAR T cells once administered. Strategies to do so include biodegradable CARs, inducible CARs, suicide-switch containing CARs and two-component modular CARs. Limited and mixed results are available, confirming the risk of lasting toxicity for nonswitchable CARs. Initial results of modular CARs suggest toxicity can be mitigated whilst maintaining CAR activity by the use of modular CAR concepts that allows for ‘ON’ and ‘OFF’ switching.
HIV, Aging, and Comorbidities Research in Clinical Cohorts: 3 Lessons Learned Using Examples From the CNICS Cohort
Authors: Crane Heidi M. , Drumright Lydia 
Published: January 2022

Background:
Owing to ongoing improvements in antiretroviral therapy, people with HIV (PWH) are achieving near-normal lifespans with many surviving into middle and old age. Despite this success, PWH have a higher than expected risk of developing non-AIDS comorbidities, multimorbidity, and functional decline at ages younger than those without HIV.

Methods:
As part of the Inter-CFAR (Center for AIDS Research) Symposium, HIV and Aging in the era of Antiretroviral Therapy and COVID-19, we presented a research update from HIV clinical cohorts and specifically described 3 lessons learned from the Centers for AIDS Research Network of Integrated Clinical Systems cohort that are important for HIV and aging research moving forward.

Results:
Adjudicated outcomes are particularly beneficial for less common comorbidities such as myocardial infarction. Multiple ascertainment approaches increase sensitivity over using diagnoses alone (89% vs. 44%). Adjudication eliminates false-positive events and allows myocardial infarction types to be identified. Comorbidity research has often relied on composite outcomes, such as all cardiovascular diseases, often to increase power. Mechanistic differences across outcomes demonstrate the importance of moving away from many composite outcomes. Timely data are needed to ensure findings are relevant to improve care or outcomes for the population of PWH who are currently aging.

Conclusions:
A better understanding of the causes, mechanisms, prevention and treatment of functional decline, comorbidities, and multimorbidities is a crucial research focus as PWH are aging. Clinical cohorts with timely, comprehensive harmonized clinical data and carefully adjudicated outcomes are ideally positioned to improve understanding of these questions.
Brief Report: Transgender Women and Preexposure Prophylaxis Care: High Preexposure Prophylaxis Adherence in a Real-World Health Care Setting in New York City
Authors: Starbuck Lila , Golub Sarit A. , Klein Augustus , Harris Alexander B. , Guerra Amiyah , Rincon Christopher , Radix Asa E. 
Published: January 2022

Background:
Transgender women and trans feminine individuals (TGW/TFI) are a high priority population for the provision of HIV preexposure prophylaxis (PrEP) care within the United States, but there is limited research that focuses specifically on PrEP adherence within this population.

Setting:
Observational study of patients prescribed PrEP at a community-based health center.

Methods:
We enrolled 100 TGW/TFI PrEP patients at a community health center during clinic visits. Adherence data were collected at 3 time points, using self-report surveys, patient interviews, and urine assays measuring tenofovir. Data were summarized descriptively.

Results:
The sample was diverse in age, race/ethnicity, and socioeconomic characteristics. Participants demonstrated strong PrEP adherence; at least 80% of the sample reported 90% or greater adherence at each time point. Concordance between self-report and urine assay was high. Among patients who reported taking PrEP within the past 48 hours, 82%–92% had detectable urine tenofovir. However, many patients reported PrEP stop periods of 4 or more days (28%–39% per time point).

Conclusions:
Our data highlight TGW/TFI's capacity to adhere to daily PrEP and sustain PrEP use over time. The concordance between patient self-report and urine TFV levels suggest that providers can trust patient reports of PrEP adherence behavior and support the use of adherence conversations in clinical settings, without the need for point of care biological monitoring. Findings also underscore the importance of continued attention to drivers of PrEP stops at the patient, clinic, and systems levels and the development of strategies that support sustained PrEP use.
An Auxiliary Cranioparietal Anchorage System to Improve the Stability of the Rigid External Distraction Device in Children With Crouzon Syndrome
Authors: Liu Jing , Tong Haizhou , Wang Yongqian , Li Haidong , Wu Di , Yin Ningbei , Song Tao 
Published: January 2022

Abstract:
Rigid external distraction (RED) device instability because of thin skulls in syndromic craniosynostosis patients remains challenging. The authors propose the use of an auxiliary cranioparietal anchorage system to improve RED device stability in patients with Crouzon syndrome. Five consecutive patients with Crouzon syndrome underwent Le Fort III osteotomy with midface advancement using a modified external device. Cephalometric analysis and three-dimensional computed tomography images were evaluated preoperatively and after device removal. Mechanical analyses of the RED device with and without the auxiliary cranioparietal anchorage system were performed. Both postoperative photographs and follow-up computed tomographs showed obvious midfacial advancement with no intracranial pin perforation or external frame migration. Mechanical analysis showed that the new system reduced the possibility of postoperative external frame migration. The auxiliary cranioparietal anchorage system might be considered an adjunct to the RED device in patients with Crouzon syndrome to avoid postoperative complications.
Chromosome-level genome assembly and annotation of two lineages of the ant Cataglyphis hispanica: stepping stones towards genomic studies of hybridogenesis and thermal adaptation in desert ants
Authors: Darras Hugo , De Souza Araujo Natalia , Baudry Lyam , Guiglielmoni Nadège , Lorite Pedro , Marbouty Martial , Rodriguez Fernando , Arkhipova Irina , Koszul Romain , Flot Jean-François , Aron Serge 
Published: January 2022

AbstractCataglyphis are thermophilic ants that forage during the day when temperatures are highest and sometimes close to their critical thermal limit. Several Cataglyphis species have evolved unusual reproductive systems such as facultative queen parthenogenesis or social hybridogenesis, which have not yet been investigated in detail at the molecular level. We generated high-quality genome assemblies for two hybridogenetic lineages of the Iberian ant Cataglyphis hispanica using long-read Nanopore sequencing and exploited chromosome conformation capture (3C) sequencing to assemble contigs into 26 and 27 chromosomes, respectively. Further karyotype analyses confirm this difference in chromosome numbers between lineages; however, they also suggest it may not be fixed among lineages. We obtained transcriptomic data to assist gene annotation and built custom repeat libraries for each of the two assemblies. Comparative analyses with 19 other published ant genomes were also conducted. These new genomic resources pave the way for exploring the genetic mechanisms underlying the remarkable thermal adaptation and the molecular mechanisms associated with transitions between different genetic systems characteristic of the ant genus Cataglyphis.
Characterization of CAP1 and ECA4 adaptors participating in clathrin-mediated endocytosis
Authors: Adamowski Maciek , Matijević Ivana , Friml Jiří 
Published: January 2022

AbstractFormation of endomembrane vesicles is crucial in all eukaryotic cells and relies on vesicle coats such as clathrin. Clathrin-coated vesicles form at the plasma membrane and the trans-Golgi Network. They contain adaptor proteins, which serve as binding bridges between clathrin, vesicle membranes, and cargoes. A large family of monomeric ANTH/ENTH/VHS adaptors is present in A. thaliana. Here, we characterize two homologous ANTH-type clathrin adaptors, CAP1 and ECA4, in clathrin-mediated endocytosis (CME). CAP1 and ECA4 are recruited to sites at the PM identified as clathrin-coated pits (CCPs), where they occasionally exhibit early bursts of high recruitment. Subcellular binding preferences of N- and C-terminal fluorescent protein fusions of CAP1 identified a functional adaptin-binding motif in the unstructured tails of CAP1 and ECA4. In turn, no function can be ascribed to a double serine phosphorylation site conserved in these proteins. Double knockout mutants do not exhibit deficiencies in general development or CME, but a contribution of CAP1 and ECA4 to these processes is revealed in crosses into sensitized endocytic mutant backgrounds. Overall, our study documents a contribution of CAP1 and ECA4 to CME in A. thaliana and opens questions about functional redundancy among non-homologous vesicle coat components.
Fixation dynamics of beneficial alleles in prokaryotic polyploid chromosomes and plasmids
Authors: Santer Mario , Kupczok Anne , Dagan Tal , Uecker Hildegard 
Published: January 2022

AbstractTheoretical population genetics has been mostly developed for sexually reproducing diploid and for monoploid (haploid) organisms, focusing on eukaryotes. The evolution of bacteria and archaea is often studied by models for the allele dynamics in monoploid populations. However, many prokaryotic organisms harbor multicopy replicons – chromosomes and plasmids – and theory for the allele dynamics in populations of polyploid prokaryotes remains lacking. Here we present a population genetics model for replicons with multiple copies in the cell. Using this model, we characterize the fixation process of a dominant beneficial mutation at two levels: the phenotype and the genotype. Our results show that, depending on the mode of replication and segregation, the fixation time of mutant phenotypes may precede the genotypic fixation time by many generations; we term this time interval the heterozygosity window. We furthermore derive concise analytical expressions for the occurrence and length of the heterozygosity window, showing that it emerges if the copy number is high and selection strong. Replicon ploidy thus allows for the maintenance of genetic variation following phenotypic adaptation and consequently for reversibility in adaptation to fluctuating environmental conditions.
Uncovering One-Dimensional Reaction Coordinate that Underlies Structure-Function Relationship of Proteins
Authors: Wu Shanshan , Li Huiyu , Ma Ao 
Published: January 2022

AbstractUnderstanding the mechanism of functional protein dynamics is critical to understanding protein functions. Reaction coordinates is a central topic in protein dynamics and the grail is to find the one-dimensional reaction coordinate that can fully determine the value of committor (i.e. the reaction probability in configuration space) for any protein configuration. We present a powerful new method that can, for the first time, identify the rigorous one-dimensional reaction coordinate in complex molecules. This one-dimensional reaction coordinate is determined by a fundamental mechanical operator--the generalized work functional. This method only requires modest computational cost and can be readily applied to large molecules. Most importantly, the generalized work functional is the physical origin of the collectivity in functional protein dynamics and provides a tentative roadmap that connects the structure of a protein to its function.
Synaptic Potentiation of Engram cells is Necessary and Sufficient for Context Fear Memory
Authors: Cardozo Leonardo M. , de Sousa André F. , Dillingham Blythe C. , Dang Westley , Job Nicholas , Yoo Eun J. , Ranamukhaarachchi Sural K. , Yuan Qi , Mayford Mark 
Published: January 2022

AbstractThe nature and distribution of the synaptic changes that underlie memory are not well understood. We examined the synaptic plasticity behind context fear conditioning and found that learning produced synaptic potentiation specifically onto engram neurons in the basolateral amygdala. This potentiation lasted at least 7 days, was reversed by extinction, and its disruption impaired memory recall. High frequency optogenetic stimulation of the CS and US-activated ensembles, or biochemical induction of synaptic potentiation in US-responsive neurons alone, was sufficient to produce a context fear association without prior associative training. These results suggest that plasticity of CS inputs onto US-responsive amygdala neurons underlies memory formation and is necessary and sufficient to establish context fear associations.
Interactions between influenza A virus nucleoprotein and gene segment UTRs facilitate selective modulation of viral gene expression
Authors: Diefenbacher Meghan , Tan Timothy JC , Bauer David LV , Stadtmueller Beth , Wu Nicholas C. , Brooke Christopher B. 
Published: January 2022

AbstractThe influenza A virus (IAV) genome is divided into eight negative-sense, single-stranded RNA segments. Each segment exhibits a unique level and temporal pattern of expression, however the exact mechanisms underlying the patterns of individual gene segment expression are poorly understood. We previously demonstrated that a single substitution in the viral nucleoprotein (NP:F346S) selectively modulates neuraminidase (NA) gene segment expression while leaving other segments largely unaffected. Given what is currently known about NP function, there is no obvious explanation for how changes in NP can selectively modulate the replication of individual gene segments. We found that the specificity of this effect for the NA segment is virus strain specific and depends on the UTR sequences of the NA segment. While the NP:F346S substitution did not significantly alter the RNA binding or oligomerization activities of NPin vitro, it specifically decreased the ability of NP to promote NA segment vRNA synthesis. In addition to NP residue F346, we identified two other adjacent aromatic residues in NP (Y385 & F479) capable of similarly regulating NA gene segment expression, suggesting a larger role for this domain in gene-segment specific regulation. Our findings reveal a new role for NP in selective regulation of viral gene segment replication and demonstrate how the expression patterns of individual viral gene segments can be modulated during adaptation to new host environments.Author summaryInfluenza A virus (IAV) is a respiratory pathogen that remains a significant source of morbidity and mortality. Escape from host immunity or emergence into new host species often requires mutations that modulate the functional activities of the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) which are responsible for virus attachment to and release from host cells, respectively. Maintaining the functional balance between the activities of HA and NA is required for fitness across multiple host systems. Thus, selective modulation of viral gene expression patterns may be a key determinant of viral immune escape and cross-species transmission potential. We identified a novel mechanism by which the viral nucleoprotein (NP) gene can selectively modulate NA segment replication and gene expression through interactions with the segment UTR. Our work highlights an unexpected role for NP in selective regulation of expression from the individual IAV gene segments.
Prevalence and determinants of persistent symptoms after infection with SARS-CoV-2: Protocol for an observational cohort study (LongCOVID-study)
Authors: Mutubuki Elizabeth N. , van der Maaden Tessa , Leung Ka Yin , Wong Albert , Tulen Anna D. , de Bruijn Siméon , Haverman Lotte , Knoop Hans , Franz Eelco , van Hoek Albert Jan , van den Wijngaard Cees C. 
Published: January 2022

AbstractBackgroundA substantial proportion of individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) report persisting symptoms weeks and months following acute infection. Estimates on prevalence vary due to differences in study designs, populations, heterogeneity of symptoms and the way symptoms are measured. Common symptoms include fatigue, cognitive impairment and dyspnea. However, knowledge regarding the nature and risk factors for developing persisting symptoms is still limited. Hence in this study we aim to determine the prevalence, severity, risk factors and impact on quality of life of persisting symptoms in the first year following acute SARS-CoV-2 infection.MethodsThe LongCOVID-study is both a prospective and retrospective cohort study with a one year follow up. Participants aged 5 years and above with self-reported positive or negative tests for SARS-CoV-2 will be included in the study. The primary outcome is the prevalence and severity of persistent symptoms in participants that tested positive for SARS-CoV-2 compared to controls. Symptom severity will be assessed for fatigue using the Checklist Individual Strength (CIS subscale fatigue severity), pain (Rand-36/SF-36 subscale bodily pain), dyspnea (Medical Research Council (mMRC)) and cognitive impairment using the Cognitive Failure Questionnaire (CFQ). Secondary outcomes include loss of health-related quality of life (HRQoL) and risk factors for persisting symptoms following infection with SARS-CoV-2.DiscussionA better understanding regarding the nature of persisting symptoms following SARS-CoV-2 infection will enable better diagnosis, management and will consequently minimize negative consequences on quality of life.
TCF7L2 acts as a molecular switch in midbrain to control mammal vocalization through a transcriptional repression mechanism
Authors: Qi Huihui , Luo Li , Lu Caijing , Chen Runze , Zhou Xianyao , Zhang Xiaohui , Jia Yichang 
Published: January 2022

AbstractVocalization is an essential medium for sexual and social signaling in birds and mammals. Periaqueductal gray (PAG) a conserved midbrain structure is believed to be responsible for innate vocalizations, but its molecular regulation remains largely unknown. Here, through a mouse forward genetic screening we identified one of the key Wnt/ β-catenin effectors TCF7L2/TCF4 controls ultrasonic vocalization (USV) production and syllable complexity during maternal deprivation and sexual encounter. Expression of TCF7L2 in PAG excitatory neurons is necessary for the complex trait, while TCF7L2 loss reduces neuronal gene expressions and synaptic transmission in PAG. TCF7L2-mediated vocal β-catenin-binding domain but dependent of its DNA binding ability. Patient mutations associated with severe speech delay disrupt the transcriptional repression effect of TCF7L2, while mice carrying those mutations display severe USV impairments. Therefore, we conclude that TCF7L2 orchestrates gene expression in midbrain to control vocal production through a transcriptional repression mechanism.