bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case report: Biallelic variants in POLR3B gene lead to 4H leukodystrophy from the study of brother and sister
Authors: Bai Hengzhou , Li Dingming , Zheng Yi , Jiang XiaoHui 
Published: August 2022

Introduction:
4H leukodystrophy, one of POLR3-related leukodystrophy, is a rare hereditary brain white matter disease caused by the pathogenic biallelic variations in POLR3A, POLR3B, or POLR1C. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism is mainly presented in patients with 4H leukodystrophy.

Patient concerns:
Here, we reported the brother and the sister with new compound heterozygous (c.1615G>T and c.165-167del) with various degrees of phenotypes including dysbasia, myopia, dental abnormal, and hypogonadotropic hypogonadism.

Diagnosis:
The brother and sister were diagnosed with 4H leukodystrophy.

Interventions:
Gonadotrophins treatment of the brother could significantly improve the development of secondary sexual characteristics and genitalia.

Outcomes:
This study showed that the same genotype of POLR3B may have variable clinical phenotypes in the brother and sister.

Conclusion:
The exploration of molecular functions and genetic counseling are crucial for further diagnosis and treatment of POLR3-related leukodystrophy.
Depressive Symptoms and Caregiving Intensity Before and After Onset of Dementia in Partners
Authors: Harris Melissa L. , Errickson Josh , Ha Jinkyung , Hoffman Geoffrey J. 
Published: August 2022

Background:
Caring for a partner with dementia poses significant emotional burden and high care demands, but changes in impacts before and after dementia onset is unclear.

Objective:
Examine changes in depressive symptoms and hours of care provided by caregivers through the course of their partners’ cognitive decline.

Methods:
Retrospective, observational study using household survey data from 2000–2016 Health and Retirement Study and count models to evaluate older individuals’ (ages ≥51 y) depressive symptoms (measured using the shortened Center for Epidemiologic Studies Depression Scale) and weekly caregiving in the 10 years before and after their partners’ dementia onset (identified using Telephone Interview Cognitive Status screening). Relationships were examined overall and by sex and race.

Results:
We identified 8298 observations for 1836 older caregivers whose partners developed dementia. From before to after partners’ dementia onset, caregivers’ mean (SD) depressive symptoms increased from 1.4 (1.9) to 1.9 (2.1) (P<0.001) and weekly caregiving increased from 4.4 (19.7) to 20.8 (44.1) (P<0.001) hours. Depressive symptoms and caregiving hours were higher for women compared with men. Depressive symptoms were higher for Blacks compared with Whites, while caregiving hours were higher for Whites. The expected count of caregivers’ depressive symptoms and caregiving hours increased by 3% (P<0.001) and 9% (P=0.001) before partners’ dementia onset and decreased by 2% (P<0.001) and 1% (P=0.63) following partners’ dementia onset. No differences observed by sex or race.

Discussion:
Depressive symptoms and instrumental burdens for caregivers increase substantially before the onset of dementia in partners. Early referral to specialty services is critical.
NUTM1-rearranged Carcinoma of the Thyroid
Authors: Barletta Justine A. , Gilday Steven D. , Afkhami Michelle , Bell Diana , Bocklage Theresa , Boisselier Pierre , Chau Nicole G. , Cipriani Nicole A. , Costes-Martineau Valerie , Ghossein Ronald A. , Hertzler Hans J. , Kramer Alan M. , Limaye Sewanti , Lopez Carlos A. , Ng Tony L. , Weissferdt Annikka , Xu Bin , Zhang Songlin , French Christopher A. 
Published: August 2022

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non–NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell–derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non–NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non–NC-like morphology (P=0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3-NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.
Effect of Pranayama on Perceived Stress, Well Being and Quality of Life of Frontline Healthcare Professionals on Covid-19 Duty: A Quasi-Randomized Clinical Trial
Authors: Sarwal Rakesh , Dhamija Rajinder K. , Jain Khushbu , Basavaraddi Ishwar V. 
Published: August 2022

ABSTRACTBackgroundThe COVID-19 pandemic has brought unparalleled challenges for health systems worldwide, the impact of which has also been borne by the Healthcare Professionals (HCPs). Numerous studies have revealed the positive effects of Pranayama and Meditation on mental health. The effect of Pranayama in improving mental health of frontline HCP exposed to Covid-19 patients has not been studied.Aim & ObjectiveThis quasi-randomized clinical trial was done to study the effect of especially designed Pranayama protocol on perceived stress, wellbeing and quality of life of frontline health care professionals who were exposed to COVID-19 patients in hospital settings.MethodologyThis study was done with 280 frontline healthcare professionals (HCP) assigned duties with COVID-19 patients during September-November, 2020 in 5 government hospitals and COVID-19 quarantine/isolation centres in New Delhi, India. The HCPs were first assessed for COVID-19 infection in the past using antibody test, and only those found negative were recruited. The enrolled respondents were randomly assigned to two arms – an intervention arm where there were to practice 28-day Pranayama module (morning and evening sessions) under supervision of a trainer, and a Control arm where the HCPs continued routine physical activity (walking, jogging etc.). Baseline and end-line (total: 250 HCPs) Psychological parameters of Perceived Stress, Well Being and Quality of Life were collected through self-reported questionnaires.ResultsThe intervention (HCPs: 123) and control (HCPs: 127) groups (Total: 250) were comparable in their demographic profile and baseline characteristics. Intervention with Pranayama module led to a significant reduction (Mean diff: -2.46; P-value: 0.028) in perceived stress score in the intervention group compared to the control group. The wellbeing index in Interventional group intervention showed a non-significant increase. The WHO Quality-of-life score increased in the intervention group as compared to the controls (mean difference 2.78, p-value: 0.17). Of its four components, the one for Psychological domain increased significantly (mean diff: 1.52, P-value: 0.019), while those for Physical domain and Environmental domains increased (mean diff: 0.64, P-value: 0.29 and mean diff: 0.68, p-value: 0.48) though not statistical significantly.CconclusionThe intervention of twice daily practice of the Pranayama module for 28 days in frontline HCPs performing COVID-19 duties had a noteworthy effect in lowering Perceived Stress, improving perceived Quality of life, especially its Psychological domains as measured through standardized questionnaires.CTRI NumberCTRI/2020/07/026667
MOLECULAR INSIGHTS INTO BINDING BEHAVIOUR OF LAMOTRIGINE WITH INITIATION FACTOR 2 PROTEIN: AN INTEGRATED COMPUTATIONAL STUDIES
Authors: Arora Smriti , Patra Jeevan 
Published: August 2022

CONSPECTUSAimsThe ribosomal protein (r-protein) of bacteria is composed of 2.6 MDa ribonucleoproteins of the 30S and 50S subunits, which are essential elements for protein translation. The translational initiation step is an intensive regulated multi-step reaction in protein biosynthesis. During bacterial protein synthesis, the correct reading frame of the mRNA defines when the initiator fMet-tRNAiMet binds to the start codon AUG at the P-site of the 30S subunit. The formation of the P-site of the 30S subunit initiation complex (30S-IC) is governed by three ubiquitous initiation factors (IFs) such as IF1, IF2, and IF3. IF2 protein is an essential player that plays during the last stage of the initiation process. Earlier, Stokes and his co-workers studied chemicals probes using 30K diverse drugs that induced cold-sensitive growth inhibition in the bacterium. The assay studies revealed, Lamotrigine (LTG) effectively binds at domain II of IF2 protein. In our research, we took an attempt in identifying promising active residues that could responsible for anti-bacterial bioactivity with help of computational studies.Computational MethodsIn the present study, initially, we performed C-α backbone alignment with the retrieved IF2 chain from AlphaFold. Further, we utilized SiteMap and CastP for the identification of plausible active binding sites. Further, we bound LTG with the designated domain(s) of IF2 protein and studied its binding affinity potential with help of adaptive molecular dynamics simulations at atomic levels using Desmond.Key FindingsOur research findings have shown accurate results and we could able to prove the assertion in contrast with the findings of Stokes and his co-workers where the LTG bind at domain II of IF2 protein. The key interacting residue Glu179 was revealed to have strong hydrogen bonding contacts with LTG at the sub-nanomolar range. In addition, we predicted the alternative promising site I Further, we gained in-depth analysis for studying multiple sites, to understand the synergism inhibitory activity. Promisingly, LTG could be able to bound with at Site 1 showing better affinity over the proposed domain II and other predicted sites. The adaptive molecular dynamics studies confirmed the promising active residuesSignificanceThe binding site predictions approach provides an insight for further development of anti-bacterial therapeutics that might helpful for bacteria disease management and exhibiting inhibitory activity against various strains.
Utah Array Characterization and Histological Analysis of a Multi-Year Implant in Non-Human Primate Motor and Sensory Cortices
Authors: Patel Paras R. , Welle Elissa J. , Letner Joseph G. , Shen Hao , Bullard Autumn J. , Caldwell Ciara M. , Vega-Medina Alexis , Richie Julianna M. , Thayer Hope E. , Patil Parag G. , Cai Dawen , Chestek Cynthia A. 
Published: August 2022

AbstractThe Utah array is widely used in both clinical studies and neuroscience. It has a strong track record of safety. However, it is also known that implanted electrodes promote the formation of scar tissue in the immediate vicinity of the electrodes, which negatively impacts the ability to record neural waveforms. This scarring response has been primarily studied in rats and mice, which may have a very different response than primate brain. Here, we present a rare nonhuman primate histological dataset (n=1 rhesus macaque) obtained 848 and 590 days after implantation in two brain hemispheres. For 2 of 4 arrays that remained within the cortex, NeuN was used to stain for neuron somata at 3 different electrode depths. Images were filtered and denoised, with neurons then counted in the vicinity of the arrays as well as a nearby section of control tissue. Additionally, 3 of 4 arrays were imaged with a scanning electrode microscope (SEM) to evaluate any materials damage that might be present. Overall, we found a 63% percent reduction in the number of neurons surrounding the electrode compared to control areas. In terms of materials, the arrays remained largely intact with metal and Parylene C present, though tip breakage and cracks were observed on many electrodes. Overall, these results suggest that the tissue response in the nonhuman primate brain shows similar neuron loss to previous studies using rodents. Electrode improvements, for example using smaller or softer probes, may therefore substantially increase the neuronal recording yield in primate cortex.
Auditory accessory stimulus boosts pupil-linked arousal and reduces choice bias
Authors: Bruel B.M. , Katopodis V.G. , de Vries R. , Donner T.H. , McGinley M.J. , de Gee J.W. 
Published: August 2022

AbstractRecent work indicates that pupil-linked phasic arousal signals reduce the impact of prior expectations and biases on decision formation. It has remained unclear whether phasic arousal (i) causes the bias reduction, if (ii) choosing against one’s bias causes phasic arousal, or if (iii) a third variable is driving both. Here, using an auditory accessory stimulus, we found evidence for the first scenario: on accessory stimulus vs normal trials, pupil-linked phasic arousal was robustly elevated and choice bias was reduced. With computational modeling of behavior, we established that the bias reduction was not due to a change in response caution (i.e., speed-accuracy tradeoff), but due to a change in a bias in the accumulation of evidence leading up to a choice. Thus, pupil-linked phasic arousal shapes choice behavior.
An educated guess: how coral reef fish make decisions under uncertainty
Authors: Newport Cait , Sibeaux Adelaide , Wallis Guy , Wilkins Lucas , de Perera Theresa Burt 
Published: August 2022

ABSTRACTMaking informed decisions is fundamental to intelligent life and is crucial to survival. The problem many organisms face, is how to make optimal decisions in the face of incomplete, unreliable, or conflicting information. In many aquatic environments, fish use visual information to guide key behaviours, but the environment itself can alter or mask the very signals they rely on. Here, we asked how a highly visual species,Rhinecanthus aculeatus, responds to a learned discrimination task as signal reliability decreases, and whether probabilistic information gained during previous experience can be incorporated into their decision strategy. Fish were first trained to select a target (dark grey circle) from three distractors (light grey circles). In the first experiment, the target was more likely to appear in one of four possible stimulus positions. In the second experiment, the target appeared in all positions equally. In a series of trials, the difference in brightness between the target and distractors was reduced until all four stimuli were identical. We found that target selection accuracy decreased with decreasing target and distractor disparity. However, in Experiment 1 where the target was more likely to be in one position, fish increasingly selected stimuli in the biased position as target selection accuracy decreased, but not in Experiment 2. These results demonstrate 1) that fish learned more than a simple select/avoid rule based on stimulus brightness, but also integrated information (stimulus position) that could be considered ancillary to the primary task. 2) Fish can learn probability distributions and apply this knowledge as uncertainty increases, ultimately increasing the overall frequency of correct choices. Our results reveal that probabilistic decision rules can be used by fish when visual information is unreliable, indicating a possible mechanism for decision making given the inherent noise in incoming sensory information.
Cryptic functional diversity in ant tandem runs
Authors: Mizumoto Nobuaki , Tanaka Yasunari , Valentini Gabriele , Richardson Thomas O. , Annagiri Sumana , Pratt Stephen C , Shimoji Hiroyuki 
Published: August 2022

AbstractAnts have evolved diverse recruitment methods to guide colony members to valuable resources, such as food or nest sites. One of these methods, tandem running, consists of an informed leader directly guiding a naive follower every step of the way from nest to resource. Although this behavior appears superficially similar in the different ant taxa in which it has independently evolved, this similarity could conceal underlying functional and mechanistic differences. Here we present a combined network and information-theoretic analysis, which reveals fundamental differences in the tandem recruitment between two distantly related ant genera, Temnothorax and Diacamma. Temnothorax uses tandem running to recruit additional recruiters, whereas Diacamma uses it principally to move the passive majority of the colony, a task that Temnothorax accomplishes with a different behavior, social carrying. Accordingly, the structure of the tandem run recruitment networks of Diacamma was different from those of Temnothorax, with Diacamma networks more closely resembling the social carrying networks of Temnothorax. Furthermore, an information-theoretic analysis of the spatial trajectories of leaders and followers revealed that Diacamma tandem runs lack bidirectional information flow, the signature of route-learning in Temnothorax tandem runs. These results suggest that Diacamma uses tandem runs not to share information, but to transport nestmates. By quantifying the cryptic diversity of communication behavior, this study increases the resolution of our understanding of animal societies.
Estimating Treatment Effects for Time-to-Treatment Antibiotic Stewardship in Sepsis
Authors: Liu Ruoqi , Buck Katherine H. , Caterino Jeffrey M. , Zhang Ping 
Published: August 2022

ABSTRACTSepsis is a life-threatening condition with high in-hospital mortality rate. The timing of antibiotic (ATB) administration poses a critical problem for sepsis management. Existing work studying antibiotic timing either ignores the temporality of the observational data or the heterogeneity of the treatment effects. In this paper, we propose a novel method to estimate TreatmenT effects for Time-to-Treatment antibiotic stewardship in sepsis (T4). T4 estimates individual treatment effects (ITEs) by recurrently encoding temporal and static variables as potential confounders, and then decoding the outcomes under different treatment sequences. We propose a mini-batch balancing matching that mimics the randomized controlled trial process to adjust the confounding. The model achieves interpretability through a global-level attention mechanism and a variable-level importance examination. Meanwhile, we incorporate T4 with uncertainty quantification to help prevent overconfident recommendations. We demonstrate that T4 can identify effective treatment timing with estimated ITEs for antibiotic stewardship on two real-world datasets. Moreover, comprehensive experiments on a synthetic dataset exhibit the outstanding performance of T4 compared to the state-of-the-art models on ITE estimation.
Gli2andGli3Regulate Horizontal Basal Cell-Mediated Regeneration of the Olfactory Epithelium
Authors: Shirazyan Anna , Park Haeyoung , Joiner Ariell M. , Ra Justine , Kim Melissa S. , Kumari Archana , Franks Nicole E. , Peng Tien , Bradley Robert K. , Mistretta Charlotte M. , Dlugosz Andrzej A. , Allen Benjamin L. 
Published: August 2022

SummaryThe olfactory epithelium (OE) is a specialized neuroepithelium that is replenished by two stem cell populations: globose basal cells (GBCs) and horizontal basal cells (HBCs). Previous work indicated that HBCs contain primary cilia, organelles that mediate Hedgehog (HH) pathway activity. However, a role for HH signaling in HBCs has not been investigated. We find that GLI2 and GLI3, transcriptional effectors of the HH pathway, are expressed in HBCs in the adult OE and that their expression expands following injury. Further,Gli2-expressing descendants contribute to all major OE cell types during OE regeneration. HBC-specific expression of constitutively active GLI2 drives inappropriate HBC proliferation, alters HBC identity, and culminates in a failure of HBCs to differentiate into olfactory sensory neurons (OSNs) following injury. HBC- specific deletion of endogenousGli2andGli3results in decreased HBCs and OSNs following OE injury. These data identify GLI2 and GLI3 as key regulators of HBC-mediated OE regeneration.
Evolution within a given virulence phenotype (pathotype) is driven by changes in aggressiveness: a case study of French wheat leaf rust populations
Authors: Fontyn Cécilia , Meyer Kevin JG , Boixel Anne-Lise , Delestre Ghislain , Piaget Emma , Picard Corentin , Suffert Frédéric , Marcel Thierry C , Goyeau Henriette 
Published: August 2022

ABSTRACTPlant pathogens are constantly evolving and adapting to their environment, including their host. Virulence alleles emerge, and then increase, and sometimes decrease in frequency within pathogen populations in response to the fluctuating selection pressures imposed by the deployment of resistance genes. In some cases, these strong selection pressures cannot fully explain the evolution observed in pathogen populations. A previous study on the French population ofPuccinia triticina, the causal agent of wheat leaf rust, showed that two major pathotypes — groups of isolates with a particular combination of virulences — predominated but then declined over the 2005-2016 period. The relative dynamics and the domination of these two pathotypes — 166 317 0 and 106 314 0 —, relative to the other pathotypes present in the population at a low frequency although compatible, i.e. virulent on several varieties deployed, could not be explained solely by the frequency ofLrgenes in the landscape. Within these two pathotypes, we identified two main genotypes that emerged in succession. We assessed three components of aggressiveness — infection efficiency, latency period and sporulation capacity — for 44 isolates representative of the fourP. triticinapathotype-genotype combinations. We showed, for both pathotypes, that the more recent genotypes were more aggressive than the older ones. Our findings were highly consistent for the various components of aggressiveness for pathotype 166 317 0 grown on Michigan Amber — a ‘naive’ cultivar never grown in the landscape — or on Apache — a ‘neutral’ cultivar, which does not affect the pathotype frequency in the landscape and therefore was postulated to have no or minor selection effect on the population composition. For pathotype 106 314 0, the most recent genotype had a shorter latency period on several of the cultivars most frequently grown in the landscape, but not on ‘neutral’ and ‘naive’ cultivars. We conclude that the quantitative components of aggressiveness can be significant drivers of evolution in pathogen populations. A gain in aggressiveness stopped the decline in frequency of a pathotype, and subsequently allowed an increase in frequency of this pathotype in the pathogen population, providing evidence that adaptation to a changing varietal landscape not only affects virulence but can also lead to changes in aggressiveness.