bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harbingers of Aggressive Prostate Cancer: Precision Oncology Case Studies
Authors: Cyrta Joanna , Prandi Davide , Arora Arshi , Hovelson Daniel H. , Sboner Andrea , Rodriguez Antonio , Fedrizzi Tarcisio , Beltran Himisha , Robinson Dan R. , Gopalan Anurandha , True Lawrence , Nelson Peter S. , Robinson Brian D. , Mosquera Juan Miguel , Tomlins Scott A. , Shen Ronglai , Demichelis Francesca , Rubin Mark A. 
Published: December 2021

AbstractPrimary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa.In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intra-tumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (nine patients). Activating AR alterations were seen in eight (67%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only).WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice.Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the “index” primary PCa area.
Emergence of planar cell polarity from the interplay of local interactions and global gradients
Authors: Singh Divyoj , Ramaswamy Sriram , Jolly Mohit Kumar , Rizvi Mohd. Suhail 
Published: December 2021

AbstractPlanar cell polarity (PCP) – tissue-scale alignment of the direction of asymmetric localization of proteins at cell-cell interface – is essential for embryonic development and physiological functions. Abnormalities in PCP can lead to neural tube closure defects and misaligned hair follicles. Decoding the mechanism responsible for PCP establishment and maintenance remains a fundamental open question. While the roles of various molecules – broadly classified into “global” and “local” modules – have been well-studied, their necessity and sufficiency in explaining PCP and connecting their perturbations to experimentally observed patterns has not been examined. Here, we develop a minimal model that captures the proposed features of these modules – a global tissue-level gradient and local asymmetric distribution of protein complexes. Our model suggests that while polarity can emerge without a gradient, the gradient can provide the direction of polarity and maintain PCP robustly in presence of stochastic perturbations. We also recapitulated swirling patterns seen experimentally and features of domineering non-autonomy, using only three free model parameters - protein binding rate, concentration of proteins forming heterodimer across cell boundaries and gradient steepness. We explain how self-stabilizing asymmetric localizations in presence of tissue-level gradient can lead to robust PCP patterns and reveal minimal design principles for a polarized system.
Identifying potential key genes and existing drugs for Multiple sclerosis, Schizophrenia, and Autism- an in silico approach
Authors: Dey Sajal Kumar , Bhowmick Sushmita , Chakraborty Souvik 
Published: December 2021

AbstractNowadays, neurological conditions are a major concern as it not only preys on a patient’s health but also is a huge economic burden that is placed on the patient’s family. The diagnosis and treatment of disease sometimes cause methodological limitations. This is mainly common for individuals who have the signs of MS and schizophrenia (SZ). Patients suffering from multiple sclerosis are more likely to develop schizophrenia. Besides, a significant portion of patients who have been diagnosed with Autism Spectrum Disorder (ASD) later acquire the symptoms of Schizophrenia. In this study, we used bioinformatics tools to determine differentially expressed genes (DEGs) in all these diseases, and then we created a protein-protein interaction network using the online software STRING and identified 15 significant genes with the help of Cytohubba a plug-in tool in Cytoscape, the offline software (version3.8.2). We then used a drug-gene interaction database to conduct a drug-gene interaction study of the 15 hub genes and from there we identified 37 FDA-approved drugs. These findings may provide a new and common therapeutic approach for MS, SZ, and ASD therapy.
Mutated neuronal voltage-gated CaV2.1 channels causing familial hemiplegic migraine 1 increase the susceptibility for cortical spreading depolarization and seizures and worsen outcome after experimental traumatic brain injury
Authors: Terpolilli Nicole A. , Dolp R. , Waehner K. , Schwarzmaier S. M. , Török E. , Todorov Boyan , Ferrari Michel D. , van den Maagdenberg Arn M.J.M. , Plesnila Nikolaus 
Published: December 2021

AbstractPatients suffering from familial hemiplegic migraine type 1 (FHM1) may have a disproportionally severe outcome after head trauma, but the underlying mechanisms are unclear. Hence, we subjected knock-in mice carrying the severer S218L or milder R192Q FHM1 gain-of-function missense mutation in the CACNA1A gene that encodes the α1A subunit of neuronal voltage-gated CaV2.1 (P/Q-type) calcium channels and their wild-type (WT) littermates to experimental traumatic brain injury (TBI) by controlled cortical impact (CCI) and investigated cortical spreading depolarizations (CSDs), lesion volume, brain edema formation, and functional outcome. After TBI, all mutant mice displayed considerably more CSDs and seizures than WT mice, while S218L mutant mice had a substantially higher mortality. Brain edema formation and the resulting increase in intracranial pressure was more pronounced in mutant mice, while only S218L mutant mice had larger lesion volumes and worse functional outcome. Here we show that gain of CaV2.1 channel function worsens histopathological and functional outcome after TBI in mice. This phenotype was associated with a higher number of CSDs, increased seizure activity, and more pronounced brain edema formation. Hence, our results suggest increased susceptibility for CSDs and seizures as potential mechanisms for bad outcome after TBI in FHM1 mutation carriers.
Neural basis for anxiety and anxiety-related physiological responses during a driving situation: An fMRI study
Authors: Sasaoka Takafumi , Harada Tokiko , Sato Daichi , Michida Nanae , Yonezawa Hironobu , Takayama Masatoshi , Nouzawa Takahide , Yamawaki Shigeto 
Published: December 2021

AbstractWhile the exteroceptive and interoceptive prediction of a negative event increases a person’s anxiety in daily life situations, the relationship between the brain mechanism of anxiety and the anxiety-related autonomic response has not been fully understood. In this fMRI study, we examined the neural basis of anxiety and anxiety-related autonomic responses in a daily driving situation. Participants viewed a driving video clip in the first-person perspective. During the video clip, participants were presented with a cue to indicate whether a subsequent crash could occur (attention condition) or not (safe condition). Enhanced activities in the anterior insula, bed nucleus of the stria terminalis, thalamus, and periaqueductal gray, and higher sympathetic nerve responses (pupil dilation and peripheral arterial stiffness) were triggered by the attention condition but not with the safe condition. Autonomic response-related functional connectivity was detected in the visual cortex, cerebellum, brainstem, and MCC/PCC with the right anterior insula and its adjacent regions as seed regions. Thus, the right anterior insula and adjacent regions, in collaboration with other regions play a role in eliciting anxiety based on the prediction of negative events, by mediating anxiety-related autonomic responses according to interoceptive information.
Human ventromedial prefrontal cortex lesions enhance expectation-related pain modulation
Authors: Motzkin JC , Hiser J , Carroll I , Wolf R , Baskaya MK , Koenigs M , Atlas LY 
Published: December 2021

AbstractPain is strongly modulated by expectations and beliefs. Research across species indicates that subregions of the ventromedial prefrontal cortex (VMPFC) play a fundamental role in learning and generating predictions about valued outcomes. Consistent with this overarching framework, neuroimaging studies of experimental pain indicate that VMPFC activation tracks expectations of pain relief and statistically mediates expectation-related reductions in responses to painful stimuli across a distributed pain processing network. However, lesion studies in preclinical models and in humans with refractory chronic pain suggest that VMPFC may play a more general role in representing the affective and motivational qualities of pain that contribute to its strong aversive drive. To test whether VMPFC is necessary for pain processing in general, or instead plays a more specific role in the modulation of pain by expectations, we studied responses to experimental heat pain in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage.All participants underwent quantitative sensory testing (QST) to characterize pain sensitivity, followed by a pain expectancy task. Participants were instructed that auditory cues would be followed by heat calibrated to elicit low or high pain. Following a conditioning phase, each cue was intermittently paired with a single temperature calibrated to elicit moderate pain. We compared ratings of moderate heat stimuli and subjective expectancy ratings as a function of cue to evaluate whether VMPFC lesions impact cue-based expectancy and expectancy effects on pain intensity and unpleasantness. We also analyzed QST measures to evaluate whether VMPFC lesions were associated with overall shifts in pain sensitivity.Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expectations as a function of pain-predictive cues, and stronger cue-based modulation of pain ratings, particularly for ratings of pain unpleasantness. There were no group differences in pain sensitivity, nor in the relationship between pain and autonomic arousal, indicating that the impact of VMPFC lesions is specific to expectancy-based modulation of pain unpleasantness.Our findings suggest that the VMPFC is not essential for basic subjective and physiological responses to painful stimuli. Rather, our findings of significantly enhanced cue- related expectancy effects may suggest that VMPFC plays an important role in updating expectations or integrating sensory information with expectations to guide subjective judgements about pain. Taken together, these results expand our understanding VMPFC’s contribution to pain and highlight the role of VMPFC in integrating cognitive representations with sensory information to yield affective responses.
Repeated genetic adaptation to high altitude in two tropical butterflies
Authors: Montejo-Kovacevich Gabriela , Meier Joana I. , Bacquet Caroline N. , Warren Ian A. , Chan Yingguang Frank , Kucka Marek , Salazar Camilo , Rueda Nicol , Montgomery Stephen H. , McMillan W. Owen , Kozak Krzysztof M. , Nadeau Nicola J. , Martin Simon , Jiggins Chris D. 
Published: December 2021

AbstractRepeated evolution can provide insight into the mechanisms that facilitate adaptation to novel or changing environments. Here we study adaptation to high altitude in two divergent tropical butterflies, H. erato and H. melpomene, which have repeatedly and independently adapted to high elevations on either side of the Andean mountains. We sequenced 518 whole genomes from elevational transects and found many regions under selection at high altitude, with repeated genetic differentiation across multiple replicates, including allopatric comparisons. In contrast, there is little ‘molecular parallelism’ between H. erato and H. melpomene. With a further 85 whole genomes of five close relatives, we find that a large proportion divergent regions have arisen from standing variation and putative adaptive introgression from high-altitude specialist species. Taken together our study supports a key role of standing genetic variation and gene flow from pre-adapted species in promoting parallel genetic local adaptation to the environment.
Evolutionary history of sexual differentiation mechanism in insects
Authors: Chikami Yasuhiko , Okuno Miki , Toyoda Atsushi , Itoh Takehiko , Niimi Teruyuki 
Published: December 2021

AbstractGain of alternative splicing gives rise to functional diversity in proteins and underlies the complexity and diversity of biological aspects. However, it is still not fully understood how alternatively spliced genes develop the functional novelty. To this end, we infer the evolutionary history of the doublesex gene, the key transcriptional factor in the sexual differentiation of arthropods. doublesex is controlled by sex-specific splicing and promotes both male and female differentiation in some holometabolan insects. In contrast, doublesex promotes only male differentiation in some hemimetabolan insects. Here, we investigate ancestral states of doublesex using Thermobia domestica belonging to Zygentoma, the sister group of winged insects. We find that doublesex of T. domestica expresses sex-specific isoforms but is only necessary for male differentiation of sexual morphology. This result ensures the hypothesis that doublesex was initially only used to promote male differentiation during insect evolution. However, T. domestica doublesex has a short female-specific region and upregulates the expression of vitellogenin homologs in females, suggesting that doublesex may have already controlled some aspects of feminization in the common ancestor of winged insects. Reconstruction of the ancestral sequence and prediction of the protein structure show that the female-specific isoform of doublesex has a long C-terminal disordered region in holometabolan insects, but not in non-holometabolan species. We propose that doublesex acquired a female-specific isoform and then underwent a change in the protein motif structure, which became essential for female differentiation in sexual dimorphisms.
Psychometric properties of the Barkin Index of Maternal Functioning with Ethiopian mothers
Authors: Gebeyehu Selamawit , Gizachew Yordanos , Chisa Yilma , Tekabe Beemnt , Trevethan Robert 
Published: December 2021

AbstractBackgroundThe functional status of mothers after childbirth has implications for maternal, child, and family health. There is a lack of adequate reliable and valid instruments in Ethiopia for assessing women’s postpartum functional status.ObjectiveThis study was intended to reveal the psychometric properties of the Barkin Index of Maternal Functioning (BIMF) for assessing Ethiopian mothers’ functional status.MethodStructured interviews were used to obtain BIMF data from 202 women who had a child less than 1 year of age. Descriptive statistics were calculated for the BIMF items; internal consistency was assessed with interitem correlations and coefficient alphas; construct validity was examined through exploratory factor analyses (EFAs) after face and content validities had been confirmed; and test–retest reliability was assessed with intraclass correlation coefficients (ICCs).ResultsNarrow standard deviations and significant skewness and kurtosis characterized most of the individual BIMF items. Most interitem correlations were < |.15| and 13 of the 20 BIMF items did not load satisfactorily on any factor in exploratory factor analyses. Two factors emerged from the remaining items, one with three items and the other with four. Coefficient alphas were .54 for the first of these factors, .48 for the second, and .58 for all 20 items. The ICCs for test– retest reliability were < .40.ConclusionsBIMF data from the sample of Ethiopian women in this study exhibited unusually low levels of variability and high levels of skewness and kurtosis. Furthermore, in the context of this study, the BIMF could not be regarded as reliable either in terms of internal (interitem) consistency or temporal (test–retest) consistency. Researchers using the BIMF in Ethiopian contexts are advised to examine the nature of their data carefully, identify the factor structure of their samples’ data, and consider ways in which the index might be improved, or replaced.
Protocol: Identification and evaluation of critical factors in achieving high and sustained childhood immunization coverage in selected low- and lower-middle income countries
Authors: Bednarczyk Robert A. , Hester Kyra A. , Dixit Sameer M. , Ellis Anna S. , Escoffery Cam , Kilembe William , Micek Katie , Sakas Zoë , Sarr Moussa , Freeman Matthew C. ,   the Vaccine Exemplars Research Consortium
Published: December 2021

AbstractIntroductionIncreases in global childhood vaccine delivery have led to decreases in morbidity from vaccine-preventable diseases. However, these improvements in vaccination have been heterogeneous, with some countries demonstrating greater levels of change and sustainability. Understanding what these high-performing countries have done differently and how their decision-making processes will support targeted improvements in childhood vaccine delivery.Methods and analysisWe studied three countries - Nepal, Senegal, Zambia - with exemplary improvements in coverage between 2000-2018 as part of the Exemplars in Global Health Program. We apply established implementation science frameworks to understand the “how” and “why” underlying improvements in vaccine delivery and coverage. Through mixed methods research we will identify drivers of catalytic change in vaccine coverage and the decision-making process supporting these interventions and activities. Methods include quantitative analysis of available datasets and in-depth interviews and focus groups with key stakeholders in the global, national, and sub-national government and non-governmental organization space, as well as community members and local health delivery system personnel.Ethics and disseminationWorking as a multinational and multidisciplinary team, and under oversight from all partner and national-level (where applicable) institutional review boards, we collect data from participants who provided informed consent. Findings are disseminated through a variety of forms, including peer-reviewed manuscripts related to country-specific case studies and vaccine system domain-specific analyses, presentations to key stakeholders in the global vaccine delivery space, and narrative dissemination on the Exemplars.Health website.Strengths and limitations of this studyThis study is led by a multidisciplinary team and grounded in several theoretical frameworks across disciplines from implementation science to behavioral theory.We utilized a cross cutting, cross-disciplinary, approach, which assessed relevant domains across our selected exemplars countries as well as within the subjects that arise from the data, over a roughly 20-year time horizon.We selected three countries with historically high unvaccinated populations to represent different geographies, cultures, and governments, as well as to highlight regions with historically high unvaccinated populations.We did not study a less successful, or “non-exemplar”, counterfactual country.The research tools identified and explored catalytic events and the implementation of external policies and development of internal policies and systems, with a focus on participants’ current experiences and perceptions of prior activities.
Investigating group-based classes (‘weaning workshops’) to support complementary infant feeding in Irish primary care settings: A cross-sectional survey
Authors: Flannery Caragh , Shea Caroline , O’Brien Yvonne , O’Halloran Joanne , Matvienko-Sikar Karen , Kelly Colette , Toomey Elaine 
Published: December 2021

AbstractObjectiveThis study aims to 1) investigate current practice regarding ‘weaning workshops’ to support complementary infant feeding delivered within Irish primary care, 2) explore the experiences and opinions of community dietitians regarding optimal content and modes of delivery of weaning workshops, and 3) identify the key factors to be considered in the development and implementation of weaning workshops delivered within primary care.DesignCross-sectional surveySettingIrish primary careParticipants47 community-based dietitiansResultsSixteen dietitians reported that workshops were run in their area with variable frequency, with ten reporting that workshops were never run in their area. Participants reported that mostly mothers of medium socioeconomic status attended weaning workshops when infants were aged between 4-7 months, and that feedback from workshop attendees was predominantly positive. Dietitians identified that key factors to be considered in future development and delivery of weaning workshops are 1) workshop characteristics such as content, timing and venue, 2) organisational characteristics such as availability of resources and multidisciplinary involvement, and 3) attendee characteristics such as socioeconomic status.ConclusionsThis study highlights substantial variability regarding provision of weaning workshops in Ireland, and a lack of standardisation regarding the provider, content, and frequency of workshops where workshops are being delivered. The study also provides unique insights into the experiences and opinions of primary care community dietitians regarding the development and delivery of weaning workshops in terms of optimal content and delivery options. These perspectives will make a valuable contribution given the dearth of evidence in this area internationally.
Changes Over Time in COVID-19 Vaccination Inequalities in Eight Large U.S. Cities
Authors: Gaddis S. Michael , Carey Colleen M. , DiRago Nicholas V. 
Published: December 2021

AbstractWe estimate the associations between community socioeconomic composition and changes in COVID-19 vaccination levels in eight large cities at three time points. Between March and April, low SES communities had significantly lower change in percent vaccinated than high SES communities. Between April and May, this difference was not significant. Thus, the large vaccination gap between communities during restricted vaccine eligibility did not narrow when eligibility opened up. The link between COVID-19 vaccination and community disadvantage may lead to a bifurcated recovery where advantaged communities move on from the pandemic more quickly while disadvantaged communities continue to suffer.