bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acis-regulatory sequence of the wing selector gene,vestigial, drives the evolution of scaling relationships inDrosophilaspecies
Authors: Farfán-Pira Keity J. , Martínez-Cuevas Teresa I. , Evans Timothy A. , Nahmad Marcos 
Published: June 2022

AbstractScaling between specific organs and overall body size has long fascinated biologists because they are a primary mechanism through which organismal shapes evolve. Yet, the genetic mechanisms that underlie the evolution of allometries remain elusive. Here we measured wings and tibia lengths in fourDrosophilaspecies (D. melanogaster, D. simulans, D. ananassae, andD. virilis) and show that the first three of them follow a single evolutionary allometry. However,D. virilisexhibits a divergent wing-to-tibia allometry due to a dramatic underscaling of their wings with respect to their bodies compared to the other species. We asked whether the evolution of this scaling relationship could be explained by changes in a specificcis-regulatory regulatory region of the wing selector gene,vestigial(vg), whose function is broadly conserved in insects and its expression pattern determines wing size inD. melanogaster. To test this hypothesis directly, we used CRISPR/Cas9 to replace the DNA sequence of the predicted Quadrant Enhancer (vgQE) fromD. virilisfor the correspondingvgQEsequence in the genome ofD. melanogaster. Strikingly, we discovered thatD. melanogasterflies carrying theD. virilis vgQEsequence have wings that are much smaller with respect to controls, partially rescuing the wing-to-tibia ratio observed inD. virilis. Our results show that thiscis-regulatory element inD. viriliscontributes to the underscaling of wings in this species. This provides evidence that scaling relationships may be unconstrained and may evolve gradually through genetic variations incis-regulatory elements.Summary statementUsing CRISPR/Cas9 replacement of acis-regulatory element, this study suggests that changes within thevestigialQuadrant Enhancer sequence are responsible for the evolution of wing allometries inDrosophilaspecies.
Neural circuits underlying habituation of visually evoked escape behaviors in larval zebrafish
Authors: Fotowat Haleh , Engert Florian 
Published: June 2022

AbstractLarval zebrafish that are exposed repeatedly to dark looming stimuli will quickly habituate to these aversive signals and cease to respond with their stereotypical escape swims.A dark looming stimulus can be separated into two independent components: one that is characterized by an overall spatial expansion, where overall luminance is maintained at the same level, and a second, that represents an overall dimming within the whole visual field in the absence of any motion energy. Using specific stimulation patterns that isolate these independent components, we first extracted the behavioral algorithms that dictate how these separate information channels interact with each other and across the two eyes during the habituation process. Concurrent brain wide imaging experiments then permitted the construction of circuit models that suggest the existence of three separate neural pathways. The first is a looming channel which responds specifically to concentrically expanding edges and relays that information to the brain stem escape network to generate directed escapes.The second is a dimming specific channel that serves to support and amplify the looming pathway. While the looming channel operates in a purely monocular fashion where stimuli are relayed exclusively to the contralateral hemisphere, dimming responses are processed in both monocular and binocular pathways. Finally, we identify a third, separate and largely monocular, dimming channel that appears to specifically inhibit escape responses when activated. We propose that, unlike the first two channels, this third channel is under strong contextual modulation and that it is primarily responsible for the incremental silencing of successive dark looming evoked escapes.
Generation of functional hepatocytes by forward programming with nuclear receptors
Authors: Tomaz Rute A. , Zacharis Ekaterini D. , Bachinger Fabian , Wurmser Annabelle , Yamamoto Daniel , Petrus-Reurer Sandra , Morell Carola M. , Dziedzicka Dominika , Wesley Brandon T. , Geti Imbisaat , Segeritz Charis-Patricia , de Brito Miguel Cardoso , Chhatriwala Mariya , Ortmann Daniel , Saeb-Parsy Kourosh , Vallier Ludovic 
Published: June 2022

AbstractProduction of large quantities of hepatocytes remains a major challenge for a number of clinical applications in the biomedical field. Directed differentiation of human pluripotent stem cells (hPSC) into hepatocyte-like cells (HLCs) provides an advantageous solution and a number of protocols have been developed for this purpose. However, these methods usually follow different steps of liver development in vitro which is time consuming and requires complex culture conditions. In addition, HLCs lack the full repertoire of functionalities characterising primary hepatocytes. Here, we explore the interest of forward programming to generate hepatocytes from hPSCs and to bypass these limitations. This approach relies on the overexpression of 3 hepatocyte nuclear factors (HNF1A, HNF6 and FOXA3) in combination with different nuclear receptors expressed in the adult liver using the OPTi-OX platform. Forward programming allows for the rapid production of hepatocytes (FoP-Heps) with functional characteristics using a simplified process. We also uncovered that the overexpression of nuclear receptors such as RORc can enhance specific functionalities of FoP-Heps thereby validating its role in lipid/glucose metabolism. Together, our results show that forward programming could offer a versatile alternative to direct differentiation for generating hepatocytes in vitro.
The Vacc-SeqQC Project: Benchmarking RNA-Seq for Clinical Vaccine Studies
Authors: Goll Johannes B. , Bosinger Steven E. , Jensen Travis L. , Walum Hasse , Grimes Tyler , Tharp Gregory D. , Natrajan Muktha S , Blazevic Azra , Head Rich , Gelber Casey E. , Patel Nirav B. , Sanz Patrick , Rouphael Nadine G. , Anderson Evan J. , Mulligan Mark J. , Hoft Daniel F 
Published: June 2022

AbstractOver the last decade, the field of systems vaccinology has emerged, in which high throughput transcriptomics and other omics assays are used to probe changes of the innate and adaptive immune system in response to vaccination. RNA-Seq technology has matured in recent years and is now widely deployed for transcriptional analysis of clinical specimens. The goal of this study was to benchmark technical parameters of RNA-Seq in the context of a multi-site, double-blind randomized clinical trial using primary patient samples. We collected longitudinal peripheral blood mononuclear cell (PBMC) samples from 10 subjects after vaccination with a live attenuated Francisella tularensis vaccine and performed RNA-Seq at two different sites using aliquots from the same sample to generate two large-scale replicate datasets. We evaluated the impact of: (i) filtering lowly-expressed genes, (ii) using external RNA controls, (iii) fold change and false discovery rate (FDR) filtering, (iv) read length, and (v) sequencing depth on differential expressed genes (DEGs) concordance between replicate datasets. Using synthetic mRNA spike-ins, we developed a method for empirically establishing minimal read-count thresholds for maintaining fold change accuracy on a per-experiment basis. We defined a reference PBMC transcriptome by pooling sequence data, and established the impact of read depth and gene filtering on transcript representation. Lastly, we modeled statistical power to detect DE genes for a range of sample sizes, effect sizes, and coverage depths. The results from this study provide RNA sequencing benchmarks and guidelines for planning future similar vaccine studies.
Development of 5-FU-modified tumor suppressor microRNAs as a platform for novel microRNA-based cancer therapeutics
Authors: Yuen John G. , Fesler Andrew , Hwang Ga-Ram , Chen Lan-Bo , Ju Jingfang 
Published: June 2022

AbstractMicroRNA (miRNAs) are pleiotropic post-transcriptional modulators of gene expression. Its inherently pleiotropic nature make miRNAs strong candidates for the development of cancer therapeutics, yet despite its potential, there remains a challenge to deliver nucleic acid-based therapies into cancer cells. We developed a novel approach to modify miRNAs by replacing the uracil bases with 5-fluorouracil (5-FU) in the guide strand of tumor suppressor miRNAs, thereby combining the therapeutic effect of 5-FU with tumor suppressive effect of miRNAs to create a potent, multi-targeted therapeutic molecule without altering its native RNA interference (RNAi) function. To demonstrate the general applicability of this approach to other tumor suppressive miRNAs, we screened a panel of 12 novel miRNA mimetics in several cancer types including leukemia, breast, gastric, lung, and pancreatic cancer. Our results show that 5-FU-modified miRNA mimetics have increased potency (low nM range) in inhibiting cancer cell proliferation and that these mimetics can be delivered into cancer cells without delivery vehicle both in vitro and in vivo, thus representing significant advancements in the development of therapeutic miRNAs for cancer. This work demonstrates the potential of fluoropyrimidine modifications that can be broadly applicable and may serve as a platform technology for future miRNA and nucleic acid-based therapeutics.
Time-varying hierarchical core voxels disclosed by k-core percolation on dynamic inter-voxel connectivity resting-state fMRI
Authors: Huh Youngmin , Kang Yeon Koo , Whi Wonseok , Lee Hyekyoung , Kang Hyejin , Lee Dong Soo 
Published: June 2022

Abstractk-core percolation on the scale-free static brain connectivity revealed hierarchical structure of inter-voxel correlations, which was successfully visualized by hyperbolic disc embedding on resting-state fMRI. In static study, flagplots and brain rendered kmax-core display showed the changes of hierarchical structures of voxels belonging to functional independent components (IC). In this dynamic sliding-window study, temporal progress of hierarchical structure of voxels were investigated in individuals and in sessions of an individual. kmax-core and coreness k values characterizing time-varying core voxels were visualized on animated stacked-histogram/flagplots and animated brain-rendered images. Resting-state fMRI of Human Connectome Project and of Kirby weekly revealed the slow progress and multiple abrupt state transitions of the voxels of coreness k and at the uppermost hierarchy, representing their correlative time-varying mental states in individuals and in sessions. We suggest this characteristic core voxels-IC compositions on dynamic study fingerprint the time-varying resting states of human minds.One Sentence SummaryDynamic state transitions of hierarchical functional inter-voxel connectivity implied time-varying mental states at rest on fMRI
Electrophysiological properties of neurons in the intermediate thoracolumbar spinal cord mediating proprioception
Authors: Espinosa Felipe , Pop Iliodora V. , Lai Helen C. 
Published: June 2022

AbstractAnimals must know where their body is in relationship to their environment to move appropriately. Proprioception, the sense of limb and body position, is required to produce feedforward predictions of future movement as well as provide feedback information during movement to update the system. How proprioception is processed at the level of the spinal cord is not well understood. Most work has focused on Clarke’s column (CC) neurons, a component of the dorsal spinocerebellar tract (DSCT). CC neurons receive hindlimb proprioceptive information and send it directly to the cerebellum with no axon collaterals to other neurons in the spinal cord. In contrast to CC neurons, we previously found that a subset of thoracolumbar Atoh1-lineage neurons also receives proprioceptive afferent inputs, but project locally within the spinal cord including synapsing on motor neurons. We set out to understand how CC and Atoh1-lineage neurons in the thoracolumbar spinal cord respond to electrical activity. Using in vitro acute spinal cord slices and whole-cell patch clamp, we characterized the passive and active electrical properties of CC and thoracolumbar Atoh1-lineage neurons. We find that most CC neurons increase their action potential firing frequency linearly upon increased current injection up to high frequencies likely due to a hyperpolarization-activated current (Ih). In contrast, most Atoh1-lineage neurons do not have an Ih current and therefore, their firing frequency fades with increasing current injection. Interestingly, although Atoh1-lineage neurons are classically subdivided into a contralaterally-projecting Medial and ipsilaterally-projecting Lateral population, we find no obvious electrophysiological signatures that could distinguish these spatially distinct populations. Finally, we set out to determine the organization of the inputs to CC and Atoh1-lineage neurons. In a hemisected spinal cord preparation, while recording from neurons in the lower thoracic to upper lumbar segments, we find that CC neurons receive low threshold inputs (proprioceptive or low threshold mechanoreceptor) from lumbar 2 to 4 dorsal roots, while Atoh1-lineage Medial neurons do not. This raises the possibility that Atoh1-lineage Medial neurons receive proprioceptive inputs from more local dorsal roots. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization even though they are both reported to receive proprioceptive information and are in close proximity in lamina V-VII of the thoracolumbar spinal cord.
The impact of rare protein coding genetic variation on adult cognitive function
Authors: Chen Chia-Yen , Tian Ruoyu , Ge Tian , Lam Max , Sanchez-Andrade Gabriela , Singh Tarjinder , Urpa Lea , Liu Jimmy Z. , Sanderson Mark , Rowley Christine , Ironfield Holly , Fang Terry ,   Biogen Biobank Team,   the SUPER-Finland study,   the Northern Finland Intellectual Disability study, Daly Mark , Palotie Aarno , Tsai Ellen A. , Huang Hailiang , Hurles Matthew E. , Gerety Sebastian S. , Lencz Todd , Runz Heiko 
Published: June 2022

AbstractCompelling evidence suggests that cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein coding variants impact cognitive function in the adult population (N=485,930). We identify eight genes associated with adult cognitive function through rare coding variants with large effects. We demonstrate how the dosage of a single gene, KDM5B, may determine the variability of cognitive, behavioral, and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our findings uncover a contribution of rare coding variants to cognitive function and highlight that the spectrum of cognitive function in the normal adult population is influenced by the action of single genes.
Development and implementation of optimized endogenous contrast sequences for delineation in adaptive radiotherapy on a 1.5T MR-Linear-accelerator (MR-Linac): A prospective R-IDEAL Stage 0-2a quantitative/qualitative evaluation of in vivo site-specific quality-assurance using a 3D T2 fat-suppressed platform for head and neck cancer
Authors: Salzillo Travis C. , Dresner M. Alex , Way Ashley , Wahid Kareem A. , McDonald Brigid A. , Mulder Sam , Naser Mohamed A. , He Renjie , Ding Yao , Yoder Alison , Ahmed Sara , Corrigan Kelsey L. , Manzar Gohar S. , Andring Lauren , Pinnix Chelsea , Stafford R. Jason , Mohamed Abdallah S.R. , Christodouleas John , Wang Jihong , Fuller Clifton David 
Published: June 2022

AbstractPurposeIn order to improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T MR-Linac, 3D fat-suppressed T2-weighted MRI sequences were developed and optimized.MethodsAfter initial testing of fat suppression techniques, SPectral Attenuated Inversion Recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a non-suppressed T2-weighted sequence were acquired on five HNC patients on the Unity MR-Linac. The primary tumor, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated by five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences based on a combination of qualitative and quantitative metrics.ResultsSequences were analyzed for signal-to-noise (SNR), contrast-to-noise (CNR) compared to fat and muscle, conspicuity, pairwise distance metrics, segmentor assessment, and MR physicist assessment. From this analysis, the non-suppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but was superior for the pterygoid muscles. Two SPAIR sequences consistently received the highest scores among the analysis categories and are recommended for use to Unity MR-Linac users for HNC radiotherapy treatment planning.ConclusionsTwo deliverables resulted from this study. First, an optimized 3D fat-suppressed T2-weighted sequence was developed that can be disseminated to Unity MR-Linac users. Second, a robust image quality analysis process pathway, used to objectively score the various SPAIR sequences, was developed and can be customized and generalized to any image quality optimization. Improved segmentation accuracy with the proposed SPAIR sequence can potentially lead to improved treatment outcomes and reduced toxicity by maximizing target coverage and minimizing organ-at-risk exposure.
Shared genetic architecture between mental health and the brain functional connectome in the UK Biobank
Authors: Roelfs Daniel , Frei Oleksandr , van der Meer Dennis , Tissink Elleke , Shadrin Alexey , Alnæs Dag , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias 
Published: June 2022

AbstractPsychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30.701 participants aged 45-82 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular synaptic processes. These findings provide further genetic evidence of an association between brain function and mental health traits in the population.
Hand washing at critical times and associated factors among mothers/caregivers of under-five children in Nefas Silk Lafto Sub-City, Addis Ababa, Ethiopia, 2019: Facility based cross-sectional study
Authors: Wana Ermias Wabeto , Mengesha Nardos Anbese 
Published: June 2022

AbstractBackgroundHand washing is the simplest, most affordable and effective means of limiting spread of infections. It has especial importance for children because they are more susceptible to infections acquired from unwashed hands. Despite increasing efforts to improve hand washing at critical times, mothers/caregivers of under-five children fail to practice; but, the reason is unclear. Thus, this study was aimed to identify the magnitude and factors associated with hand washing at critical times among mothers/caregivers of under-five children.MethodsAn institution based cross-sectional study was conducted in Nefas Silk Lafto Sub-City by April 2019, and 312 mothers/caregivers were participated. The data were collected by interviewing mothers, entered and analyzed with statistical package for social science 20 (SPSS-20). The findings were presented with crude odds ratios (COR) and Adjusted Odds Ratios (AOR) with their respective 95% confidence intervals (CI). A P-value less than 0.05 was used statistical significance level.Results232 (74.4%; 95% CI [69.6%-79.2%]) mothers/caregivers washed their hands at critical times. Illiterate mothers had 66% reduced (AOR= 0.34; 95%CI [0.17-0.69]) odds of washing hands at critical times than literate mothers. Mothers who did not own tap water in their back yard had 62% (AOR= 0.38; 95%CI [0.18-0.80]) reduced odds of hand washing at critical times than their counterparts. As compared to the mothers from the poorest households, those from middle, richer and the richest households had 4.56 (AOR= 4.56; 95%CI [1.84-11.33]), 5.61 (AOR= 5.61; 95%CI [2.11-15.30]) and 6.14 (AOR= 6.14; 95%CI [2.24-16.72]) times increased likelihood of washing hands at critical times.ConclusionThree fourth of mothers practiced hand washing at critical times, and improving maternal literacy, household economy and availability of water source in backyard are needed to maintain and enhance the practice.
Rapid progression to death after hepatocellular carcinoma diagnosis particularly among persons with advanced HIV disease in Kampala, Uganda
Authors: Nsibirwa Sara K. , Aizire Jim , Thomas David L. , Ocama Ponsiano , Kirk Gregory D. 
Published: June 2022

AbstractBackgroundHIV infection is associated with more rapid progression of some comorbidities. This study assessed the impact of HIV-infection where the presentation and outcome of HCC was different in persons living with HIV (PLWH) compared to those without HIV infection.MethodsHCC patients attending the Mulago National Referral Hospital in Uganda were enrolled into a natural history study of HCC between March 2015 and February 2019. Standardized methods were used to collect clinical, ultrasound and laboratory data at enrolment. HCC cases were confirmed based on a combination of clinical, ultrasound, tumor marker and pathology data. Follow-up contact was made at one, three, six, and twelve months post-enrolment to determine vital status. Symptoms and signs at diagnosis and subsequent survival were compared by HIV status. Kaplan Meier curves were used to assess HCC survival.ResultsOf 441 persons with HCC, 383 (87.0%) died within 12 months following HCC diagnosis. The median (IQR) survival was 42 (20, 106) days. The most commonly reported symptom clusters were pain (80%), gastrointestinal symptoms (28%) and anorexia / cachexia (10%), and no differences were detected in these presenting symptoms (nor most other initial findings) in the 79 (18%) PLWH compared to those without HIV. After adjusting for baseline demographic and clinical characteristics, HIV infection was associated with increased mortality but only among those with severe HIV-associated immunosuppression (CD4 count <200 cells per cubic milliliter), aHR (95% C) = 2.12 (1.23-3.53), p=0.004, and not among PLWH with ≥200 CD4 cells per cubic milliliter, aHR (95% C) = 1.15 (0.82-1.60), p=0.417.ConclusionAmong relatively young Ugandans, HCC is a devastating disease with rapid mortality that is especially rapid among PLWH. HIV was associated with slightly higher mortality, notably among PLWH with lower CD4 cell counts. As a substantial majority of PLWH diagnosed with HCC were engaged in HIV care, further investigation should determine the effectiveness of incorporating screening and early identification of HCC among high-risk individuals into existing HIV care programs. Concurrent with growing access to curative localized treatment for HCC in sub-Saharan Africa, leveraging HIV care infrastructure affords opportunities for earlier HCC intervention.