bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale epidemiological study on feline autosomal dominant polycystic kidney disease and identification of novelPKD1gene variants
Authors: Shitamori Fumitaka , Nonogaki Ayaka , Motegi Tomoki , Matsumoto Yuki , Sakamoto Mika , Tanizawa Yasuhiro , Nakamura Yasukazu , Yonezawa Tomohiro , Momoi Yasuyuki , Maeda Shingo 
Published: March 2023

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease in cats. In most cases, the responsible abnormality is a nonsense single nucleotide polymorphism in exon 29 of thePKD1gene (chrE3:g.42858112C>A, the conventionalPKD1variant). Epidemiological studies on feline ADPKD caused by the conventionalPKD1variant have been conducted in several countries, including Japan. However, they were limited to Persian cats or cats already suspected of ADPKD. There are no data on the prevalence of the conventionalPKD1variant among a wider cat population in Japan that is not limited to certain breeds or clinical backgrounds. This large-scale epidemiological study involving 1,281 cats aimed to establish a new genotyping assay to detect the conventionalPKD1variant rapidly. Among the cats examined in this study, 1.8% (23/1,281) harbored the conventionalPKD1variant. The odds of having the conventionalPKD1variant were significantly higher in Persian cats, Scottish Folds, and Exotic Shorthairs than in the other breeds. Furthermore, targeted resequencing ofPKD1was performed in cats with ADPKD and healthy cats to search for new variants that may be involved in ADPKD. We identified four variants unique to ADPKD cats that were not found in healthy cats, all of which were in exon 15. This indicates that variants in exon 15 ofPKD1, in addition to the conventional variant in exon 29, are key factors in the pathogenesis of ADPKD in cats.
Rainbow trout in the inlet tributaries of Lake Chinishibetsu, Shiretoko Peninsula
Authors: Sahashi Genki , Kuroki Mari , Nobetsu Takahiro , Morita Kentaro 
Published: March 2023

AbstractRainbow trout, Oncorhynchusmykiss, is one of the most widely introduced fish species in the world, and its impacts on native fishes and ecosystems are of considerable concern. One of the rivers inhabited by rainbow trout in the Shiretoko Peninsula is the Chinishibetsu River, and the origin of rainbow trout in this river is thought to be Lake Chinishibetsu in the upper reaches of the system, where the private stocking of rainbow trout was conducted in the 1960s. However, the basic biology of rainbow trout in the Lake Chinishibetsu area is currently unknown. This study addresses this knowledge gap by examining the biology of rainbow trout in the inlet tributaries of Lake Chinishibetsu based on sampling conducted during the rainbow trout spawning season. A total of 104 rainbow trout, ranging in age from 1+ to 8+ years, were collected from the two inlet tributaries of Lake Chinishibetsu. White-spotted charrSalvelinus leucomaenisand Siberian stone loachBarbatula oreas, neither of which is native to the Shiretoko Peninsula, were also collected and had presumably invaded the area at the same time as the rainbow trout. The sampled rainbow trout included immature and mature males and females. The distribution of fork lengths of mature females was bimodal, and the sex ratio of mature rainbow trout was male-biased. Our results indicate that the rainbow trout population in the inlet tributaries of Lake Chinishibetsu is reproducing continuously and exhibits a dimorphic life history with river residents and lake migrants of both sexes. Additionally, rainbow trout continue to be collected downstream of the Chinishibetsu River, which is the primary habitat for this species in the Shiretoko Peninsula. Therefore, unless rainbow trout are eliminated from Lake Chinishibetsu, which serves as a source of non-native species upstream of the Chinishibetsu River, it will be difficult to control rainbow trout distributions and minimize population sizes on the Shiretoko Peninsula.
Uncovering Hidden Cancer Self-Dependencies through Analysis of shRNA-Level Dependency Scores
Authors: Toghrayee Zohreh , Montazeri Hesam 
Published: March 2023

AbstractLarge-scale short hairpin RNA (shRNA) screens on well-characterized human cancer cell lines have been widely used to identify novel cancer dependencies. However, the off-target effects of shRNA reagents pose a significant challenge in the analysis of these screens. To mitigate these off-target effects, various approaches have been proposed that aggregate different shRNA viability scores targeting a gene into a single gene-level viability score. Most computational methods for discovering cancer dependencies rely on these gene-level scores. In this paper, we propose a computational method, named NBDep, to find cancer self-dependencies by directly analyzing shRNA-level dependency scores instead of gene-level scores. The NBDep algorithm begins by removing known batch effects of the shRNAs and selecting a subset of concordant shRNAs for each gene. It then uses negative binomial random effects models to statistically assess the dependency between genetic alterations and the viabilities of cell lines by incorporating all shRNA dependency scores of each gene into the model. We applied NBDep to the shRNA dependency scores available at Project DRIVE, which covers 26 different types of cancer. The proposed method identified more well-known and putative cancer genes compared to alternative gene-level approaches in pan-cancer and cancer-specific analyses. Additionally, we demonstrated that NBDep controls type-I error and outperforms statistical tests based on gene-level scores in simulation studies.Author SummaryLarge-scale shRNA screening is increasingly being used in cancer genomics to discover genes involved in cancer by analyzing the viabilities of cell lines upon knocking down a gene using a pool of short hairpin RNAs (shRNA). However, off-target effects, which result from the knockdown of unintended genes, are a major issue in RNAi screening. To address this issue, various computational methods have been developed to aggregate shRNA viability scores into gene-level dependency scores. In this paper, we propose a method called NBDep to identify cancer gene drivers that directly addresses the challenge of off-target effects at the shRNA level. NBDep identifies cancer gene drivers in three classes: amplification, missense, and non-missense alterations. In this method, we first remove known batch effects, select a subset of the most consistent shRNAs of each gene, and then perform a negative binomial mixed-effect model. The NBDep method not only identifies well-recognized and novel cancer driver genes but also has more statistical power than gene-level-score methods while controlling type-error. In summary, NBDep presents a new technique for analyzing shRNA screens and has the potential to uncover previously unknown cancer dependencies.
Endogenous viral elements constitute a complementary source of antigens for personalized cancer vaccines
Authors: Garde Christian , Pavlidis Michail A. , Garces Pablo , Lange Emma J. , Ramarathinam Sri H. , Sokač Mateo , Pandey Kirti , Faridi Pouya , Ahrenfeldt Johanne , Chung Shanzou , Friis Stine , Kleine-Kohlbrecher Daniela , Birkbak Nicolai J. , Kringelum Jens V. , Rønø Birgitte , Purcell Anthony W. , Trolle Thomas 
Published: March 2023

SUMMARYPersonalized cancer vaccines (PCVs) largely leverage neoantigens arising from somatic mutations limiting their application to patients with relatively high tumor mutational burden (TMB). This underscores the need for alternative antigens to design PCVs for low TMB cancers. To this end, we substantiate endogenous retroviral elements (EVEs) as tumor antigens through large-scale genomic analyses of healthy tissues and solid cancers. These analyses revealed that the breadth of EVE expression in tumors stratify checkpoint inhibitor treated melanoma patients into groups with differential overall and progression-free survival. To enable the design of PCVs containing EVE-derived epitopes with therapeutic potential, we developed a computational pipeline, ObsERV. We show that EVE-derived peptides are presented as epitopes on tumors and can be predicted by ObsERV. Preclinical testing of ObsERV demonstrates induction of sustained poly-functional CD4+ and CD8+ T-cell responses as well as long-term tumor protection. As such, EVEs may facilitate and improve PCVs especially for low-TMB patients.
Cancer Immunotherapy through Tissue Adhering Polymers
Authors: Borthwick Neil J. , Maikawa Caitlin L. , Weller Sven , Andresen Thomas L. , Hansen Anders E. , Autzen Anton A.A. 
Published: March 2023

AbstractTLR 7/8 agonists are highly potent immunostimulators, though their clinical translation has been met with mixed success, due to their high toxicity as a result of an unregulated systemic immune activation. There is enormous potential to augment cancer immunotherapies with synthetic TLR 7/8 agonists, though a thorough control of pharmacokinetics and localization is needed for the general use of TLR 7/8 agonists in cancer immunotherapy. Herein, we control localization of TLR 7/8 agonists, by exploiting the extensive tissue retention of poly(acrylic acid-co-styrene). In a murine CT26 model, we find that covalently attaching TLR 7/8 agonists to the copolymer allows for retaining the drug in the tumor microenvironment for at least 15 weeks, after intratumoral injection, and results in a curative monotherapy. The copolymer itself is a new avenue for attaining prolonged tissue rentention for covalently attached drugs.
Repeated exposure to high-THCCannabissmoke during gestation alters sex ratio, behavior, and amygdala gene expression of Sprague Dawley rat offspring
Authors: Sandini Thaisa M. , Onofrychuk Timothy J. , Roebuck Andrew J. , Hammond Austin , Udenze Daniel , Hayat Shahina , Herdzik Melissa A. , McElroy Dan L. , Orvold Spencer N. , Greba Quentin , Laprairie Robert B. , Howland John G 
Published: March 2023

AbstractDue to the recent legalization ofCannabisin many jurisdictions and the consistent trend of increasing THC content inCannabisproducts, there is an urgent need to understand the impact ofCannabisuse during pregnancy on fetal neurodevelopment and behavior. To this end, we repeatedly exposed female Sprague-Dawley rats toCannabissmoke from gestational days 6 to 20 (n=12; Aphria Mohawk; 19.51% THC, <0.07% cannabidiol) or room-air as a control (n=10) using a commercially available system. Maternal reproductive parameters, behavior of the adult offspring, and gene expression in the offspring amygdala were assessed. Body temperature was decreased in dams following smoke exposure and more fecal boli were observed in the chambers before and after smoke exposure in those dams exposed to smoke. Maternal weight gain, food intake, gestational length, litter number, and litter weight were not altered by exposure toCannabissmoke. A significant increase in the male-to-female ratio was noted in theCannabis-exposed litters. In adulthood, both male and femaleCannabissmoke-exposed offspring explored the inner zone of an open field significantly less than control offspring. GestationalCannabissmoke exposure did not affect behavior on the elevated plus maze test or social interaction test in the offspring.Cannabisoffspring were better at visual pairwise discrimination and reversal learning tasks conducted in touchscreen-equipped operant conditioning chambers. Analysis of gene expression in the adult amygdala using RNAseq revealed subtle changes in genes related to development, cellular function, and nervous system disease in a subset of the male offspring. These results demonstrate that repeated exposure to high-THCCannabissmoke during gestation alters maternal physiological parameters, sex ratio, and anxiety-like behaviors in the adulthood offspring.Significance statementCannabisuse by pregnant women has increased alongside increased THC content in recent years. As smokingCannabisis the most common method of use, we used a validated model ofCannabissmoke exposure to repeatedly expose pregnant rats to combusted high-THCCannabissmoke. Our results show alterations in litter sex ratio, anxiety-like behavior, and decision making in the offspring which may relate to subtle changes in expression of amygdala genes related to development, cellular function, and nervous system disease. Thus, we believe this gestationalCannabisexposure model may be useful in delineating long-term effects on the offspring.
Interactions of the Protein Tyrosine Phosphatase PTPN3 with Viral and Cellular Partners through its PDZ Domain: Insights into Structural Determinants and Phosphatase Activity
Authors: Genera Mariano , Colcombet-Cazenave Baptiste , Croitoru Anastasia , Raynal Bertrand , Mechaly Ariel , Caillet Joël , Haouz Ahmed , Wolff Nicolas , Caillet-Saguy Célia 
Published: March 2023

AbstractThe human protein tyrosine phosphatase non-receptor type 3 (PTPN3) is a phosphatase containing a PDZ (PSD-95/Dlg/ZO-1) domain that has been found to play both tumor-suppressive and tumor-promoting roles in various cancers, despite limited knowledge of its cellular partners and signaling functions. Notably, the high-risk genital human papillomavirus (HPV) types 16 and 18 and the hepatitis B virus (HBV) target the PDZ domain of PTPN3 through PDZ-binding motifs (PBMs) in their E6 and HBc proteins respectively.This study focuses on the interactions between the PTPN3 PDZ domain (PTPN3-PDZ) and PBMs of viral and cellular protein partners. The solved X-ray structures of complexes between PTPN3-PDZ and PBMs of E6 of HPV18 and the tumor necrosis factor-alpha converting enzyme (TACE) reveal two novel interactions. We provide new insights into key structural determinants of PBM recognition by PTPN3 by screening the selectivity of PTPN3-PDZ recognition of PBMs, and by comparing the PDZome binding profiles of PTPN3-recognized PBMs and the interactome of PTPN3-PDZ.The PDZ domain of PTPN3 was known to auto-inhibit the protein’s phosphatase activity. We discovered that the linker connecting the PDZ and phosphatase domains is involved in this inhibition, and that the binding of PBMs does not impact this catalytic regulation.Overall, the study sheds light on the interactions and structural determinants of PTPN3 with its cellular and viral partners, as well as on the inhibitory role of its PDZ domain on its phosphatase activity.
Trait repetitive negative thinking in depression is associated with functional connectivity in negative thinking state rather than resting state
Authors: Misaki Masaya , Tsuchiyagaito Aki , Guinjoan Salvador M. , Rohan Michael L. , Paulus Martin P. 
Published: March 2023

AbstractResting-state functional connectivity (RSFC) has been proposed as a potential indicator of repetitive negative thinking (RNT) in depression. However, identifying the specific functional process associated with RSFC alterations is challenging, and it remains unclear whether alterations in RSFC for depressed individuals are directly related to the RNT process or to individual characteristics distinct from the negative thinking process per se. To investigate the relationship between RSFC alterations and the RNT process in individuals with major depressive disorder (MDD), we compared RSFC with functional connectivity during an induced negative-thinking state (NTFC) in terms of their predictability of RNT traits and associated whole-brain connectivity patterns using connectome-based predictive modeling (CPM) and connectome-wide association (CWA) analyses. Thirty-six MDD participants and twenty-six healthy control participants underwent both resting state and induced negative thinking state fMRI scans. Both RSFC and NTFC distinguished between healthy and depressed individuals with CPM. However, trait RNT in depressed individuals, as measured by the Ruminative Responses Scale-Brooding subscale, was only predictable from NTFC, not from RSFC. CWA analysis revealed that negative thinking in depression was associated with higher functional connectivity between the default mode and executive control regions, which was not observed in RSFC. These findings suggest that RNT in depression involves an active mental process encompassing multiple brain regions across functional networks, which is not represented in the resting state. Although RSFC indicates brain functional alterations in MDD, they may not directly reflect the negative thinking process.
Virtual screening of antimicrobial plant extracts by machine-learning classification of chemical compounds in semantic space
Authors: Yabuuchi Hiroaki , Hayashi Kazuhito , Shigemoto Akihiko , Fujiwara Makiko , Nomura Yuhei , Nakashima Mayumi , Ogusu Takeshi , Mori Megumi , Tokumoto Shin-ichi , Miyai Kazuyuki 
Published: March 2023

AbstractPlant extract is a mixture of diverse phytochemicals, and considered as an important resource for drug discovery. However, large-scale exploration of the bioactive extracts has been hindered by various obstacles until now. In this research, we have introduced and evaluated a new computational screening strategy that classifies bioactive compounds and plants in semantic space generated by word embedding algorithm. The classifier showed good performance in binary (presence/absence of bioactivity) classification for both compounds and plant genera. Furthermore, the strategy led to the discovery of antimicrobial activity of essential oils fromLindera trilobaandCinnamomum sieboldiiagainstStaphylococcus aureus. The results of this study indicate that machine-learning classification in semantic space can be a highly efficient approach for exploring bioactive plant extracts.
Spinal sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered thoracic lateral hemisections but cannot restore posture and interlimb coordination during quadrupedal locomotion in adult cats
Authors: Audet Johannie , Yassine Sirine , Lecomte Charly G , Mari Stephen , Félix Soucy , Caroline Morency , Merlet Angèle N , Harnie Jonathan , Beaulieu Claudie , Gendron Louis , Rybak Ilya A. , Prilutsky Boris I. , Frigon Alain 
Published: March 2023

ABSTRACTSpinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the fore-and hindlimbs. Spinal cord injury disrupts these pathways. To investigate the control of interlimb coordination and hindlimb locomotor recovery, we performed two lateral thoracic hemisections placed on opposite sides of the cord (right T5-T6 and left T10-T11) at an interval of approximately two months in eight adult cats. In three cats, we then made a complete spinal transection caudal to the second hemisection at T12-T13. We collected electromyography and kinematic data during quadrupedal and hindlimb-only locomotion before and after spinal lesions. We show that 1) cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one, 2) coordination between the fore-and hindlimbs displays 2:1 patterns and becomes weaker and more variable after both hemisections, 3) left-right asymmetries in hindlimb stance and swing durations appear after the first hemisection and reverse after the second, and 4) support periods reorganize after staggered hemisections to favor support involving both forelimbs and diagonal limbs. Cats expressed hindlimb locomotion the day following spinal transection, indicating that lumbar sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered hemisections. These results reflect a series of changes in spinal sensorimotor circuits that allow cats to maintain and recover some level of quadrupedal locomotor functionality with diminished motor commands from the brain and cervical cord, although the control of posture and interlimb coordination remains impaired.Significance StatementCoordinating the limbs during locomotion depends on pathways in the spinal cord. We used a spinal cord injury model that disrupts communication between the brain and spinal cord by sectioning half of the spinal cord on one side and then about two months later, half the spinal cord on the other side at different levels of the thoracic cord in cats. We show that despite a strong contribution from neural circuits located below the second spinal cord injury in the recovery of hindlimb locomotion, the coordination between the forelimbs and hindlimbs weakens and postural control is impaired. We can use our model to test approaches to restore the control of interlimb coordination and posture during locomotion after spinal cord injury.
From Microstates to Macrostates in the Conformational Dynamics of GroEL: a Single-Molecule FRET Study
Authors: Liebermann Demian G. , Jungwirth Jakub , Riven Inbal , Barak Yoav , Levy Dorit , Horovitz Amnon , Haran Gilad 
Published: March 2023

AbstractThe chaperonin GroEL is a multi-subunit molecular machine that assists in protein folding in theE. colicytosol. Past studies have shown that GroEL undergoes large allosteric conformational changes during its reaction cycle. However, a measurement of subunit dynamics and their relation to the allosteric cycle of GroEL has been missing. Here, we report single-molecule FRET measurements that directly probe the conformational transitions of one subunit within GroEL and its single-ring variant under equilibrium conditions. We find that four microstates span the conformational manifold of the protein and interconvert on the submillisecond time scale. A unique set of relative populations of these microstates, termed a macrostate, is obtained by varying solution conditions, e.g., adding different nucleotides or the co-chaperone GroES. Strikingly, ATP titration studies demonstrate that the partition between the apo and ATP-liganded conformational macrostates traces a sigmoidal response with a Hill coefficient similar to that obtained in bulk experiments of ATP hydrolysis, confirming the essential role of the observed dynamics in the function of GroEL.Significance StatementGroEL is a large protein-folding machine whose activity is accompanied by considerable conformational motions. Here, we use single-molecule FRET spectroscopy in combination with photon-by-photon statistical analysis to characterize the motions of a single GroEL subunit in real time and in the presence of ADP, ATP, and the co-chaperone GroES. Our results reveal transitions between four conformations on a timescale much faster than the functional cycle. We show that the motions of an individual subunit are directly coupled to the concerted allosteric mechanism of GroEL. This work, therefore, further demonstrates the impact of fast conformational dynamics on the biochemical function of molecular machines.
Thalamic regulation of ocular dominance plasticity in adult visual cortex
Authors: Qin Yi , Ahmadlou Mehran , Suhai Samuel , Neering Paul , de Kraker Leander , Heimel J. Alexander , Levelt Christiaan N. 
Published: March 2023

SummaryExperience-dependent plasticity in the adult visual system is generally thought of as a cortical process. However, several recent studies have shown that perceptual learning or monocular deprivation can also induce plasticity in the adult dorsolateral geniculate nucleus (dLGN) of the thalamus. How plasticity in the thalamus and cortex interact in the adult visual system is ill understood. To assess the influence of thalamic plasticity on plasticity in primary visual cortex (V1), we made use of our previous finding that during the critical period, ocular dominance (OD) plasticity occurs in dLGN and requires thalamic synaptic inhibition. Using multielectrode recordings we find that this is also true in adult mice, and that in the absence of thalamic inhibition and plasticity, OD plasticity in adult V1 is absent. To study the influence of V1 on thalamic plasticity we silenced V1 and show that during the critical period, but not in adulthood, the OD shift in dLGN is partially caused by feedback from V1. We conclude that during adulthood, the thalamus plays an unexpectedly dominant role in experience-dependent plasticity in V1. Our findings highlight the importance of considering the thalamus as a potential source of plasticity in learning events that are typically thought of as cortical processes.