bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pin4 Links Post-transcriptional and Transcriptional Responses to Glucose Starvation in Yeast
Authors: Ristová Michaela , Bexley Katherine , Shchepachev Vadim , Cook Atlanta G. , Tollervey David 
Published: November 2024

ABSTRACTAdaptation to environmental change is essential in all organisms, with RNA-binding proteins (RBPs) playing critical roles in rapid cellular responses. We analyzed the largely uncharacterized yeast RBP Pin4, and its involvement in adaptation to glucose depletion. A UV crosslinking technique to identify protein-RNA interactions (reCRAC) revealed that in glucose conditions Pin4 selectively binds a specific motif in 3’ UTRs of mRNAs involved in glycolysis, amino acid, and mitochondrial metabolism. Following glucose withdrawal, Pin4-RNA binding was greatly reduced, with residual binding favoring transcripts associated with protein translation. Cells lacking Pin4 were greatly impaired in recovery from nutrient starvation and hypersensitive to oxidative stress, consistent with the mRNA targets. RNAseq and reporter assays indicated that loss of Pin4 caused increased target mRNA abundance. In wildtype yeast, glucose depletion induces “diauxic shift”, with massive changes in transcription patterns. Very unexpectedly, this response was almost entirely abolished in cells lacking Pin4, or carrying a point mutation in its RNA-recognition motif. We conclude that Pin4 contributes to energy homeostasis by regulating post-transcriptional and transcriptional responses, and postulate that this key stress response pathway is riboregulated.
Early seedling development in dark conditions is directly controlled by plastids through the GUN1-dependent plastid retrograde pathway
Authors: Sajib Salek Ahmed , Bykowski Michał , Barreto Pedro , Mauve Caroline , Delannoy Etienne , Blanchet Sophie , Chamas Rim , Schwarzländer Markus , Kowalewska Łucja , Gakière Bertrand , Merendino Livia 
Published: November 2024

AbstractIn dark growth conditions, seedlings develop specific features such as an elongated hypocotyl, a tightly folded apical hook, and non-green cotyledons. This dark-specific process, known as skotomorphogenesis, relies primarily on mitochondria and eventually etioplasts for energy. Our previous research shows that skotomorphogenesis is reprogrammed in response to mitochondrial and plastidial dysfunction. Even though the direct link between mitochondria and skotomorphogenesis was described, the impact of plastid dysfunction on early development could not be separated from mitochondrial stress.In this study, we aim to determine the direct connection between plastid functionality and skotomorphogenic response. In this situation, we analyze the phenotypic, molecular, and metabolic effects of treating etiolated seedlings using lincomycin and spectinomycin, which target plastid translation. Our results with the lincomycin treatment highlight the direct role of plastids in the control of early development, even in dark growth conditions, in the absence of any photosynthetic activity, and without the involvement of mitochondrial intermediates. Additionally, our findings suggest that GUN1 plays a regulatory role in regulating nuclear gene expression in response to plastid translation inhibition. Thanks to our study, we can now build a more precise model proposing a straight link between the reprogramming of early development and the dysfunction of plastids in dark-growth conditions.Significance statementIn underground germination conditions, seedlings follow a dark-specific development program, called skotomorphogenesis, that is required for their efficient emergence from the soil. Our study demonstrates that plastids play a crucial role in controlling skotomorphogenesis, even in the absence of photosynthetic activity and without affecting mitochondrial function, and therefore we propose that regulation of etioplast functions might contribute to the adaptation of seedling development to constraining environmental conditions.
The Arabidopsis Class I formin AtFH5 contributes to seedling resistance to salt stress
Authors: Kollárová Eva , Forero Anežka Baquero , Yildiz Ali Burak , Kočová Helena , Žárský Viktor , Cvrčková Fatima 
Published: November 2024

AbstractThe family of formins, evolutionarily conserved multidomain proteins engaged in the control of actin and microtubule cytoskeleton organization, exhibits considerable diversity in plants. Angiosperms have two formin clades consisting of multiple paralogs, Class I and Class II, the former being often transmembrane proteins located at the plasmalemma or endomembranes. According to available transcriptome data, theArabidopsis thalianaClass I transmembrane formin AtFH5 (At5g54650) exhibits a distinct pattern of transcript abundance in various seedling root tissues with massive increase of transcript level upon salinity stress. To examine a possible role of AtFH5 in NaCl stress response, we generated transgenic plants expressing green fluorescent protein (GFP)-tagged AtFH5 under its native promoter and characterized its tissue and intracellular localization under standard culture conditions and under NaCl stress. While we confirmed the induction of AtFH5 expression by salt treatment, the distribution of tagged protein, with maxima in the border-like cells of the root cap, in the phloem and at lateral root emergence sites, did not reflect previously reported transcript abundance, suggesting posttranscriptional regulation of gene expression. Subcellular localization studies employing also membrane trafficking inhibitors suggested that AtFH5 protein level may be modulated by endocytosis and autophagy. Notably, loss-of-functionatfh5mutants exhibited increased sensitivity to NaCl stress, indicating that AtFH5 contributes to the development of seedling salt tolerance. These findings highlight the functional importance of AtFH5 in abiotic stress responses.
Transient upregulation of procaspase-3 during oligodendrocyte fate decisions
Authors: Kamen Yasmine , Chapman Timothy W. , Piedra Enrique T. , Ciolkowski Matthew E. , Hill Robert A. 
Published: November 2024

ABSTRACTOligodendrocytes are generated throughout life and in neurodegenerative conditions from brain resident oligodendrocyte precursor cells (OPCs). The transition from OPC to oligodendrocyte involves a complex cascade of molecular and morphological states that position the cell to make a fate decision to integrate as a myelinating oligodendrocyte or die through apoptosis. Oligodendrocyte maturation impacts the cell death mechanisms that occur in degenerative conditions, but it is unclear if and how the cell death machinery changes as OPCs transition into oligodendrocytes. Here, we discovered that differentiating oligodendrocytes transiently upregulate the zymogen procaspase-3, equipping these cells to make a survival decision during differentiation. Pharmacological inhibition of caspase-3 decreases oligodendrocyte density, indicating that procaspase-3 upregulation promotes differentiation. Moreover, using procaspase-3 as a marker, we show that oligodendrocyte differentiation continues in the aging cortex and white matter. Taken together, our data establish procaspase-3 as a differentiating oligodendrocyte marker and provide insight into the underlying mechanisms occurring during the decision to integrate or die.
Modeling Complex Animal Behavior with Latent State Inverse Reinforcement Learning
Authors: Jha Aditi , Geadah Victor , Pillow Jonathan W. 
Published: November 2024

AbstractUnderstanding complex animal behavior is crucial for linking brain computation to observed actions. While recent research has shifted towards modeling behavior as a dynamic process, few approaches exist for modeling long-term, naturalistic behaviors such as navigation. We introduce discrete Dynamical Inverse Reinforcement Learning (dDIRL), a latent state-dependent paradigm for modeling complex animal behavior over extended periods. dDIRL models animal behavior as being driven by internal state-specific rewards, with Markovian transitions between the distinct internal states. Using expectation-maximization, we infer reward functions corresponding to each internal states and the transition probabilities between them, from observed behavior. We applied dDIRL to water-starved mice navigating a labyrinth, analyzing each animal individually. Our results reveal three distinct internal states sufficient to describe behavior, including a consistent water-seeking state occupied for less than half the time. We also identified two clusters of animals with different exploration patterns in the labyrinth. dDIRL offers a nuanced understanding of how internal states and their associated rewards shape observed behavior in complex environments, paving the way for deeper insights into the neural basis of naturalistic behavior.
Structural basis of augment taurine uptake by taurine transporter alleviating cellular senescence
Authors: Zhang Heng , Cui Nana , Ma Xiong , Xu H. Eric 
Published: November 2024

AbstractTaurine, a sulfur-containing amino acid, is critical for diverse physiological processes including liver function, cardiovascular health, and neurological development. Its deficiency has been linked to liver damage, cardiomyopathy, retinal degeneration, and accelerated aging. Despite its importance in metabolic regulation and disease prevention, the structural basis for taurine’s cellular uptake and its potential therapeutic applications have remained elusive. Here, we present high-resolution cryo-electron microscopy structures of the human taurine transporter (TauT) in multiple conformational states, revealing key insights into the taurine transport mechanism. We identify five distinct taurine-binding sites, elucidating a continuous pathway for taurine translocation across the cell membrane. Notably, we discover a novel gating mechanism involving a conserved salt bridge, which when disrupted, significantly enhances taurine uptake. Leveraging these structural insights, we demonstrate that augmented taurine uptake via TauT alleviates stress-induced senescence in biliary epithelial cells, potentially through the upregulation of the stress-responsive gene ATF3. Our findings not only advance the understanding of neurotransmitter transport but also unveil TauT as a promising therapeutic target for age-related liver diseases and other senescence-associated disorders. This work bridges structural biology with physiological function, offering new avenues for developing interventions to combat cellular aging and taurine-deficiency related diseases.
Genome-wide analysis of heart failure yields insights into disease heterogeneity and enables prognostic prediction in the Japanese population
Authors: Enzan Nobuyuki , Miyazawa Kazuo , Koyama Satoshi , Kurosawa Ryo , Ieki Hirotaka , Yoshida Hiroki , Takechi Fumie , Fukuyama Masashi , Osako Ryosuke , Tomizuka Kohei , Liu Xiaoxi , Ozaki Kouichi , Onouchi Yoshihiro ,   BioBank Japan Project, Matsuda Koichi , Momozawa Yukihide , Aburatani Hiroyuki , Kamatani Yoichiro , Yamaguchi Takanori , Hiroshi Akazawa , Node Koichi , Ellinor Patrick T. , Levin Michael G. , Damrauer Scott M. , Voight Benjamin F. , Joseph Jacob , Sun Yan V. , Terao Chikashi , Ninomiya Toshiharu , Komuro Issei , Ito Kaoru 
Published: November 2024

AbstractTo understand the genetic basis of heart failure (HF) in the Japanese population, we performed genome-wide association studies (GWASs) comprising 16,251 all-cause HF cases, 4,254 HF with reduced ejection fraction cases, 7,154 HF with preserved ejection fraction cases, and 11,122 non-ischemic HF cases among 213,828 individuals and identified five novel loci. A subsequent cross-ancestry meta-analysis and multi-trait analysis of the GWAS data identified 19 novel loci in total. Among these susceptibility loci, a common non-coding variant inTTN(rs1484116) was associated with reduced cardiac function and worse long-term mortality. We leveraged the HF meta-GWASs along with cardiac function-related GWASs to develop a polygenic risk score (PRS) for HF. The PRS successfully identified early-onset HF and those with an increased risk of long-term HF mortality. Our results shed light on the shared and distinct genetic basis of HF between Japanese and European populations and improve the clinical value of HF genetics.
Prevalence and associated factors of advanced HIV disease among ART-naïve and ART-experienced people with HIV at AHF-supported sites in Zambia
Authors: Chewe Webster , Chanda Chitalu , Hamooya Benson M. , Siame Lukundo , Mfune Ruth Lindizyani , Kayembe Mazinga , Mpoyi Eric , Dube Nduduzo 
Published: November 2024

AbstractBackgroundIndividuals with advanced HIV disease (AHD) have a heightened risk of mortality despite access to antiretroviral therapy (ART). Sub-Saharan Africa (SSA) has a disproportionate burden of AHD-associated deaths. However, there is limited country-specific data on AHD’s burden and associated risk factors to help design targeted interventions. Therefore, this study determined the prevalence and factors associated with AHD among ART-naïve and ART-experienced adults with HIV at five AIDS Healthcare Foundation (AHF)-supported facilities in Zambia.MethodologyWe conducted a cross-sectional study among 231 ART-naïve and ART-experienced people living with HIV (PLHIV) and collected demographic and clinical data using a structured questionnaire. The primary outcome was AHD, defined as a CD4 count less than 200 cells/µL using the VISITECT® CD4 point-of-care test. Multivariable logistic regression was used to assess factors associated with AHD.ResultsAmong the study participants, 59.7% were female, and 54% were aged 19–35 years. Most participants were ART-naïve (79.2%), with 85.3% classified in WHO clinical stage 1. The prevalence of AHD was 47.6% (110/231), significantly higher among ART-naïve participants [51.9% (95/183)] compared to ART-experienced participants [31.2% (15/48), p=0.011]. ART-naïve participants aged 19–35 years exhibited a notably higher prevalence of AHD (51.6%) compared to those aged 13-18, 36-45, and >45 years (5.3%, 34.7%, and 8.4%, respectively) and had significantly higher baseline viral load values (25,000 copies/mL vs. 9,690 copies/mL, p=0.037). Additionally, among ART-naïve participants, a significantly higher proportion of individuals in WHO stages 2, 3, and 4 had AHD compared to those without AHD. Across all participants, the factors significantly associated with AHD included anemia (adjusted odds ratio [aOR] 3.03, 95% confidence interval [CI]: 1.15–7.97) and being from the New Masala Clinic health facility (aOR 3.79, 95% CI: 1.17–12.30)ConclusionAdvanced HIV disease was prevalent, particularly among ART-naïve individuals, and it was significantly associated with anemia and health facility location. There is a need for formulation of interventions, especially among ART-naïve PLHIV who are anemic. Additionally, studies to integrate point-of-care diagnostics such as the VISITECT® CD4 test into routine HIV care be conducted in resource-limited settings are warranted for early detection of AHD.
Characterizing Behavioral Dynamics in Bipolar Disorder with Computational Ethology
Authors: Zhang Zhanqi , Chou Chi K. , Rosberg Holden , Perry William , Young Jared W , Minassian Arpi , Mishne Gal , Aoi Mikio 
Published: November 2024

AbstractNew technologies for the quantification of behavior have revolutionized animal studies in social, cognitive, and pharmacological neurosciences. However, comparable studies in understanding human behavior, especially in psychiatry, are lacking. In this study, we utilized data-driven machine learning to analyze natural, spontaneous open-field human behaviors from people with euthymic bipolar disorder (BD) and non-BD participants. Our computational paradigm identified representations of distinct sets of actions (motifs) that capture the physical activities of both groups of participants. We propose novel measures for quantifying dynamics, variability, and stereotypy in BD behaviors. These fine-grained behavioral features reflect patterns of cognitive functions of BD and better predict BD compared with traditional ethological and psychiatric measures and action recognition approaches. This research represents a significant computational advancement in human ethology, enabling the quantification of complex behaviors in real-world conditions and opening new avenues for characterizing neuropsychiatric conditions from behavior.
Koolen-de Vries Syndrome causal geneKANSL1is required for motile ciliogenesis
Authors: Schmidt James D. , Terala Ananya , McCluskey Kate E. , Wang Belinda , Pfalzer Anna C. , Willsey Helen Rankin 
Published: November 2024

ABSTRACTKoolen-de Vries Syndrome (KdVS), characterized by hypersociability, intellectual disability, and seizures, is caused by pathogenic variants in the geneKANSL1, which encodes a chromatin regulator in the NSL complex that also directly functions in mitotic spindle microtubule stability. Here we explored whether KANSL1 functions at the cilium, a microtubule-rich organelle critical for brain development, neuronal excitability, and sensory integration. Leveraging theXenopusmodel, we found that Kansl1 is highly expressed in developing ciliated tissues and localizes within motile cilia. Moreover,Kansl1depletion caused ciliogenesis defects that could be partially rescued by humanKANSL1. Based on these findings, we explored the prevalence of cilia-related clinical features including structural heart defects, hypogonadism, and structural respiratory defects among 99 individuals with KdVS, ages 1 month to 37 years old. To directly test if KdVS causes ciliary dysfunction in humans, we measured the well-established ciliary functional biomarker, nasal nitric oxide, in 11 affected individuals and observed a significant decrease when compared to unaffected family members. Together, this work establishes a ciliary contribution ofKANSL1mutations to KdVS. This work adds to a growing literature highlighting the relevance of the cilium to neurodevelopmental disorders, particularly to those impacting sociability. Going forward, KANSL1 provides a unique opportunity to study a monogenic mechanism of hypersociability that may be useful in elaborating the molecular underpinnings of social behavior.
RhoA Allosterically Activates Phospholipase Cε via its EF Hands
Authors: Ohri Vaani , Samassekou Kadidia , Muralidharan Kaushik , Garland-Kuntz Elisabeth E. , Fisher Isaac J. , Hogan William C. , Davis Bailey M. , Lyon Angeline M. 
Published: November 2024

ABSTRACTPhospholipase Cε (PLCε) cleaves phosphatidylinositol lipids to increase intracellular Ca2+and activate protein kinase C (PKC) in response to stimulation of cell surface receptors. PLCε is activated via direct binding of small GTPases at the cytoplasmic leaflets of cellular membranes. In the cardiovascular system, the RhoA GTPase regulates PLCε to initiate a cardioprotective pathway, but the underlying molecular mechanism is not known. We present here the cryo-electron microscopy (cryo-EM) reconstruction of RhoA bound to PLCε. The G protein binds a unique insertion in the PLCε EF hands. Deletion of or mutations to this PLCε insertion decrease RhoA-dependent activation without impacting regulation by other G proteins. Together, our data support a model wherein RhoA binding to PLCε allosterically activates the lipase and increases its interactions with the membrane, resulting in maximum activity and cardiomyocyte survival.
Variable Cerebral Blood Flow Responsiveness to Acute Hypoxic Hypoxia
Authors: Johnson Hannah R , Wang Max C , Stickland Rachael C , Chen Yufen , Parrish Todd B , Sorond Farzaneh A , Bright Molly G 
Published: November 2024

AbstractCerebrovascular reactivity (CVR) to changes in blood carbon dioxide and oxygen levels is a robust indicator of vascular health. Although CVR is typically assessed with hypercapnia, the interplay between carbon dioxide and oxygen, and their ultimate roles in dictating vascular tone, can vary with pathology. Methods to characterize vasoreactivity to oxygen changes, particularly hypoxia, would provide important complementary information to established hypercapnia techniques. However, existing methods to study hypoxic CVR, typically with arterial spin labeling (ASL) MRI, demonstrate high variability and paradoxical responses. To understand whether these responses are real or due to methodological confounds of ASL, we used phase-contrast MRI to quantify whole-brain blood flow in 21 participants during baseline, hypoxic, and hypercapnic respiratory states in three scan sessions. Hypoxic CVR reliability was poor-to-moderate (ICC=0.42 for CVR relative to PETO2changes, ICC=0.56 relative to SpO2changes) and was less reliable than hypercapnic CVR (ICC=0.67). Without the uncertainty from ASL-related confounds, we still observed paradoxical responses at each timepoint. Concurrent changes in blood carbon dioxide levels did not account for paradoxical responses. Hypoxic CVR and hypercapnic CVR shared approximately 40% of variance across the dataset, indicating that the two effects may indeed reflect distinct, complementary elements of vascular regulation.
LATE MERISTEM IDENTITY2 regulates cuticle formation on the seed surface and influences seed longevity
Authors: Oshima Yoshimi , Narumi Takako , Kaneko Yasuko , Ishikawa Toshiki , Kawai-Yamada Maki , Ohme-Takagi Masaru , Mitsuda Nobutaka 
Published: November 2024

AbstractThe seed coat protects the embryo from severe external environment. Like the aerial plant parts, the exterior surface of the seed coat is surrounded by a cuticle consisting of lipid polyesters and wax. However, the protective role of the cuticle in mature seeds has not been characterized. We herein study the transcriptional regulation of cuticle formation on the seed surface, which influences seed longevity. A chimeric repressor ofArabidopsis thalianaR2R3 MYB transcription factor geneLATE MERISTEM IDENTITY2(LMI2)and aTorenia fournieriortholog (TfMYBML3) was expressed inA. thalianaandT. fournieri, respectively. These lines andA. thaliana LMI2T-DNA insertion lines were analyzed for cuticle deficiencies.A. thaliana LMI2mutants and chimeric repressor lines exhibited a similar cuticle deficiency in immature seeds. Transmission electron microscopy observations, polyester composition analyses, and gene expression investigations revealed thatLMI2plays an essential role in cuticle development in the seed coat epidermis by regulating cutin biosynthesis. Thelmi2-2mutant exhibited shorter seed longevity than the wild-type controls in an accelerated aging test. These results indicate that LMI2 is a key regulator of cuticle formation in the seed coat, and is important for maintaining seed longevity.Significance statementCuticle is well known to have multiple important roles for surviving in the terrestrial environment, but their specific role on the seed coat and transcriptional regulation have not yet been elucidated. Here we show thatLATE MERISTEM IDENTITY 2, encoding a transcription factor regulating floral meristem transition, is required for seed cuticle formation and maintaining seed longevity, providing evidence for a link between surface cuticle and seed longevity.