bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diversity and impact of single-stranded RNA viruses in CzechHeterobasidionpopulations
Authors: Dálya László Benedek , Černý Martin , de la Peña Marcos , Poimala Anna , Vainio Eeva J. , Hantula Jarkko , Botella Leticia 
Published: May 2024

AbstractHeterobasidion annosumsensu lato comprises some of the most devastating conifer pathogens conifers. Exploring virocontrol as a potential strategy to mitigate economic losses caused by these fungi holds promise for the future. In this study, we conducted a comprehensive screening for viruses in a 98H. annosums.l. specimens from different regions of Czechia aiming to identify viruses inducing hypovirulence. Initial examination for dsRNA presence was followed by RNA-Seq analyses using pooled RNA libraries constructed fromH. annosumandHeterobasidion parviporum, with diverse bioinformatic pipelines employed for virus discovery. Our study uncovered 25 distinct ssRNA viruses, including two ourmia-like viruses, one mitovirus, one fusarivirus, one tobamo-like virus, one cogu-like virus, one bisegmented narna-like virus and one segment of another narna-like virus, and 17 ambi-like viruses, for which hairpin and hammerhead ribozymes were detected. Coinfections of up to 10 viruses were observed in sixHeterobasidionisolates, while another six harbored a single virus. 73% of the isolates analyzed by RNA-Seq were virus-free. These findings show that the virome ofHeterobasidionpopulations in Czechia is highly diverse and differs from that in the boreal region. We further investigated the host effects of certain identified viruses through comparisons of the mycelial growth rate and proteomic analyses and found that certain tested viruses caused growth reductions of up to 22% and significant alterations in the host proteome profile. Their intraspecific transmission rates ranged from 0% to 33%. Further studies are needed to fully understand the biocontrol potential of these virusesin planta.ImportanceFirst report of a fusarivirus, a tobamo- and a cogu-like virus inHeterobasidionCertain viruses caused mycelial growth reduction inH. annosumhost strainsViral infections lead to proteome changes inHeterobasidion
Cholesterol Metabolite 27-Hydroxycholesterol Enhances the Secretion of Cancer Promoting Extracellular Vesicles by a Mitochondrial ROS-Induced Impairment of Lysosomal Function
Authors: Das Gupta Anasuya , Park Jaena , Sorrells Janet E. , Kim Hannah , Krawczynska Natalia , Vidana Gamage Hashni Epa , Nelczyk Adam T. , Boppart Stephen A. , Boppart Marni D. , Nelson Erik R. 
Published: May 2024

AbstractExtracellular vesicles (EVs) serve as crucial mediators of cell-to-cell communication in normal physiology as well as in diseased states, and have been largely studied in regard to their role in cancer progression. However, the mechanisms by which their biogenesis and secretion are regulated by metabolic or endocrine factors remain unknown. Here, we delineate a mechanism by which EV secretion is regulated by a cholesterol metabolite, 27-Hydroxycholesterol (27HC), where treatment of myeloid immune cells (RAW 264.7 and J774A.1) with 27HC impairs lysosomal homeostasis, leading to shunting of multivesicular bodies (MVBs) away from lysosomal degradation, towards secretion as EVs. This impairment of lysosomal function is caused by mitochondrial dysfunction and subsequent increase in reactive oxygen species (ROS). Interestingly, cotreatment with a mitochondria-targeted antioxidant rescued the lysosomal impairment and attenuated the 27HC-mediated increase in EV secretion. Overall, our findings establish how a cholesterol metabolite regulates EV secretion and paves the way for the development of strategies to regulate cancer progression by controlling EV secretion.
Atlas of imprinted and allele-specific DNA methylation in the human body
Authors: Rosenski Jonathan , Peretz Ayelet , Magenheim Judith , Loyfer Netanel , Shemer Ruth , Glaser Benjamin , Dor Yuval , Kaplan Tommy 
Published: May 2024

AbstractAllele-specific DNA methylation, determined genetically or epigenetically, is involved in gene regulation and underlies multiple pathologies. Yet, our knowledge of this phenomenon is partial, and largely limited to blood lineages. Here, we present a comprehensive atlas of allele-specific DNA methylation, using deep whole-genome sequencing across 39 normal human cell types. We identified 325k genomic regions, covering 6% of the genome and containing 11% of all CpG sites, that show a bimodal distribution of methylated and unmethylated molecules. In 34K of these regions, genetic variations at individual alleles segregate with methylation patterns, thus validating allele-specific methylation. We also identified 460 regions showing parentally-imprinted methylation, the majority of which were not previously reported. Surprisingly, sequence-dependent and parent-dependent methylation patterns are often restricted to specific cell types, revealing unappreciated variation in the human allele-specific methylation across the human body. The atlas provides a resource for studying allele-specific methylation and regulatory mechanisms underlying imprinted expression in specific human cell types.HighlightsA comprehensive atlas of allele-specific methylation in primary human cell types325k genomic regions show a bimodal pattern of of hyper- and hypo-methylation of DNAAllele-specific methylation at 34k genomic regionsTissue-specific effects at known imprinting control regions (ICRs)100s of novel loci exhibiting parentally-imprinted methylationParentally-imprinting methylation is often cell-type-specific
Engineered Ubiquitin Variants Mitigate Pathogenic Bacterial Ubiquitin Ligase Function
Authors: Dubrule Bradley E. , Wagner Ashley , Zhang Wei , Middleton Adam J. , Subramanian Adithya S. , Eitzen Gary , Sidhu Sachdev S. , Bhavsar Amit P. 
Published: May 2024

AbstractDuring infection some pathogenic gram-negative bacteria, such asSalmonella, manipulate the host ubiquitination system through the delivery of secreted effectors known as novel E3 ubiquitin ligases (NELs). Despite the presence of NELs amongst these well-studied bacterial species, their unique structure has limited the tools that are available to probe their molecular mechanisms and explore their therapeutic potential. In this work, we report the identification of two high affinity engineered ubiquitin variants that can modulate the activity of theSalmonella entericaserovar Typhimurium encoded NEL, SspH1. We show that these ubiquitin variants suppress SspH1-mediated toxicity phenotypes inSaccharomyces cerevisiae. Additionally, we provide microscopic and flow cytometric evidence that SspH1-mediated toxicity is caused by interference withS. cerevisiaecell cycle progression that can be suppressed in the presence of ubiquitin variants.In vitroubiquitination assays revealed that these ubiquitin variants increased the amount of SspH1-mediated ubiquitin chain formation. Interestingly, despite the increase in ubiquitin chains, we observe a relative decrease in the formation of SspH1-mediated K48-linked ubiquitin chains on its substrate, PKN1. Taken together our findings suggest that SspH1 toxicity inS. cerevisiaeoccurs through cell cycle interference and that an engineered ubiquitin variant approach can be used to identify modulators of bacterially encoded ubiquitin ligases.Author SummaryNovel E3 ligases (NELs) are a family of secreted effectors found in various pathogenic gram- negative bacteria. During infection these effectors hijack vital host ubiquitin signaling pathways to aid bacterial invasion and persistence. Despite interacting with a protein as highly conserved as ubiquitin, they have a distinct architecture relative to the eukaryotic E3 enzymes. This unique architecture combined with the indispensable role ubiquitin signaling plays in host cell survival has made hindering the contribution of NELs to bacterial infections a difficult task. Here, we applied protein engineering technology to identify two ubiquitin variants (Ubvs) with high affinity for SspH1, aSalmonella-encoded NEL. We provide evidence that these high affinity Ubvs suppress a known SspH1-meidated toxicity phenotype in the eukaryotic model systemSaccharomyces cerevisiae. We also show that this suppression occurs without interfering with host ubiquitin signaling. Furthermore, we demonstrate the ability of a Ubv to modulate the activity of SspH1in vitro, ultimately altering the lysine linkages found in SspH1-mediated ubiquitination. To our knowledge, this is the first evidence that an engineered ubiquitin variant approach can be implemented to modulate the activity of a family of previously untargetable bacterial-encoded E3 ligases.
Dysregulation of Kappa Opioid Receptor Neuromodulation of Lateral Habenula Synaptic Function following a Repetitive Mild Traumatic Brain Injury
Authors: Flerlage William J. , Simmons Sarah C. , Thomas Emily H. , Gouty Shawn , Cox Brian M. , Nugent Fereshteh S. 
Published: May 2024

AbstractMild traumatic brain injury (mTBI) increases the risk of cognitive deficits, affective disorders, anxiety and substance use disorder in affected individuals. Substantial evidence suggests a critical role for the lateral habenula (LHb) in pathophysiology of psychiatric disorders. Recently, we demonstrated a causal link between persistent mTBI-induced LHb hyperactivity due to synaptic excitation/inhibition (E/I) imbalance and motivational deficits in self-care grooming behavior in young adult male mice using a repetitive closed head injury mTBI model. One of the major neuromodulatory systems that is responsive to traumatic brain and spinal cord injuries, influences affective states and also modulates LHb activity is the dynorphin/kappa opioid receptor (Dyn/KOR) system. However, the effects of mTBI on KOR neuromodulation of LHb function is unknown. To address this, we first used retrograde tracing to anatomically verify that the mouse LHb indeed receives Dyn/KOR expressing projections. We identified several major KOR-expressing and Dyn-expressing synaptic inputs projecting to the mouse LHb. We then functionally evaluated the effects ofin vitroKOR modulation of spontaneous synaptic activity within the LHb of male and female sham and mTBI mice at 4week post-injury using the repetitive closed head injury mTBI model. Similar to what we previously reported in the LHb of male mTBI mice, mTBI presynaptically diminished spontaneous synaptic activity onto LHb neurons, while shifting synaptic E/I toward excitation in female mouse LHb. Furthermore, KOR activation in either mouse male/female LHb generally suppressed spontaneous glutamatergic transmission without altering GABAergic transmission, resulting in a significant reduction in E/I ratios and decreased excitatory synaptic drive to LHb neurons of male and female sham mice. Interestingly following mTBI, while responses to KOR activation at LHb glutamatergic synapses were observed comparable to those of sham, LHb GABAergic synapses acquired an additional sensitivity to KOR-mediated inhibition. Thus, in contrast to sham LHb, we observed a reduction in GABA release probability in response to KOR stimulation in mTBI LHb, resulting in a chronic loss of KOR-mediated net synaptic inhibition within the LHb. Overall, our findings uncovered the previously unknown sources of major Dyn/KOR-expressing synaptic inputs projecting to the mouse LHb. Further, we demonstrate that an engagement of intra-LHb Dyn/KOR signaling provides a global suppression of excitatory synaptic drive to the mouse LHb which could act as an inhibitory braking mechanism to prevent LHb hyperexcitability. The additional engagement of KOR-mediated modulatory action on LHb GABAergic transmission by mTBI could contribute to the E/I imbalance after mTBI, with Dyn/KOR signaling serving as a disinhibitory mechanism for LHb neurons in male and female mTBI mice.
Ecological not social factors explain brain size in cephalopods
Authors: Basava Kiran , Bendixen Theiss , Leonhard Alexander , George Nicole Lauren , Vanhersecke Zoé , Omotosho Joshua , Mather Jennifer , Muthukrishna Michael 
Published: May 2024

AbstractSocial factors have been argued to be the main selection pressure for the evolution of large brains and complex behavior on the basis of data from mammals and birds. Coleoid cephalopods (octopuses, squid, and cuttlefish) have large brains, complex nervous systems and show signs of intelligent behavior comparable to that of birds, cetaceans, and primates. However, many cephalopods live largely solitary, semelparous, short lives, and many are cannibalistic, leaving little to no opportunity for parental care, complex group dynamics, or social learning. This suggests that the large brains found in cephalopods are not the result of social selection pressures. Here, motivated by the predictions of the “Asocial Brain Hypothesis” formal model, we compare the relationships between brain size and social, ecological, and other factors in cephalopods, predicting that ecological factors should be the primary selection pressure. Consistent with these predictions, we find that benthic (seafloor) habitats—arguably more complex environments than open-ocean (pelagic) habitats—are strongly associated with larger brain sizes, whereas measures of sociality are not, therefore suggesting ecology as a primary selection pressure on brain size in cephalopods. These results align with the “Asocial Brain Hypothesis,” which predicts that ecological complexity rather than sociality drives the evolution of large brains in asocial animals. Our findings challenge the long-standing emphasis on social drivers of brain expansion and show that ecological selection pressures can produce complex brains in highly divergent evolutionary lineages, which diverged from vertebrates over 500 million years ago. This result highlights the need for more general frameworks that capture different pathways to large brains and intelligence—both social and asocial—and underscores the power of modeling and comparative approaches to unify disparate findings in the study of brain evolution.
Pupil dilations prior to freely timed actions reflect the reported timing of conscious intention
Authors: Gavenas Jake , Schurger Aaron , Maoz Uri 
Published: May 2024

Freely timed actions are typically preceded by a slow anticipatory buildup of cortical brain activity, which has been extensively studied. However, such free actions are also preceded by slow pupil dilations in both humans and other animals, which have barely been examined. We investigated the neurocognitive significance of antecedent pupil dilations (APDs) in a voluntary-action paradigm. Participants performed self-paced actions and reported the timing of movement, conscious intention, or other events using a clock. APDs began a second or more before movement, and control conditions suggest that they did not reflect processing related to reporting demands, motor execution, or general anticipation. Critically, APD timing covaried with the reported timing of intention awareness but did not covary with the reported timing of overt movement or an external stimulus. Furthermore, decoding algorithms could distinguish APDs with above-chance accuracy more than 500 milliseconds before button-press. Our results suggest that APDs reflect a shift in awareness prior to movement onset and potentially offer a non-invasive method of predicting spontaneous movements before they occur.Highlights:1. Freely timed movements are preceded by antecedent pupil dilations (APDs).2. APDs do not reflect reporting, motor execution, or general anticipation.3. APDs are informative of upcoming movements 500+ milliseconds before button-press.4. APD timing specifically correlates with timing of intention awareness.
Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes in R6/2 mice
Authors: Simmons Danielle A. , Selvaraj Sridhar , Chen Tingshuo , Cao Gloria , Sauto Camelo Talita , McHugh Tyne L.M. , Gonzalez Selena , Martin Renata , Simanauskaite Juste , Uchida Nobuko , Porteus Matthew , Longo Frank M. 
Published: May 2024

SummaryHuntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder characterized by striatal atrophy. Reduced trophic support due to decreased striatal levels of neurotrophins (NTs), mainly brain-derived neurotrophic factor (BDNF), contributes importantly to HD pathogenesis; restoring NTs has significant therapeutic potential. Human pluripotent stem cells (hPSC) offer a scalable platform for NT delivery but has potential safety risks including teratoma formation. We engineered hPSCs to constitutively produce BDNF and contain inducible safeguards to eliminate these cells if safety concerns arise. This study examined the efficacy of intrastriatally transplanted striatal progenitor cells (STRpcs) derived from these hPSCs against HD phenotypes in R6/2 mice. Engrafted STRpcs overexpressing BDNF alleviated motor and cognitive deficits and reduced mutant huntingtin aggregates. Activating the inducible safety switch with rapamycin safely eliminated the engrafted cells. These results demonstrate that BDNF delivery via a novel hPSC-based platform incorporating safety switches could be a safe and effective HD therapeutic.
Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes
Authors: Qiu Yuhan , Chen Andrew , Yu Rebecca , Llevenes Pablo , Seen Michael , Ko Naomi Y. , Monti Stefano , Denis Gerald V. 
Published: May 2024

AbstractPatients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomesin vitro(72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis.SignificanceIR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.
Allyship against interpersonal pregnancy discrimination: exploring observers’ spontaneous responses toward pregnancy self-disclosure, interpersonal discrimination and male allyship
Authors: Warren Meg Aum , Bock Haley , Sekhon Tejvir , Winkelman Katie 
Published: May 2024

PurposePregnant employees experience considerable interpersonal discrimination. This study explores the range of possible reactions of observers to pregnancy self-disclosure, interpersonal discrimination and various allyship interventions, and the attentional processes that lead to those reactions. Consequently, it uncovers socio-cognitive processes underlying support for and backlash toward pregnancy in the workplace.Design/methodology/approach This study used a thought-listing technique to explore observers’ spontaneous thoughts related to pregnancy. Working adults were randomly assigned to read through one of the six scenarios depicting pregnancy self-disclosure, interpersonal discrimination and male allyship interventions (i.e. stating the organization’s anti-discrimination policy, confronting the transgressor by calling out sexism, pivoting the conversation to highlight the strengths of the pregnant employee and a hybrid intervention combining highlighting strengths and confrontation) after which participants listed the top three thoughts that came to their mind (1,668 responses). Responses were thematically analyzed to explore spontaneous reactions toward the pregnant employee, transgressor and ally in the scenario.Findings Surprisingly, across all scenarios, the most sexist thoughts emerged during pregnancy self-disclosure, even in the absence of any transgression. After a transgression occurred, any allyship intervention was better than none in eliciting lesser sexist backlash against the pregnant employee. Stating the organization’s anti-discrimination policy was most beneficial for the pregnant employee in eliciting the least sexist backlash but at the cost of generating unfavorable impressions of the ally. Calling out the transgressor’s bias elicited the most sexist backlash toward the pregnant employee, yet it created favorable impressions of the ally. In contrast, highlighting the strengths of the pregnant employee created the most favorable impression of the ally while eliciting a few sexist thoughts about the pregnant employee. Overall, the hybrid intervention was the most effective at balancing the competing goals of generating support for the pregnant employee, creating favorable impressions of the ally, as well as holding the transgressor accountable.Originality/value This study demonstrates that the type of allyship intervention critically redirects the attentional focus of observers to certain aspects of a discrimination episode and relevant schemas which can generate support or backlash toward targets, transgressors and allies, thereby advancing or obstructing equity and inclusion in organizations.
Pharmaceutical exports and patents in India – a systems approach
Authors: Bhattacharyya Sucharita , Chaudhuri Bibek Ray , Chatterjee Susmita , Chakraborty Debashis 
Published: May 2024

Purpose
The Indian pharmaceutical industry currently faces multiple challenges, including rising costs and slowing export growth, which in turn have limited its ability to expand presence in global canvas. Given the nature of sectoral dynamics, a pharmaceutical firm must undertake huge investments in R&D to introduce product innovation, in turn enhancing market share and sustaining profit streams. The development of novel medicines, confirmed by the granting of patent rights, provides a pharma company edge over its competitors. In addition, presence of innovator firms within the industry invigorates the sectoral value chain and raises efficiency. Hence, it is important to analyze whether granting patent rights enhances the exports of pharmaceutical products in the Indian context.

Design/methodology/approach
The current study explored this question using a simultaneous-equation framework. Specifically, the authors use the methods developed by Davidson and MacKinnon (1993) and Greene (2003) to obtain heteroscedasticity-consistent estimates. The time-series properties of the data were further probed, and robust estimates were used to test the theory. Methods developed by Baltagi (1981) have been used further to refine the authors’ estimations.

Findings
After controlling for relevant variables, it is observed that granting of patents caused a significantly positive impact on pharmaceutical exports. Furthermore, the change in the patent administration regime had a significant impact on patent fillings, which further impacted their exportability. Compared to patents granted patents filed had a higher impact on pharmaceutical exports.

Originality/value
This study attempts to apply the framework developed by Goldstein and Khan (1978) with necessary modifications to suit the context of a developing country. The application of the 3SLS method to estimate the export supply equation for pharmaceutical products is a novel approach to the research question in general and to the Indian context in particular. System autocorrelation and heteroscedasticity tests were performed to refine the results further.