bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum metabolomic analysis of men on a low-carbohydrate diet for biochemically recurrent prostate cancer reveal the potential role of ketogenesis to slow tumor growth: A secondary analysis of the CAPS2 diet trial
Authors: Chi Jen-Tsan , Lin Pao-Hwa , Tolstikov Vladimir , Howard Lauren , Chen Emily Y. , Bussberg Valerie , Greenwood Bennett , Narain Niven R. , Kiebish Michael A. , Freedland Stephen J. 
Published: January 2022

AbstractBackgroundSystemic treatments for prostate cancer (PC) have significant side effects. Thus, newer alternatives with fewer side effects are urgently needed. Animal and human studies suggest the therapeutic potential of low carbohydrate diet (LCD) for PC. To test this possibility, Carbohydrate and Prostate Study 2 (CAPS2) trial was conducted in PC patients with biochemical recurrence (BCR) after local treatment to determine the effect of a 6-month LCD intervention vs. usual care control on PC growth as measured by PSA doubling time (PSADT). We previously reported the LCD intervention led to significant weight loss, higher HDL, and lower triglycerides and HbA1c with a suggested longer PSADT. However, the metabolic basis of these effects are unknown.MethodsTo identify the potential metabolic basis of effects of LCD on PSADT, serum metabolomic analysis was performed using baseline, month 3, and month 6 banked sera to identify the metabolites significantly altered by LCD and that correlated with varying PSADT.ResultsLCD increased the serum levels of ketone bodies, glycine and hydroxyisocaproic acid. Reciprocally, LCD reduced the serum levels of alanine, cytidine, asymmetric dimethylarginine (ADMA) and 2-oxobutanoate. As high ADMA level is shown to inhibit nitric oxide (NO) signaling and contribute to various cardiovascular diseases, the ADMA repression under LCD may contribute to the LCD-associated health benefit. Regression analysis of the PSADT revealed a correlation between longer PSADT with higher level of 2-hydroxybutyric acids, ketone bodies, citrate and malate. Longer PSADT was also associated with LCD reduced nicotinamide, fructose-1, 6-biphosphate (FBP) and 2-oxobutanoate.ConclusionThese results suggest a potential association of ketogenesis and TCA metabolites with slower PC growth and conversely glycolysis with faster PC growth. The link of high ketone bodies with longer PSADT supports future studies of ketogenic diets to slow PC growth.
Robust expansion of phylogeny for fast-growing genome sequence data
Authors: Ye Yongtao , Shum Marcus H. , Tsui Joseph L. , Yu Guangchuang , Smith David K. , Zhu Huachen , Wu Joseph T. , Guan Yi , Lam Tommy T. 
Published: January 2022

AbstractMassive sequencing of SARS-CoV-2 genomes has led to a great demand for adding new samples to a reference phylogeny instead of building the tree from scratch. To address such challenge, we proposed an algorithm ‘TIPars’ by integrating parsimony analysis with pre-computed ancestral sequences. Compared to four state-of-the-art methods on four benchmark datasets (SARS-CoV-2, Influenza virus, Newcastle disease virus and 16S rRNA genes), TIPars achieved the best performance in most tests. It took only 21 seconds to insert 100 SARS-CoV-2 genomes to a 100k-taxa reference tree using near 1.4 gigabytes of memory. Its efficient and accurate phylogenetic placements and incrementation for phylogenies with highly similar and divergent sequences suggest that it will be useful in a wide range of studies including pathogen molecular epidemiology, microbiome diversity and systematics.
Graphic insights into the network basis for heat-gated TRPV1
Authors: Wang Guangyu 
Published: January 2022

AbstractNon-covalent interactions in bio-macromolecules are individually weak but collectively important. How they take a concerted action in a complex biochemical reaction network to realize their thermal stability and activity is still challenging to study. Here graph theory was used to investigate how the temperature-dependent non-covalent interactions as identified in the structures of the thermo-gated capsaicin receptor TRPV1 could form a systemic fluidic grid-like mesh network with topological grids to maintain the 3D structure of TRPV1 and to govern heat-sensing. The results showed that the heat-evoked melting of the biggest grid may initiate a specific temperature threshold for both channel activation and inactivation. Meanwhile, a thermostable balance between an open state and a putatively inactivated state from the same pre-open closed state may account for heat efficacy and the use-dependent desensitization, which were further stabilized by smaller grids. Altogether, both the biggest and smaller grids may be necessary for the temperature sensitivity. Therefore, this grid thermodynamic model may be broadly significant for the structural thermostability and the functional thermoactivity of biological macromolecules.HighlightsThermo-driven cyclization or decyclization of a DNA hairpin and a network grid in protein was thermodynamically comparableThe temperature thresholds of TRPV1 for channel activation and inactivation were comparable theoretically and experimentallyThe thermo-sensitivities of TRPV1 for channel activation and inactivation were comparable theoretically and experimentallyThe grid-based systemic thermal instability of TRPV1 was useful to identify different gating statesThe release of the phosphatidylinositol lipid from the vanilloid site was required for the heat-evoked activation of TRPV1
An investigation into the spatiotemporal patterns of the Nymphalid butterfly Vagrans egista sinha (Kollar, [1844])
Authors: Pop Paul , Barwal Kuldeep Singh , Singh Randeep , Pandey Puneet , Singh Harminder Pal , Sondhi Sanjay 
Published: January 2022

AbstractVagrans egista sinha (Kollar, [1844]), the Himalayan Vagrant is a subspecies of Nymphalid (Brush-footed) butterflies spread across Asia, whose western limit is in the north-west India. Observations of this subspecies have considerably increased over the past half-a-decade, with a spike in new sightings to the west of their previously known range. This has been considered as a range extension. The current study reports new records of this species from Bilaspur District, Himachal Pradesh, India (which are the first records for the district), through systematic and opportunistic sampling. This raises the question of whether the purported range extension towards the west could instead be a range shift or vagrancy, and whether there is any shift in elevational ranges in the populations across their known range. Questions pertaining to spatial differences in elevational ranges and seasonal variation, across their range, also piqued our curiosity. Using data from academic sources (such as published literature and museum collections), supplemented by data from public participation in scientific research and personal observations, these research questions are addressed. The accuracy of results when using citizen science data is also explored using the same dataset, focused on the impact of method of extraction of coordinates, and elevation derived from it under different scenarios. It was discovered that there has not been a range shift (either longitudinal or latitudinal) and observations don’t suggest vagrancy but a case of range extension. Other results indicated that there was no climb of population to higher elevations, no spatial differences in elevational ranges in the populations, or seasonal variation in activities across their range. It was also discovered that the method of data collection by, and extraction from, citizen science databases, can influence the accuracy of the results. Some problems involved in collecting data are discussed, and remedial solutions are suggested.
Antibody response to SARS-CoV-2 mRNA vaccine in lung cancer patients: Reactivity to vaccine antigen and variants of concern
Authors: Valanparambil Rajesh M , Carlisle Jennifer , Linderman Susanne L. , Akthar Akil , Millett Ralph Linwood , Lai Lilin , Chang Andres , McCook Ashley A. , Switchenko Jeffrey , Nasti Tahseen H. , Saini Manpreet , Wieland Andreas , Manning Kelly E. , Ellis Madison , Moore Kathryn M. , Foster Stephanie L. , Floyd Katharine , Davis-Gardner Meredith E. , Edara Venkata-Viswanadh , Patel Mit , Steur Conor , Nooka Ajay K. , Green Felicia , Johns Margaret A. , O’Brein Fiona , Shanmugasundaram Uma , Zarnitsyna Veronika I , Ahmed Hasan , Nyhoff Lindsay E. , Mantus Grace , Garett Michael , Edupuganti Srilatha , Behra Madhusmita , Antia Rustom , Wrammert Jens , Suthar Mehul S. , Dhodapkar Madhav V. , Ramalingam Suresh , Ahmed Rafi 
Published: January 2022

AbstractPurposeWe investigated SARS-CoV-2 mRNA vaccine-induced binding and live-virus neutralizing antibody response in NSCLC patients to the SARS-CoV-2 wild type strain and the emerging Delta and Omicron variants.Methods82 NSCLC patients and 53 healthy adult volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and live-virus neutralization response to 614D (WT), B.1.617.2 (Delta), B.1.351 (Beta) and B.1.1.529 (Omicron) variants were evaluated by Meso Scale Discovery (MSD) assay and Focus Reduction Neutralization Assay (FRNT) respectively. We determined the longevity and persistence of vaccine-induced antibody response in NSCLC patients. The effect of vaccine-type, age, gender, race and cancer therapy on the antibody response was evaluated.ResultsBinding antibody titer to the mRNA vaccines were lower in the NSCLC patients compared to the healthy volunteers (P=<0.0001). More importantly, NSCLC patients had reduced live-virus neutralizing activity compared to the healthy vaccinees (P=<0.0001). Spike and RBD-specific binding IgG titers peaked after a week following the second vaccine dose and declined after six months (P=<0.001). While patients >70 years had lower IgG titers (P=<0.01), patients receiving either PD-1 monotherapy, chemotherapy or a combination of both did not have a significant impact on the antibody response. Binding antibody titers to the Delta and Beta variants were lower compared to the WT strain (P=<0.0001). Importantly, we observed significantly lower FRNT50 titers to Delta (6-fold), and Omicron (79-fold) variants (P=<0.0001) in NSCLC patients.ConclusionsBinding and live-virus neutralizing antibody titers to SARS-CoV-2 mRNA vaccines in NSCLC patients were lower than the healthy vaccinees, with significantly lower live-virus neutralization of B.1.617.2 (Delta), and more importantly, the B.1.1.529 (Omicron) variant compared to the wild-type strain. These data highlight the concern for cancer patients given the rapid spread of SARS-CoV-2 Omicron variant.
Distinct roles of core autophagy-related genes (ATGs) in zebrafish definitive hematopoiesis
Authors: Chen Xiang-Ke , Yi Zhen-Ni , Lau Jack Jark-Yin , Ma Alvin Chun-Hang 
Published: January 2022

AbstractDespite the well-described discrepancy between some of the macroautophagy/autophagy-related genes (ATGs) in the regulation of hematopoiesis, the varying essentiality of core ATGs in vertebrate definitive hematopoiesis remains largely unclear. Here, we employed zebrafish (Danio rerio) to compare the function of six core atgs from the core autophagy machineries, which included atg13, beclin1 (becn1), atg9a, atg2a, atg5, and atg3, in vertebrate definitive hematopoiesis via CRISPR-Cas9 ribonucleoprotein targeting. Zebrafish embryos with various atg mutations showed autophagic deficiency throughout the body, including hematopoietic cells. The atgs mutations unsurprisingly caused distinctive hematopoietic abnormalities in zebrafish. Notably, becn1 or atg9a mutation resulted in hematopoietic stem cells (HSCs) expansion during the development of the embryo into a larva, which can be attributed to the proteomic changes in metabolism, HSCs regulators, and apoptosis. Besides, atg3 mutation lowered the leukocytes in developing zebrafish embryos. Intriguingly, a synergistic effect on HSCs expansion was identified in atg13+becn1 and atg9a+atg2a or atg3 double mutations, in which atg13 mutation and atg2a or atg3 mutation exacerbated and mitigated the HSCs expansion in becn1 and atg9a mutations, respectively. In addition, the myeloid cell type-specific effects of various atgs were also determined between neutrophils and macrophages. Of these, a skewed ratio of neutrophils versus macrophages was found in atg13 mutation, while both of them were reduced in atg3 mutation. These findings demonstrated the distinct roles of atgs and their interplays in zebrafish definitive hematopoiesis, thereby suggested that the vertebrate definitive hematopoiesis is regulated in an atgs-dependent manner.
Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2
Authors: Reynisdottir Tinna , Anderson Kimberley , Boukas Leandros , Bjornsson Hans Tomas 
Published: January 2022

AbstractWiedemann-Steiner syndrome (WSS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WSS, we examined the spatial distribution of likely WSS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WSS variants exhibit a 64.1-fold overrepresentation within the CXXC domain – which mediates binding to unmethylated CpGs – suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted H3K4me1 preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 96.0% positive and 92.3% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WSS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, establishing a paradigm potentially applicable to many other Mendelian disorders.
Vps68 cooperates with ESCRT-III in intraluminal vesicle formation
Authors: Alsleben Sören , Kölling Ralf 
Published: January 2022

AbstractThe endosomal sorting complex required for transport (ESCRT)-III mediates budding and abscission of intraluminal vesicles (ILVs) into multivesicular endosomes. To further define the role of the ESCRT-III associated protein Mos10/Vps60 in ILV formation, we screened for new interaction partners by SILAC/MS. Here, we focused on the newly identified interaction partner Vps68. Our data suggest that Vps68 cooperates with ESCRT-III in ILV formation. The deletion of VPS68 caused a sorting defect similar to the SNF7 deletion, when the cargo load was high. The composition of ESCRT-III was altered, the level of core components was higher and the level of associated proteins was lower in the deletion strain. This suggests that a shift occurs from an active complex to a disassembly competent complex and that this shift is blocked in the Δvps68 strain. We present evidence that during this shift Snf7 is replaced by Mos10. Vps68 has an unusual membrane topology. Two of its potential membrane helices are amphipathic helices localized to the luminal side of the endosomal membrane. Based on this membrane topology we propose that Vps68 and ESCRT-III cooperate in the abscission step by weakening the luminal and cytosolic leaflets of the bilayer at the abscission site.
Cellular and gene expression patterns associated with root bifurcation in Selaginella
Authors: Fang Tao , Motte Hans , Parizot Boris , Smet Wouter , Yang Xilan , Walker Liam , Njo Maria , Bassel George W. , Beeckman Tom 
Published: January 2022

AbstractThe roots of lycophytes branch through dichotomy or bifurcation, which means that the root apex splits into two daughter roots. This is morphologically distinct from lateral root (LR) branching in the extant euphyllophytes, where LRs develop along the root axis at different distances from the apex. The process of root bifurcation is poorly understood, while such knowledge can be important, as it may represent an evolutionarily ancient strategy that roots recruited to form new stem cells or meristems. In this study, we examined root bifurcation in the lycophyteSelaginella moellendorffii. We characterized anin vitrodevelopmental time-frame based on repetitive apex bifurcations, allowing us to sample different stages of dichotomous root branching and analyze the root meristem and root branching inS. moellendorffiiat the microscopical and transcriptional level. Our results show that, in contrast to previous assumptions, initial cells in the root meristem are mostly not tetrahedral but rather show an irregular shape. Tracking down the early stages during root branching argues for the occurrence of a symmetric division of the single initial cell resulting in two apical stem cells allowing for root meristem bifurcation. Moreover, we generated a S. moellendorffii root branching transcriptome, which resulted in the delineation of a subset of core meristem genes. The occurrence of multiple meristem-related orthologues in this dataset, including inversely correlated expression profiles of aSCARECROW (SCR)versus aRETINOBLASTOMA-RELATED1 (RBR1)homologue suggests the presence of conserved pathways in the control of meristem and root stem cell establishment or maintenance.One-sentence summaryThe root of the spike mossSelaginella moellendorffiibifurcates following a symmetric cell division of the single stem cell and involves conserved genetic modules known from angiosperm roots.
Controlled exchange of protein and nucleic acid signals from and between synthetic minimal cells
Authors: Heili Joseph M. , Stokes Kaitlin , Gaut Nathaniel J. , Deich Christopher , Gomez-Garcia Jose , Cash Brock , Pawlak Matthew R. , Engelhart Aaron E , Adamala Katarzyna P. 
Published: January 2022

AbstractSynthetic minimal cells are a class of small liposome bioreactors that have some, but not all functions of live cells. Here, we report a critical step towards the development of a bottom-up minimal cell: cellular export of functional protein and RNA products. We used cell penetrating peptide tags to translocate payloads across a synthetic cell vesicle membrane. We demonstrated efficient transport of active enzymes, and transport of nucleic acid payloads by RNA binding proteins. We investigated influence of a concentration gradient alongside other factors on the efficiency of the translocation, and we show a method to increase product accumulation in one location. We demonstrate the use of this technology to engineer molecular communication between different populations of synthetic cells, to exchange protein and nucleic acid signals. The synthetic minimal cell production and export of proteins or nucleic acids allows experimental designs that approach the complexity and relevancy of natural biological systems.
Long-term dynamic changes of NMDA receptors following an excitotoxic challenge
Authors: Granzotto Alberto , d’Aurora Marco , Bomba Manuela , Gatta Valentina , Onofrj Marco , Sensi Stefano L. 
Published: January 2022

AbstractExcitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.
Akkermansia Muciniphilainduces chronic extramedullary hematopoiesis through cooperative IL-1R and TLR signals
Authors: Wang Yuxin , Morishima Tatsuya , Sezaki Maiko , Nakato Gaku , Fukuda Shinji , Li Yuhua , Takizawa Hitoshi 
Published: January 2022

AbstractBacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to spleen, which is termed as extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria, particularly the microbiota, regulates not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbial species on hematopoietic pathology remains largely unknown. Here we found that systemic injection ofAkkermansia muciniphila(A. m.), a mucin-degrading bacterium abundantly existing in the human gut rapidly activates BM myelopoiesis, and induces a slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we termed chronic EMH. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) partially diminishedA. m.-induced chronic EMH, while additional pharmacological inhibition of the interleukin-1 receptor (IL-1R) completely alleviated splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated innate immune signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders.Article SummaryThe aim of our study is to understand howAkkermansia muciniphila (A.m.), one of the major mucin-degrading microbial species in the human gut activate the immune and hematopoietic systems in a mouse model. We found that a single injection of theA.m. membrane fraction can induce long-lasting hepatosplenomegaly with splenic EMH through cooperative IL-1R- and TLR-mediated innate immune signals.