bluuebunny/crossref_metadata_2025_split huggingface dataset:
Indoline CD4-mimetic Compounds Mediate Potent and Broad HIV-1 Inhibition and Sensitization to Antibody-dependent Cellular Cytotoxicity
Authors: Fritschi Christopher , Anang Saumya , Gong Zhen , Mohammadi Mohammadjavad , Richard Jonathan , Bourassa Catherine , Severino Kenny T. , Richter Hannah , Yang Derek , Chen Hung-Ching , Chiu Ta-Jung , Seaman Michael , Madani Navid , Abrams Cameron , Finzi Andrés , Hendrickson Wayne A. , Sodroski Joseph , Smith Amos B. 
Published: January 2023

AbstractBinding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more “open,” antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.
Inhibition of Type I PRMTs Reforms Muscle Stem Cell Identity Enhancing their Therapeutic Capacity
Authors: Dominici Claudia , Villarreal Oscar D. , Dort Junio , Heckel Emilie , Wang Yu Chang , Ragoussis Ioannis , Joyal Jean-Sebastien , Dumont Nicolas A. , Richard Stéphane 
Published: January 2023

AbstractIn skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for regeneration upon injury. In diseased skeletal muscle, it would be therapeutically advantageous to replace defective MuSCs, or rejuvenate them with drugs to enhance their self-renewal and ensure long-term regenerative potential. One limitation of the replacement approach has been the inability to efficiently expand MuSCsex vivo,while maintaining their stemness and engraftment abilities. Herein, we show that inhibition of type I protein arginine methyltransferases (PRMTs) with MS023 increases the proliferative capacity ofex vivocultured MuSCs. Single cell RNA sequencing (scRNAseq) ofex vivocultured MuSCs revealed the emergence of subpopulations in MS023-treated cells which are defined by elevated Pax7 expression and markers of MuSC quiescence, both features of enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific subpopulations to be metabolically altered with upregulated glycolysis and oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 had a better ability to repopulate the MuSC niche and contributed efficiently to muscle regeneration following injury. Interestingly, the preclinical mouse model of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. Our findings show that inhibition of type I PRMTs increased the proliferation capabilities of MuSCs with altered cellular metabolism, while maintaining their stem-like properties such as self-renewal and engraftment potential.
Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes inDrosophila
Authors: Singh Badri Nath , Tran Hiep , Kramer Joseph , Kirichenko Elmira , Changela Neha , Wang Fei , Feng Yaping , Kumar Dibyendu , Tu Min , Lan Jie , Bizet Martin , Fuks François , Steward Ruth 
Published: January 2023

AbstractModifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. TheTetgene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were therobo2receptor and itsslitligand that function in axon guidance in Drosophila and in vertebrates.Tetknock-out embryos show overlapping phenotypes withrobo2and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.
Microbe-induced plant drought tolerance by ABA-mediated root morphogenesis and epigenetic reprogramming of gene expression
Authors: Alwutayd Khairiah M. , Rawat Anamika A. , Sheikh Arsheed H. , Almeida-Trapp Marilia , Veluchamy Alaguraj , Jalal Rewaa , Karampelias Michael , Froehlich Katja , Alzaed Waad , Tabassum Naheed , Schley Thayssa Rabelo , Schaeffner Anton R. , Daur Ihsanullah , Saad Maged M. , Hirt Heribert 
Published: January 2023

AbstractThe use of beneficial microbes to mitigate drought stress tolerance of plants is of great potential albeit little understood. We show here that a root endophytic desert bacterium,Pseudomonas argentinensissp. SA190, enhances drought stress tolerance in Arabidopsis. Transcriptome and genetic analysis demonstrate that SA190-induced root morphogenesis and gene expression is mediated via the plant abscisic acid (ABA) pathway. Moreover, we demonstrate that SA190 primes the promoters of target genes in an epigenetic manner which is ABA-dependent. Application of the SA190 priming technology on crops is demonstrated for alfalfa in field trials, showing enhanced performance under desert agriculture conditions. In summary, a single beneficial root bacterial strain can help to perform agriculture under drought and water limiting conditions.SynopsisBeneficial root endophytePseudomonas argentinensissp. SA190 confers drought tolerance in plantsSA190 modulates the expression of genes under drought stress in an ABA-dependent mannerSA190 primes genes via H3K4me3 histone mark enrichmentSA190 alters host plant physiology by improving the plant water statusSA190 enhances crop performance in open field conditions with limited irrigation
The impact of early life experiences and gut microbiota on neurobehavioral development among preterm infants: A longitudinal cohort study
Authors: Chen Jie , Li Hongfei , Zhao Tingting , Chen Kun , Chen Ming-Hui , Sun Zhe , Xu Wanli , Maas Kendra , Lester Barry , Cong Xiaomei 
Published: January 2023

AbstractObjectivesTo investigate the impact of early life experiences and gut microbiota on neurobehavioral development among preterm infants during neonatal intensive care unit (NICU) hospitalization.MethodsPreterm infants were followed from the NICU admission until their 28thpostnatal day or until discharge. Daily stool samples, painful/stressful experiences, feeding patterns, and other clinical and demographic data were collected. Gut microbiota was profiled using 16S rRNA sequencing, and operational taxonomic units (OTUs) were selected to predict the neurobehaviors. The neurobehavioral development was assessed by the Neonatal Neurobehavioral Scale (NNNS) at 36 to 38 weeks of post-menstrual age (PMA). Fifty-five infants who had NNNS measurements were included in the sparse log-contrast regression analysis.ResultsPreterm infants who experienced high level of pain/stress during the NICU hospitalization that were associated with higher NNNS stress/abstinence scores. Eight operational taxonomic units (OTUs) were identified to be associated with of NNNS subscales after controlling demographic and clinical features, feeding patterns, and painful/stressful experiences. These OTUs, taxa belong to seven genera includingEnterobacteriaceae_unclassified, Escherichia-Shigella, Incertae_Sedis, Veillonella, Enterococcus, Clostridium_sensu_stricto_1, andStreptococcuswith five belonging toFirmicutesand two belonging toProteobacteriaphylum. The enriched abundance ofEnterobacteriaceae_unclassified(OTU17) andStreptococcus(OTU28) were consistently associated with less optimal neurobehavioral outcomes. The other six OTUs were also associated with infant neurobehavioral responses depending on days at NICU stay.ConclusionsThis study explored the dynamic impact of specific OTUs on neurobehavioral development among preterm infants after controlling for early life experiences, i.e., acute and chronic pain/stress, and feeding in the NICU.
Young, but not in the Dark - the Influence of Reduced Lighting on Gait Stability in Middle-aged adults
Authors: Naaman Tirtsa , Hayek Roee , Gutman Itai , Springer Shmuel 
Published: January 2023

AbstractBackgroundThe aim of this study was to investigate the effects of walking in reduced lighting with or without performing a secondary cognitive task on gait dynamics in middle-aged adults and to compare them with young and old adults.MethodsTwenty young (age 28.8±4.1), 20 middle-aged (age 50.2±4.4), and 19 elderly (age 70.7±4.2) subjects participated in the study. Subjects walked on an instrumented treadmill at a self-determined pace under four conditions in randomized order: (1) walking in usual lighting (1000 lumens); (2) walking in near-darkness (5 lumens); (3) walking in usual lighting with a serial-7 subtraction dual-task; and (4) walking in near-darkness with a serial-7 subtraction dual-task. Variability in stride time and variability in the trajectory of the center of pressure in the sagittal and frontal planes (anterior/posterior and lateral variability) were measured. Repeated measures ANOVA and post hoc analysis were used to determine the effects of age, lighting conditions, and cognitive task on each gait outcome.ResultsUnder usual lighting, stride time variability and anterior/posterior variability of the middle-aged subjects were similar to those of the young and lower than those of the old. The lateral variability of the middle-aged subjects was higher than that of young adults under both lighting conditions. Similar to the older adults, the middle-aged participants increased their stride time variability and anterior/posterior variability when walking in near-darkness, but they were the only ones to exhibit increased lateral variability in near-darkness. Young adult gait was not affected by lighting, and concurrent performance of a cognitive task while walking did not affect gait stability in all groups under any of the lighting conditions.ConclusionsGait stability decreases in middle age when walking in the dark. Recognition of functional deficits in middle age could promote appropriate interventions to optimize aging and reduce fall risk.
Flotillin-Associated rhodopsin (FArhodopsin), a widespread paralog of proteorhodopsin in aquatic bacteria with streamlined genomes
Authors: Haro-Moreno Jose M. , López-Pérez Mario , Alekseev Alexey , Podoliak Elizaveta , Kovalev Kirill , Gordeliy Valentin , Stepanauskas Ramunas , Rodriguez-Valera Francisco 
Published: January 2023

ABSTRACTMicrobial rhodopsins are often found more than once in a single genome (paralogs) that often have different functions. We screened a large dataset of open ocean single-amplified genomes (SAGs) for co-occurrences of multiple rhodopsin genes. Many such cases were found among Pelagibacterales (SAR11), HIMB59 and the GammaproteobacteriaPseudothioglobusSAGs. These genomes always had abona fideproteorhodopsin and a separate cluster of genes containing a second rhodopsin associated with a predicted flotillin coding gene and have thus been named flotillin-associated rhodopsins (FArhodopsins). They are quite divergent from the other proteorhodopsin paralog and contain either DTT, DTL or DNI motives in their key functional amino acids. FArhodopsins are mainly associated with the lower layers of the epipelagic zone. All marine FArhodopsins had the retinal binding lysine, but we found their relatives in freshwater metagenomes that lack this key amino acid. Alfa-fold predictions of marine FArhodopsins indicate that their retinal pocket might be very reduced or absent, hinting that they are retinal-less (blind). Freshwater FArhodopsins were more diverse than marine FArhodopsins, but we could not determine if they are present as paralogs of other rhodopsins, due to the lack of SAGs or isolates. Although the function of FArhodopsins could not be established, their conserved genomic context indicated involvement in the formation of membrane microdomains. The conservation of FArhodopsins in diverse and globally abundant microorganisms suggests that they may be important in the adaptation to the twilight zone of aquatic environments.IMPORTANCERhodopsins have been shown to play a key role in the ecology of aquatic microbes. Here we describe a group of widespread rhodopsins in aquatic microbes associated with dim light conditions. Their characteristic genomic context found in both marine and freshwater environments indicates a novel potential involvement in membrane microstructure that could be important for the function of the co-existing proteorhodopsin proton pumps. The absence or reduction of the retinal binding pocket points to drastically different physiology. In addition to their ecological importance, novel rhodopsins have biotechnological potential in the nascent field of optogenetics.
Significance of Wastewater Surveillance in Detecting the Prevalence of SARS-CoV-2 Variants and Other Respiratory Viruses in the Community – A Multi-Site Evaluation
Authors: Khan Majid , Li Lin , Haak Laura , Payen Shannon Harger , Carine Madeline , Adhikari Kabita , Uppal Timsy , Hartley Paul D. , Vasquez-Gross Hans , Petereit Juli , Verma Subhash C. , Pagilla Krishna 
Published: January 2023

ABSTRACTDetection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral genome in wastewater has proven to be useful for tracking the trends of virus prevalence within the community. The surveillance also provides precise and early detection of any new and circulating variants, which aids in response to viral outbreaks. Site-specific monitoring of SARS-CoV-2 variants provides valuable information on the prevalence of new or emerging variants in the community. We sequenced the genomic RNA of viruses present in the wastewater samples and analyzed for the prevalence of SARS-CoV-2 variants as well as other respiratory viruses for a period of one year to account for seasonal variations. The samples were collected from the Reno-Sparks metropolitan area on a weekly basis between November 2021 to November 2022. Samples were analyzed to detect the levels of SARS-CoV-2 genomic copies and variants identification. This study confirmed that wastewater monitoring of SARS-CoV-2 variants can be used for community surveillance and early detection of circulating variants and supports wastewater-based epidemiology (WBE) as a complement to clinical respiratory virus testing as a healthcare response effort. Our study showed the persistence of the SARS-CoV-2 virus throughout the year compared to a seasonal presence of other respiratory viruses, implicating SARS-CoV-2’s broad genetic diversity and strength to persist and infect susceptible hosts. Through secondary analysis, we further identified antimicrobial resistance (AMR) genes in the same wastewater samples and found WBE to be a feasible tool for community AMR detection and monitoring.HIGHLIGHTS/KEY FINDINGSWBE better represents regional virus prevalence under declining testing and clinical reporting rates.SARS-CoV-2 virus was present throughout the year compared to a seasonal prevalence of other respiratory viral pathogens.SARS-CoV-2 variant monitoring via WBE can provide insights into regionally co-circulating respiratory viruses, causing flu-like symptoms.WBE-AMR gene monitoring is feasible and provides valuable insight into regional AMRs.Our workflow enables the estimation of the relative proportion of different variants in any pooled samples.GRAPHICAL ABSTRACT
Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable for Parkinson’s disease
Authors: Phillips Bridget , Western Daniel , Wang Lihua , Timsina Jigyasha , Sun Yichen , Gorijala Priyanka , Yang Chengran , Do Anh , Nykänen Niko-Petteri , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Morris John C. , Schindler Suzanne E. , Fagan Anne M. , Puerta Raquel , García-González Pablo , de Rojas Itziar , Marquié Marta , Boada Mercè , Ruiz Agustin , Perlmutter Joel S. ,   Dominantly Inherited Alzheimer Network (DIAN) Consortia, Ibanez Laura , Perrin Richard J. , Sung Yun Ju , Cruchaga Carlos 
Published: January 2023

AbstractCommon and rare variants in theLRRK2locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remains unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals). We identified eleven independent SNPs in theLRRK2locus associated with the levels of 26 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk and seven were validated in the PPMI cohort. Mendelian randomization analyses identified five proteins (GPNMB, GRN, HLA-DQA2, LCT, and CD68) causal for PD and nominate one more (ITGB2). These 26 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also thatLRRK2is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.
Identification of differences in the magnitude and specificity of SARS-CoV-2 nucleocapsid antibody responses in naturally infected and vaccinated individuals
Authors: Pushpakumara Pradeep D. , Jeewandara Chandima , Bary Farha , Madushanka Deshan , Perera Lahiru , Aberathna Inoka Sepali , Nimasha Thashmi , Jayamali Jeewantha , Ranasinghe Thushali , Kuruppu Heshan , Danasekara Saubhagya , Wijewickrama Ananda , Ogg Graham S. , Malavige Gathsaurie Neelika 
Published: January 2023

AbstractBackgroundAs there are limited data on B cell epitopes for the nucleocapsid protein in SARS-CoV-2, we sought to identify the immunodominant regions within the N protein, recognized by patients with varying severity of natural infection with the Wuhan strain (WT), delta, omicron and in those who received the Sinopharm vaccines, which is an inactivated, whole virus vaccine.MethodsUsing overlapping peptides representing the N protein, with an in-house ELISA, we mapped the immunodominant regions within the N protein, in seronegative (n=30), WT infected (n=30), delta infected (n=30), omicron infected+vaccinated (n=20) and Sinopharm (BBIBP-CorV) vaccinees (n=30). We then investigated the sensitivity and specificity of these immunodominant regions and analysed their conservation with other SARS-CoV-2 variants of concern, seasonal human coronaviruses and bat Sarbecoviruses. We then investigated the kinetics of responses to these regions in those with varying severity of acute COVID-19.ResultsWe identified four immunodominant regions aa 29-52, aa 155-178, aa 274 to 297 and aa 365 to 388, were highly conserved within SARS-CoV-2 and the bat coronaviruses. The magnitude of responses to these regions varied based on the infecting SARS-CoV-2 variants, with WT infected individuals predominantly recognizing aa155 to 178 regions, delta infected individuals and vaccinated+omicron infected individuals predominantly recognizing regions aa 29 to 52 and aa 274 to 294 regions. Sinopharm vaccinees recognized all four regions, with the magnitude of responses significantly lower than other groups. >80% of individuals gave responses above the positive cut-off threshold to many of the four regions, with some differences with individuals who were infected with different VoCs. These regions were found to be 100% specific, as none of the seronegative individuals gave any responses.ConclusionsN-protein specific responses appear to be detectable in over 90% of those who were naturally infected or vaccinated with a whole virus inactivated vaccine, with responses mainly directed against four regions of the protein, which were highly conserved. As these regions were highly specific with high sensitivity, they have a potential to be used to develop diagnostic assays and to be used in development of vaccines.
Human CCR6+Th cells show both an extended stable gradient of Th17 activity and imprinted plasticity
Authors: Singh Satya P. , Parween Farhat , Edara Nithin , Zhang Hongwei H. , Chen Jinguo , Otaizo-Carrasquero Francisco , Cheng Debby , Oppenheim Nicole A. , Ransier Amy , Zhu Wenjun , Shamsaddini Amirhossein , Gardina Paul J. , Darko Samuel W. , Singh Tej Pratap , Douek Daniel C. , Myers Timothy G. , Farber Joshua M. 
Published: January 2023

ABSTRACTTh17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related (type 17) cells and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cellsin vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The CCR6+cells’ phenotypes and epigenomes are stable across cell divisions under homeostatic conditions. Nonetheless, activation in polarizing and non-polarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to type 17 cells.