bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of C-to-U RNA Editing in Human Biodiversity
Authors: Van Norden Melissa , Falls Zackary , Mandloi Sapan , Segal Brahm , Baysal Bora , Samudrala Ram , Elkin Peter L. 
Published: August 2023

AbstractIntra-organism biodiversity is thought to arise from epigenetic modification of our constituent genes and post-translational modifications after mRNA is translated into proteins. We have found that post-transcriptional modification, also known as RNA editing, is also responsible for a significant amount of our biodiversity, substantively expanding this story. The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family RNA editing enzymes APOBEC3A and APOBEC3G catalyze the deamination of cytosines to uracils (C>U) in specific stem-loop structures.1,2We used RNAsee (RNA site editing evaluation), a tool developed to predict the locations of APOBEC3A/G RNA editing sites, to determine whether known single nucleotide polymorphisms (SNPs) in DNA could be replicated in RNA via RNA editing. About 4.5% of non-synonymous SNPs which result in C>U changes in RNA, and about 5.4% of such SNPs labelled as pathogenic, were identified as probable sites for APOBEC3A/G editing. This suggests that the variant proteins created by these DNA mutations may also be created by transient RNA editing, with the potential to affect human health. Those SNPs identified as potential APOBEC3A/G-mediated RNA editing sites were disproportionately associated with cardiovascular diseases, digestive system diseases, and musculoskeletal diseases. Future work should focus on common sites of RNA editing, any variant proteins created by these RNA editing sites, and the effects of these variants on protein diversity and human health. Classically, our biodiversity is thought to come from our constitutive genetics, epigenetic phenomenon, transcriptional differences, and post-translational modification of proteins. Here, we have shown evidence that RNA editing, often stimulated by environmental factors, could account for a significant degree of the protein biodiversity leading to human disease. In an era where worries about our changing environment are ever increasing, from the warming of our climate to the emergence of new diseases to the infiltration of microplastics and pollutants into our bodies, understanding how environmentally sensitive mechanisms like RNA editing affect our own cells is essential.
Klebsiella pneumoniaeOmpR facilitates lung infection through transcriptional regulation of key virulence factors
Authors: Janssen Axel B. , de Bakker Vincent , Aprianto Rieza , Trebosc Vincent , Kemmer Christian , Pieren Michel , Veening Jan-Willem 
Published: August 2023

AbstractBacteria must adapt to the stresses of specific environmental conditions to survive. This adaptation is often achieved by altering gene expression through two-component regulatory systems (TCSs). In Gram-negative bacteria, the response to environmental changes in osmolarity and pH are primarily mediated by the EnvZ/OmpR TCS. Although the functioning of EnvZ/OmpR has been well characterized inEscherichia coli,Salmonella enterica, and theYersiniagenus, the importance of EnvZ/OmpR TCS in the opportunistic human pathogenKlebsiella pneumoniaehas been limitedly studied.Here, we investigated the importance of EnvZ/OmpR inK. pneumoniaefor fitness, gene regulation, virulence, and infection. Through the generation of a markerlessompR-deletion mutant, we show that overall fitness ofK. pneumoniaeis not impactedin vitro. Using dual RNA-seq ofK. pneumoniaeco-incubated with human lung epithelial cells we demonstrate that theK. pneumoniaeOmpR regulon includes important virulence factors, but shows otherwise limited overlap with the regulons of other Gram-negative bacteria. In addition, we show that deletion ofompRinK. pneumoniaeleads to a stronger antibacterial transcriptional response in human lung epithelial cells. Lastly, we show that OmpR is crucial forK. pneumoniaevirulence and infection through a murine lung infection model.As the adaptation of commensal bacteria to specific niches is mediated by TCSs, we show that EnvZ/OmpR plays a crucial role in successful lung infection, as well as in virulence. These results suggest that OmpR is an interesting target for anti-virulence drug discovery programs.ImportanceBacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ/OmpR TCS ofKlebsiella pneumoniaeplays an important role in successfully establishing lung infection, and virulence. In addition, we discern the transcriptional response that OmpR facilitates within this clinically relevant opportunistic pathogen, and within the host. This work suggests thatK. pneumoniaeOmpR might be a promising target for innovative anti-infectives.
A cell-autonomous mechanism regulates BCAA catabolism in white adipocytes and systemic metabolic balance
Authors: Aguillard Ashley M. , Tzeng Joyce , Ferrer Ismael , Tam Bjorn T. , Lorenzo Damaris N. 
Published: August 2023

AbstractElevated plasma branched-chain amino acids (BCAAs) are strongly associated with obesity, insulin resistance (IR), and diabetes in humans and rodent models. However, the mechanisms of BCAA dysregulation and its systemic, organ, and cell-specific implications in the development of obesity and IR are not well understood. To gain mechanistic insight into the causes and effects of plasma BCAA elevations, we leveraged mouse models with high circulating BCAA levels prior to the onset of obesity and IR. Young mice lacking ankyrin-B in white adipose tissue (WAT) or bearing an ankyrin-B variant that causes age-driven metabolic syndrome exhibit downregulation of BCAA catabolism selectively in WAT and excess plasma BCAAs. Using cellular assays, we demonstrated that ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes, and its deficit impairs BCAA uptake. Excess BCAA supplementation worsened glucose tolerance and insulin sensitivity across genotypes. In contrast, BCAA overconsumption only increased adiposity in control mice, implicating WAT utilization of BCAAs in their obesogenic effects. These results shed light into the mechanistic underpinnings of metabolic syndrome caused by ankyrin-B deficits and provide new evidence of the relevance of WAT in the regulation of systemic BCAA levels, adiposity, and glucose homeostasis.ARTICLE HIGHLIGHTSAnkyrin-B deficits in adipose tissue result in elevated circulating BCAAs before the onset of obesity and insulin resistance.Ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes and BCAA uptake.Excess BCAA supplementation worsens glucose tolerance and insulin sensitivity in ankyrin-B deficient mice.BCAA utilization by white adipose tissue is required for the obesogenic effects of BCAA overconsumption.
Oryzagenera-specific novel Histone H4 variant predisposes H4 Lysine5 Acetylation marks to modulate salt stress responses
Authors: Vivek Hari Sundar G , Sotelo-Parrilla Paula , Raju Steffi , Jha Shaileshanand , Gireesh Anjitha , Gut Fabian , Vinothkumar K.R. , Berger Frédéric , Jeyaprakash A. Arockia , Shivaprasad P.V. 
Published: August 2023

AbstractParalogous variants of canonical histones guide accessibility to DNA and function as additional layers of genome regulation. Across eukaryotes, the occurrence, mechanism of action and functional significance of several variants of core histones are well known except that of histone H4. Here we show that a novel variant of H4 (H4.V), expressing tissue-specifically among members ofOryzagenera, mediates specific epigenetic changes contributing majorly to salt tolerance. H4.V was incorporated to specific chromosomal locations where it blocked deposition of active histone marks. Under salt stress, large scale re-distribution of H4.V enabled incorporation of stress dependent histone H4 Lysine5 Acetylation (H4K5Ac) marks. Mis-expression of H4.V led to defects at morphological level especially in reproductive tissues, and in mounting stress responses. H4.V mediated these alterations by condensing chromatin at specific genomic regions as seen with cryo-EM structure of reconstituted H4.V containing nucleosomes. These results not only uncovered the presence of a H4 variant in plants, but also a novel chromatin regulation of stress responses that might have contributed to success of semi-aquaticOryzamembers under variable water-limiting conditions.One-line summaryHistone H4 variant predisposes chromatin for stress responsesAbstract Figure
Immunities Specific to Both of the M Protein Ectodomain and RBD Synergize to Confer Cross-protection against SARS-CoV-2 Infections
Authors: Tang Yibo , Tang Kaiming , Hu Yunqi , Ye Zi-Wei , Luo Wanyu , Luo Cuiting , Cao Hehe , Wang Ran , Liu Dejian , Liu Cuicui , Ge Xingyi , Chen Yaoqing , Yuan Shuofeng , Deng Lei 
Published: August 2023

AbstractThe effectiveness of the prototypic SARS-CoV-2 vaccine largely decreased overtime against the emerging virus strains, necessitating the universal vaccine development. The most abundant structural membrane (M) protein is highly conserved in amino acid sequence, which arouses our research interests in developing a universal immunogen based on it. Serological analysis showed that IgG responses specific to its N-terminal peptides can be strongly detected in many serum samples from both convalescent patients and vaccinees receiving inactivated vaccines, indicating the potential existence of human B-cell epitopes in reactive peptides. Microneutralization assays showed that the N-terminal peptide S2M2-30-specific hyperimmune serum was capable of cross-neutralizing the authentic viruses including wild-type HKU-001a, B.1.617.2/Delta, and Omicron subvariant BQ.1.1, and synergized with RBD-specific serum in reinforcing antiviral activities. Strong S2M2-30-specific immunities elicited in hACE2-transgenic mice could effectively inhibit B.1.1.7/Alpha (UK) infections. Our results suggest the potentiality of conserved M peptides as vaccine targets for conferring cross-protections against sarbecoviruses.
An essential protease, FtsH, influences daptomycin resistance acquisition inEnterococcus faecalis
Authors: Nair Zeus Jaren , Gao Iris Hanxing , Firras Aslam , Chong Kelvin Kian Long , Choo Pei Yi , Pethe Kevin , Kline Kimberly A. 
Published: August 2023

SummaryDaptomycin is a last-line antibiotic commonly used to treat vancomycin resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPRacquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPRin pathogens such as methicillin-resistantStaphylococcus aureus. SinceEnterococcus faecalisencodes two paralogs ofmprFand clinical DAPRmutations do not map tomprF,we hypothesized that functional redundancy between the paralogs preventsmprF-mediated resistance and masks other evolutionary pathways to DAPR. Here we performedin vitroevolution to DAPRinmprFmutant background. We discovered that the absence ofmprFresults in slowed DAPRevolution and is associated with inactivating mutations inftsHresulting in the depletion of the chaperone repressor HrcA. We also report thatftsHis essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced glycolysis and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti-resistance strategies.Graphical Abstract
Loss of PAX6 alters the excitatory/inhibitory neuronal ratio in human cerebral organoids
Authors: Chan Wai Kit , Negro Danilo , Munro Victoria M , Marshall Helen , Kozić Zrinko , Brown Megan , Beltran Mariana , Henderson Neil C , Price David J , Mason John O 
Published: August 2023

AbstractThe transcription factor PAX6 is a crucial regulator of multiple aspects of embryonic forebrain development. Its well-known roles in mice include regulating differentiation of excitatory and inhibitory neurons in the embryonic cortex. PAX6’s roles during human forebrain development are less well understood. Using human cerebral organoids, we investigated PAX6’s roles in human neurodevelopment. Homozygous PAX6 mutant (PAX6-/-) organoids were larger than controls and contained inhibitory cell types not found inPAX6+/+controls. These inhibitory cells exhibited clear transcriptomic similarities and comparable distribution to analogous inhibitory cells previously described inPax6-/-mice. Differentiation trajectory inferencing showed that the inhibitory cells were generated from both radial glia and neuroectodermal progenitor populations. Inferring cell-cell communication using CellChat showed that loss of PAX6 in cerebral organoids increased the probability of cells engaging with inappropriate signalling pathways. Our findings indicate that while PAX6’s role in controlling excitatory versus inhibitory neural differentiation is conserved, there are alterations in the activities of intercellular signalling pathways in humanPAX6-/-cortical progenitors that have not been described in mice, indicating potential species-specific mechanistic differences.Summary StatementTo identify likely roles of PAX6 during human embryonic development, we generated and analysed human PAX6 mutant cerebral organoids, revealing strong similarities and some differences to Pax6’s well-known roles in rodents.
V3 tip determinants of susceptibility to inhibition by CD4-mimetic compounds in natural clade A human immunodeficiency virus (HIV-1) envelope glycoproteins
Authors: Anang Saumya , Zhang Shijian , Fritschi Christopher , Chiu Ta-Jung , Smith Amos B. , Madani Navid , Sodroski Joseph 
Published: August 2023

ABSTRACTCD4-mimetic compounds (CD4mcs) bind the human immunodeficiency virus (HIV-1) gp120 exterior envelope glycoprotein (Env) and compete for binding to CD4, the host receptor. CD4mcs prematurely trigger conformational changes in Env similar to those induced by CD4, leading to transient activation of infectivity followed by irreversible virus inactivation. Natural HIV-1 variants exhibit a wide range of susceptibilities to CD4mc inhibition, only a small fraction of which can be explained by variation in the gp120 Phe-43 cavity/vestibule where CD4mcs bind. Here, we study Envs from the resistant HIV-1BG505and the more sensitive HIV-1191955_A4clade A strains. The major determinant of the relative sensitivity of the HIV-1191955_A4Env to CD4mcs mapped to a single residue change (F317Y) in the tip of the gp120 V3 variable loop. In the Envs of several HIV-1 strains, replacement of the more prevalent Phe 317 with a tyrosine residue increased virus sensitivity to multiple CD4mcs. Tryptophan substitutions at residues 317 and 316 resulted in increases and decreases, respectively, in sensitivity to CD4mcs. Some of the gp120 V3 changes increased virus sensitivity to inactivation by both CD4mc and cold exposure, phenotypes indicative of increased Env triggerability. Infection of CD4-negative cells expressing the CCR5 coreceptor by these Env variants was triggered more efficiently by CD4mcs. For the panel of studied HIV-1 Envs, resistance to the CD4mcs was associated with decreased ability to support virus entry. These studies illustrate how variation in gp120 outside the CD4mc binding site can influence the sensitivity of natural HIV-1 strains to inhibition by these compounds.IMPORTANCECD4-mimetic compounds (CD4mcs) are small-molecule inhibitors of human immunodeficiency virus (HIV-1) entry into host cells. CD4mcs target a pocket on the viral envelope glycoprotein (Env) spike that is used for binding to the receptor, CD4, and is highly conserved among HIV-1 strains. Nonetheless, naturally occurring HIV-1 strains exhibit a wide range of sensitivities to CD4mcs. Our study identifies changes distant from the binding pocket that can influence the susceptibility of natural HIV-1 strains to the antiviral effects of multiple CD4mcs. We relate the antiviral potency of the CD4mc against this panel of HIV-1 variants to the ability of the CD4mc to activate entry-related changes in Env conformation prematurely. These findings will guide efforts to improve the potency and breadth of CD4mcs against natural HIV-1 variants.
Prodomain-driven enzyme dimerization, a potent pH-dependent autoinhibition mechanism to controlPlasmodiumSub1 subtilisin-like activity prior to prime merozoite egress
Authors: Martinez Mariano , Bouillon Anthony , Brule Sébastien , Raynal Bertrand , Haouz Ahmed , Alzari Pedro M. , Barale Jean-Christophe 
Published: August 2023

AbstractMalaria symptoms are associated with the asexual multiplication ofPlasmodium falciparumwithin human red blood cells (RBC) and fever peaks coincide with the egress of daughter merozoites following the rupture of the parasitophorous vacuole (PV) and the RBC membranes (RBC). Over the last two decades it has emerged that the release of competent merozoites is tightly regulated by a complex cascade of events, including the unusual multi- step activation mechanism of the pivotal subtilisin-like protease 1 (Sub1) that takes place in three different cellular compartments and remains poorly understood. Following an initial auto- maturation in the Endoplasmic Reticulum (ER) between its pro- and catalytic domains, the Sub1 prodomain (PD) undergo further cleavages by the parasite aspartic protease plasmepsin X (PmX) within acidic secretory organelles that ultimately lead to full Sub1 activation upon discharge into the parasitophorous vacuole (PV). Here we report the crystal structure of full- lengthP. falciparumSub1 (PfS1FL) and demonstrate, through structural, biochemical and biophysical studies, that the atypicalPlasmodium-specific Sub1 PD directly triggers the assembly of inactive enzyme homodimers at acidic pH, whereas Sub1 is primarily monomeric at neutral pH. Our results shed new light into the finely tuned Sub1 spatiotemporal activation during secretion, particularly the different compartmentalization of PmX processing and full Sub1 activation, and uncover a robust mechanism of pH-dependent subtilisin autoinhibition involved in the tight regulation ofP. falciparummerozoites egress from host infected cells.SignificanceMalaria fever spikes are due to the rupture of infected erythrocytes, allowing the egress ofPlasmodiumsp. merozoites and further parasite propagation. This fleeting tightly regulated event involves a cascade of enzymes, culminating with the complex activation of the subtilisin- like protease 1, Sub1. Differently than other subtilisins, Sub1 activation strictly depends upon the processing by a parasite aspartic protease within acidic merozoite secretory organelles. However, Sub1 biological activity is requested in the pH neutral parasitophorous vacuole, to prime effectors involved in the rupture of the vacuole and erythrocytic membranes. Here we show that the unusual, parasite specific Sub1 prodomain is directly responsible for its acidic- dependent dimerization and autoinhibition, required for protein secretion, before its full activation at neutral pH in a monomeric form. pH-dependent Sub1 dimerization defines a novel, essential regulatory element involved in the finely tuned spatiotemporal activation of the egress of competentPlasmodiummerozoites.
CoCoNuTs: A diverse subclass of Type IV restriction systems predicted to target RNA
Authors: Bell Ryan T. , Sahakyan Harutyun , Makarova Kira S. , Wolf Yuri I. , Koonin Eugene V. 
Published: August 2023

AbstractA comprehensive census of McrBC systems, among the most common forms of prokaryotic Type IV restriction systems, followed by phylogenetic analysis, reveals their enormous abundance in diverse prokaryotes and a plethora of genomic associations. We focus on a previously uncharacterized branch, which we denote CoCoNuTs (coiled-coilnuclease tandems) for their salient features: the presence of extensive coiled-coil structures and tandem nucleases. The CoCoNuTs alone show extraordinary variety, with 3 distinct types and multiple subtypes. All CoCoNuTs contain domains predicted to interact with translation system components, such as OB-folds resembling the SmpB protein that binds bacterial transfer-messenger RNA (tmRNA), YTH-like domains that might recognize methylated tmRNA, tRNA, or rRNA, and RNA-binding Hsp70 chaperone homologs, along with RNases, such as HEPN domains, all suggesting that the CoCoNuTs target RNA. Many CoCoNuTs might additionally target DNA, via McrC nuclease homologs. Additional restriction systems, such as Type I RM, BREX, and Druantia Type III, are frequently encoded in the same predicted superoperons. In many of these superoperons, CoCoNuTs are likely regulated by cyclic nucleotides, possibly, RNA fragments with cyclic termini, that bind associated CARF (CRISPR-AssociatedRossmannFold) domains. We hypothesize that the CoCoNuTs, together with the ancillary restriction factors, employ an echeloned defense strategy analogous to that of Type III CRISPR-Cas systems, in which an immune response eliminating virus DNA and/or RNA is launched first, but then, if it fails, an abortive infection response leading to PCD/dormancy via host RNA cleavage takes over.
Human resource analytics revisited: a systematic literature review of its adoption, global acceptance and implementation
Authors: Ramachandran Rukma , Babu Vimal , Murugesan Vijaya Prabhagar 
Published: August 2023

PurposeThis systematic literature review aims to explore the adoption, global acceptance and implementation of human resources (HR) analytics (HRA) by reviewing literature on the subject. HRA adoption can assist HR professionals in managing complex procedures and making strategic human resource management (SHRM) decisions more effectively. The study also aims to identify the applications of analytics in various disciplines of management.Design/methodology/approachThe review is conducted using a domain-based structured literature review (SLR), emphasizing the diffusion of innovative thinking and the adoption process of HRA among early adopters. The philosophical stances are analyzed with the combination of research onion model and PRISMA protocol. Secondary data are gathered from published journals, books, case studies, conference proceedings, web pages and media stories as the primary source of information.FindingsThe study finds that skilled professionals and management assistance can significantly impact adoption intentions, enabling professionals to deal with analytics. The examples and analytical models provided by early adopters allow managers to manage complex processes and make SHRM decisions.Research limitations/implicationsThe study suggests that the lack of use of quantitative techniques is a key limitation and should be considered in future studies. Despite the rise in the number of research papers on HRA, its application in the workplace remains limited.Practical implicationsThis research can assist managers in implementing HRA and help resolve complex and inefficient processes, making SHRM decisions.Originality/valueThis study adds to the existing body of knowledge on how HRA can aid a company's efficacy and performance and can be considered one of the first to link adoption and HRA.