bluuebunny/crossref_metadata_2025 huggingface dataset:
A naturally occurring variant ofMBD4causes maternal germline hypermutation in primates
Authors: Stendahl Alexandra M. , Sanghvi Rashesh , Peterson Samuel , Ray Karina , Lima Ana C. , Rahbari Raheleh , Conrad Donald F.
Published: March 2023

As part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene Methyl-CpG binding domain 4 (MBD4). MBD4 is responsible for the repair of C>T deamination mutations at CpG locations and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: the 6 offspring of theMBD4-null dam have a 4-6 fold increase inde novomutation burden. This excess burden was predominantly C>T mutations at CpG locations consistent withMBD4loss-of-function in the dam. There was also a significant excess of C>T at CpA sites, indicating an important, underappreciated role for MBD4 to repair deamination in CpA contexts. TheMBD4-null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated withMBD4loss-of-function in humans, nor any obvious disease in the hypermutated offspring. This work provides what is likely the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal, and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.
Mechanism of histone H2B monoubiquitination by Bre1
Authors: Zhao Fan , Hicks Chad W. , Wolberger Cynthia
Published: March 2023

Monoubiquitination of histone H2BK120/123 plays multiple roles in regulating transcription, DNA replication and the DNA damage response. The structure of a nucleosome in complex with the dimeric RING E3 ligase, Bre1, reveals that one RING domain binds to the nucleosome acidic patch, where it can position the Rad6 E2, while the other RING domain contacts the DNA. Comparisons with H2A-specific E3 ligases suggests a general mechanism of tuning histone specificity via the non-E2-binding RING domain.
Neural timescales reflect behavioral demands in freely moving rhesus macaques
Authors: Manea Ana M.G. , Zilverstand Anna , Hayden Benjamin , Zimmermann Jan
Published: March 2023

Previous work has demonstrated remarkably reproducible and consistent hierarchies of neural timescales across cortical areas at rest. The question arises how such stable hierarchies give rise to adaptive behavior that requires flexible adjustment of temporal coding and integration demands. Potentially, this previously found lack of variability in the hierarchical organization of neural timescales could be a reflection of the structure of the laboratory contexts in which they were measured. Indeed, computational work demonstrates the existence of multiple temporal hierarchies within the same anatomical network when the input structure is altered. We posit that unconstrained behavioral environments where relatively little temporal demands are imposed from the experimenter are an ideal test bed to address the question of whether the hierarchical organization and the magnitude of neural timescales reflect ongoing behavioral demands. To tackle this question, we measured timescales of local field potential activity while rhesus macaques were foraging freely in a large open space. We find a hierarchy of neural timescales that is unique to this foraging environment. Importantly, although the magnitude of neural timescales generally expanded with task engagement, the brain areas’ relative position in the hierarchy was stable across the recording sessions. Notably, the magnitude of neural timescales monotonically expanded with task engagement across a relatively long temporal scale spanning the duration of the recording session. Over shorter temporal scales, the magnitude of neural timescales changed dynamically around foraging events. Moreover, the change in the magnitude of neural timescales contained functionally relevant information, differentiating between seemingly similar events in terms of motor demands and associated reward. That is, the patterns of change were associated with the cognitive and behavioral meaning of these events. Finally, we demonstrated that brain areas were differentially affected by these behavioral demands - i.e., the expansion of neural timescales was not the same across all areas. Together, these results demonstrate that the observed hierarchy of neural timescales is context-dependent and that changes in the magnitude of neural timescales are closely related to overall task engagement and behavioral demands.
Improved rescue of immature oocytes obtained from conventional gonadotropin stimulation cycles via human induced pluripotent stem cell-derived ovarian support cell co-culture
Authors: Giovannini Alexa , Piechota Sabrina , Marchante Maria , Potts Kathryn S , Rockwell Graham , Paulsen Bruna , Noblett Alexander D , Estevez Samantha L , Figueroa Alexandra B , Aschenberger Caroline , Kelk Dawn A , Forti Marcy , Marcinyshyn Shelby , Barrachina Ferran , Wiemer Klaus , Sanchez Marta , Belchin Pedro , Smela Merrick Pierson , Fortuna Patrick R.J. , Chatterjee Pranam , McCulloh David H , Copperman Alan , Ordonez-Perez Daniel , Klein Joshua U , Kramme Christian C
Published: March 2023

Structured Abstract

Purpose

To determine if rescuein vitromaturation (IVM) of human oocytes can be improved by co-culture with ovarian support cells (OSCs) derived from human induced pluripotent stem cells (hiPSCs).

Methods

Fertility patients undergoing conventional ovarian stimulation for oocyte cryopreservation or IVF donated denuded immature germinal vesicle (GV) and metaphase I (MI) oocytes for research, which were allocated between either the control or intervention cultures. Fertility patients aged 25 to 45 years old donated immature oocytes under informed consent, with no additional inclusion criteria. The 24-28 hour OSC-IVM culture condition was composed of 100,000 OSCs in suspension culture with human chorionic gonadotropin (hCG), recombinant follicle stimulating hormone (rFSH), androstenedione and doxycycline supplementation. The Media-IVM control lacked OSCs and contained the same supplementation. Primary endpoints consisted of MII formation rate and morphological quality assessment. Additionally, metaphase spindle assembly location and oocyte transcriptomic profiles were assessed compared toin vivomatured MII oocyte controls.

Results

We observed significant improvement in maturation outcome rates (∼1.7X) for oocytes that underwent IVM with OSCs. Specifically, the OSC-IVM group yielded a maturation rate of 62% ± 5.57% SEM versus 37% ± 8.96% SEM in the Media-IVM (p=0.0138, unpairedt-test). Oocyte morphological quality between OSC-IVM and the Media-IVM control did not significantly differ. OSC-IVM resulted in MII oocytes with no instances of spindle absence and no significant difference in position compared toin vivomatured IVF-MII controls. OSC-IVM treated MII oocytes display a transcriptomic signature significantly more similar to IVF-MII controls than the Media-IVM control MII oocytes did.

Conclusion

The novel OSC-IVM platform is an effective tool for rescue maturation of human oocytes obtained from conventional stimulation cycles, yielding oocytes with improved nuclear and cytoplasmic maturation. OSC-IVM shows broad utility for application in modern fertility treatment to improve the total number of available mature oocytes for fertility treatment.
Complex Formation of Immunoglobulin Superfamily Molecules Side-IV and Beat-IIb Regulates Synaptic Specificity in theDrosophilaVisual System
Authors: Osaka Jiro , Ishii Arisa , Wang Xu , Iwanaga Riku , Kawamura Hinata , Sugie Atsushi , Hakeda-Suzuki Satoko , Suzuki Takashi
Published: March 2023

Neurons establish specific synapses based on the adhesive properties of cell-surface proteins, while also retaining the ability to form synapses in a relatively non-selective manner. However, the comprehensive understanding of the underlying mechanism reconciling these opposing characteristics remains incomplete. Here, we have identified Side-IV/Beat-IIb, members of theDrosophilaimmunoglobulin superfamily, as a novel combination of cell-surface recognition molecules inducing synapse formation. The Side-IV/Beat-IIb combination transduces bifurcated signaling with Side-IV’s co-receptor, Kirre, and a synaptic scaffold protein, Dsyd-1. Genetic experiments and subcellular protein localization analyses showed the newly characterized Side-IV/Beat-IIb/Kirre/Dsyd-1 complex to have two essential functions. First, it narrows neuronal binding specificity through Side-IV/Beat-IIb extracellular interactions. Second, it recruits synapse formation factors, Kirre and Dsyd-1, to restrict synaptic loci and inhibit miswiring. This dual function explains how the combinations of cell-surface molecules enable the ranking of preferred interactions among neuronal pairs to achieve synaptic specificity in complex circuitsin vivo.
Is exercising better for your Mental Health?
Authors: Desai Dev Himanshubhai , Shukla Aparajita , Desai Himanshu
Published: March 2023

Objective

To correlate psychological changes with exercise.

Methodology

This cross sectional study was conducted on 102 participants in a known Gym with age group 17-75 (28.3 ± 10.4, 70.59% males). They were given“Rosenberg self-esteem Questionnaire”, “Satisfaction with life scale” & “Hamilton & Beck’s Depression Inventory” inpen-paper type and were asked to fill it twice; once at the present time and once in retrospection before they started doing exercise. Three different values of Self-esteem, Satisfaction and Depression were collected. Answers from these Depression, Self-esteem questionnaire and Satisfaction questionnaire were summed up to get the final individual score.

Results

Overall gain was 62.53% suggesting positive impact of exercise. Highest impact was seen in age group of 17-30 of 72.46%. Lower education groups showed significantly higher gain, compared to higher educational groups (191.80%vs42.64%,p<0.05), which may be because of already higher scores in pre-exercise stage among higher education group. Target-achievers showed significantly higher gain compared to non-target-achievers (84.84%vs33.18%,p<0.01)).

Conclusion

Exercise has an overall positive impact on satisfaction, self-esteem and reduction in depression. People are influenced by different factors into getting fit and most of them agree that body image has a value in their perception of any individual.
Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease
Authors: Mehta Puja , Sanz-Magallón Duque de Estrada Blanca , Denneny Emma K , Foster Kane , Turner Carolin T , Mayer Andreas , Milighetti Martina , Platé Manuela , Worlock Kaylee B , Yoshida Masahiro , Brown Jeremy S , Nikolić Marko Z , Chain Benjamin M , Noursadeghi Mahdad , Chambers Rachel C , Porter Joanna C , Tomlinson Gillian S
Published: March 2023

Abstract

Background

Persistent radiological lung abnormalities are evident in many survivors of acute coronavirus disease 2019 (COVID-19). Consolidation and ground glass opacities are interpreted to indicate subacute inflammation whereas reticulation is thought to reflect fibrosis. We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis.

Methods

We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern, targeting lung segments affected by the predominant abnormality.

Results

Single-cell transcriptomes of inflammatory and fibrotic post-COVID lung disease closely resembled each other across all cell types. However, CD4 central memory T cells and CD8 effector memory T cells were significantly more abundant in those with inflammatory radiology. Clustering of similar TCRs from multiple donors was a striking feature of both phenotypes, consistent with tissue localised antigen-specific immune responses. There was no enrichment for known SARS-CoV-2-reactive TCRs, raising the possibility of T cell-mediated immunopathology driven by failure in immune self-tolerance.

Conclusions

We found no evidence that post-COVID radiographic inflammation and fibrosis are associated with differential immmunopathological pathways. Both show evidence of shared antigen-specific T cell responses, suggesting a role for therapies targeting T cells in limiting post-COVID lung damage.
Early real world evidence on the relative SARS-COV-2 vaccine effectiveness of bivalent COVID-19 booster doses: a rapid review
Authors: Schepisi M. Sane
Published: March 2023

The objective of this review is to give an overall view of COVID-19 bivalent vaccines knowledge and to explore their early available real world effectiveness evidence in the Omicron era.

Presently, bivalent vaccines are generally offered to all groups eligible for their next booster, as defined by the national vaccination campaign, with varying policies between countries.

The use of bivalent vaccines is supported by immunogenity studies, which, nevetheless, have led to contradictory conclusions, and are not generally designed to measure clinical impact.

In order to critically appraise the available research on real world effectiveness, a systematic literature search was performed: out of 876 references examined, 14 studies were finally included and extracted. The findings of this review demonstrate modest to moderate additional protection of vaccination with bivalent BA.4-5 or BA.1 mRNA-booster vaccines against COVID-19 associated illness and hospitalization, -if compared with having received a monovalent dose as booster-, during a period when BA.5 and other Omicron sublineage viruses predominated globally,

Considering the complexity of the current immunity situation at global level, and the high level of heterogeneity both at study and at review level, these findings must be taken with caution. Further research on SARS-CoV-2 vaccine effectiveness against emerging SARS-CoV-2 variants is encouraged.
Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer
Authors: Ogobuiro Ifeanyichukwu , Baca Yasmine , Ribeiro Jennifer R , Walker Phillip , Wilson Gregory C , Gulhati Prateek , Marshall John L , Shroff Rachna T , Spetzler David , Oberley Matthew J , Abbott Daniel E , Kim Hong Jin , Kooby David A , Maithel Shishir K , Ahmad Syed A , Merchant Nipun B. , Xiu Joanne , Hosein Peter J. , Datta Jashodeep
Published: March 2023

Purpose

Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients.

Methods

We analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age-and molecularly-defined cohorts. Significance was determined as FDR-correctedP-values (Q)<0.05.

Results

YOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-, RNF43-, CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%;Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates ofHLA-DPA1homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients withKRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months;P=0.008) but notKRAS-mutant tumors (P=0.084).

Conclusion

In this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.
BRCA1-BARD1 combines multiple chromatin recognition modules to bridge nascent nucleosomes
Authors: Burdett Hayden , Foglizzo Martina , Musgrove Laura J. , Kumar Dhananjay , Clifford Gillian , Campbell Lisa J. , Heath George R. , Zeqiraj Elton , Wilson Marcus D.
Published: March 2023

Chromatin association of the BRCA1-BARD1 heterodimer is critical to promote homologous recombination repair of DNA double-strand breaks (DSBs) in S/G2. How the BRCA1-BARD1 complex interacts with chromatin that contains both damage induced histone H2A ubiquitin and inhibitory H4AK20 methylation is not fully understood. We characterised BRCA1-BARD1 binding and enzymatic activity to an array of mono- and di-nucleosome substrates using biochemical, structural, and single molecule imaging approaches. We find that the BRCA1-BARD1 complex preferentially interacts and modifies di-nucleosomes over mono-nucleosomes, allowing integration of H2A Lys-15 ubiquitylation signals with other chromatin modifications and features. Using high speed-AFM to provide real-time visualization of BRCA1-BARD1 complex recognising chromatin, we show a highly dynamic complex that bridges two nucleosomes and associates with the DNA linker region. Bridging is aided by multivalent cross-nucleosome interactions that enhance BRCA1-BARD1 E3 ubiqiutin ligase catalytic activity. Multivalent interactions across nucleosomes explains how BRCA1-BARD1 can recognize chromatin that retains partial di-methylation at H4 Lys-20 (H4K20me2), a parental histone mark that blocks BRCA1-BARD1 interaction with nucleosomes, to promote its enzymatic and DNA repair activities.
Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements
Authors: Hu Yan , Ma Sai , Kartha Vinay K. , Duarte Fabiana M. , Horlbeck Max , Zhang Ruochi , Shrestha Rojesh , Labade Ajay , Kletzien Heidi , Meliki Alia , Castillo Andrew , Durand Neva , Mattei Eugenio , Anderson Lauren J. , Tay Tristan , Earl Andrew S. , Shoresh Noam , Epstein Charles B. , Wagers Amy , Buenrostro Jason D.
Published: March 2023

Cis-regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time1–3. Here we sought to connect the structural changes atcis-regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidatecis-regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies “sub-cCREs” as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution.
Gamma-Mobile-Trio systems define a new class of mobile elements rich in bacterial defensive and offensive tools
Authors: Mahata Tridib , Kanarek Katarzyna , Goren Moran G. , Rameshkumar Marimuthu Ragavan , Bosis Eran , Qimron Udi , Salomon Dor
Published: March 2023

Conflicts between bacteria and their rivals led to an evolutionary arms race and the development of bacterial immune systems. Although diverse immunity mechanisms were recently identified, many remain unknown, and their dissemination within bacteria is poorly understood. Here, we describe a widespread genetic element, defined by the presence of the Gamma-Mobile-Trio (GMT) proteins, that serves as a bacterial survival kit. We show that GMT-containing genomic islands are active mobile elements with cargo comprising various anti-phage defense systems, in addition to antibacterial type VI secretion system (T6SS) effectors and antibiotic resistance genes. We identify four new anti-phage defense systems encoded within GMT islands. A thorough investigation of one system reveals that it is triggered by a phage capsid protein to induce cell dormancy. Our findings underscore the need to broaden the concept of ‘defense islands’ to include also antibacterial offensive tools, such as T6SS effectors, as they share the same mobile elements as defensive tools for dissemination.
Self-eating while being eaten: Elucidating the relationship between aphid feeding and the plant autophagy machinery in Arabidopsis leaves
Authors: Hao Let Kho , Dangol Anuma , Shavit Reut , Pitt William Jacob , Nalam Vamsi , Brotman Yariv , Michaeli Simon , Peled-Zehavi Hadas , Tzin Vered
Published: March 2023

Autophagy, an intracellular process that facilitates the degradation of cytoplasmic materials, plays a dominant role in plant fitness and immunity. While autophagy was shown to be involved in plant response to fungi, bacteria, and viruses, its role in response to insect herbivory is as yet unknown. In this study, we demonstrate a role of autophagy in plant defense against herbivory usingArabidopsis thalianaand the green peach aphid,Myzus persicae. Following six hours of aphid infestation of wildtype plants, we observed high expression of the autophagy-related genesATG8aandATG8f, as well asNBR1(Next to BRCA1 gene 1), a selective autophagy receptor. Moreover, the number of autophagosomes detected by the overexpression of GFP-fused ATG8f in Arabidopsis increased upon aphid infestation. Following this,atg5.1andatg7.2mutants were used to study the effect of autophagy on aphid reproduction and feeding behavior. While aphid reproduction on both mutants was lower than on wildtype, feeding behavior was only affected byatg7.2mutants. Moreover, upon aphid feeding, thePhytoalexin-deficient 4(PAD4) defense gene was upregulated in wildtype plants but not affected in the mutants. By contrast, the hydrogen peroxide content was much higher in the mutants relative to wildtype, which might have disturbed aphid reproduction and interfered with their feeding. Additionally, an analysis of the phloem sap metabolite profile revealed thatatg7.2mutant plants have lower levels of amino acids and sugars. These findings, together with the high hydrogen peroxide levels, suggest that aphids might exploit the plant autophagy mechanism for their survival.
ChoruMM: a versatile multi-components mixed model for bacterial-GWAS
Authors: Frouin Arthur , Laporte Fabien , Hafner Lukas , Maury Mylene , McCaw Zachary R. , Julienne Hanna , Henches Léo , Chikhi Rayan , Lecuit Marc , Aschard Hugues
Published: March 2023

Genome-wide Association Studies (GWAS) have been central to studying the genetics of complex human outcomes, and there is now tremendous interest in implementing GWAS-like approaches to study pathogenic bacteria. A variety of methods have been proposed to address the complex linkage structure of bacterial genomes, however, some questions remain about to optimize the genetic modelling of bacteria to decipher causal variations from correlated ones. Here we examined the genetic structure underlying whole-genome sequencing data from 3,824Listeria monocytogenesstrains, and demonstrate that the standard human genetics model, commonly assumed by existing bacterial GWAS methods, is inadequate for studying such highly structured organisms. We leverage these results to developChoruMM, a robust and powerful approach that consists of a multi-component linear mixed model, where components are inferred from a hierarchical clustering of the bacteria genetic relatedness matrix. OurChoruMMapproach also includes post-processing and visualization tools that address the pervasive long-range correlation observed in bacteria genome and allow to assess the type I error rate calibration.
GRAPHENE OXIDE AS A NOVEL IMMUNOTHERAPY TOOL FOR THE MODULATION OF MYELOID-DERIVED SUPPRESSOR CELL ACTIVITY IN THE CONTEXT OF MULTIPLE SCLEROSIS
Authors: Camacho-Toledano Celia , Machín-Díaz Isabel , Lebrón-Galán Rafael , González-Mayorga Ankor , Palomares Francisco J. , Serrano María C. , Clemente Diego
Published: March 2023

Multiple Sclerosis (MS) is a chronic, inflammatory disease of the central nervous system. Despite the pharmacological arsenal approved for MS, there are treatment-reluctant patients for whom cell therapy appears as the only therapeutic alternative. Myeloid-derived suppressor cells (MDSCs) are immature cells of the innate immune response able to immunosuppress T lymphocytes and to promote oligodendroglial differentiation in experimental autoimmune encephalomyelitis (EAE), a preclinical model for MS. Culture devices need to be designed so that MDSCs maintain a state of immaturity and immunosuppressive function similar to that exerted in the donor organism. Graphene oxide (GO) has been described as a biocompatible material with the capacity to biologically modulate different cell types, including immune cells. In the present work, we show how MDSCs isolated from immune organs of EAE mice maintain an immature phenotype and highly immunosuppressive activity on T lymphocytes after being cultured on 2D reduced GO films (rGO200) compared to those grown on glass. This activity is depleted when MDSCs are exposed to slightly rougher and more oxidized GO substrates (rGO90). The greater reduction in cell size of cells exposed to rGO90compared to rGO200is associated with the activation of apoptosis processes. Taken together, the exposure of MDSCs to GO substrates with different redox state and roughness appears as a good strategy to control MDSC activityin vitro. This versatility of GO nanomaterials and the impact of their physico-chemical properties in immunomodulation open the door to its possible selective therapeutic use for pathologies where MDSCs need to be enhanced or inhibited.
Reduced histone gene copy number disruptsDrosophilaPolycomb function
Authors: McPherson Jeanne-Marie E. , Grossmann Lucy C. , Armstrong Robin L. , Kwon Esther , Salzler Harmony R. , Matera A. Gregory , McKay Daniel J. , Duronio Robert J.
Published: March 2023

The chromatin of animal cells contains two types of histones: canonical histones that are expressed during S phase of the cell cycle to package the newly replicated genome, and variant histones with specialized functions that are expressed throughout the cell cycle and in non-proliferating cells. Determining whether and how canonical and variant histones cooperate to regulate genome function is integral to understanding how chromatin-based processes affect normal and pathological development. Here, we demonstrate that variant histone H3.3 is essential forDrosophiladevelopment only when canonical histone gene copy number is reduced, suggesting that coordination between canonicalH3.2and variantH3.3expression is necessary to provide sufficient H3 protein for normal genome function. To identify genes that depend upon, or are involved in, this coordinate regulation we screened for heterozygous chromosome 3 deficiencies that impair development of flies bearing reducedH3.2andH3.3gene copy number. We identified two regions of chromosome 3 that conferred this phenotype, one of which contains thePolycombgene, which is necessary for establishing domains of facultative chromatin that repress master regulator genes during development. We further found that reduction inPolycombdosage decreases viability of animals with noH3.3gene copies. Moreover, heterozygousPolycombmutations result in de-repression of the Polycomb target geneUbxand cause ectopic sex combs when either canonical or variantH3gene copy number is also reduced. We conclude that Polycomb-mediated facultative heterochromatin function is compromised when canonical and variantH3gene copy number falls below a critical threshold.
Steroid Receptor Coactivator-3 is a Key Modulator of Regulatory T Cell-Mediated Tumor Evasion
Authors: Han Sang Jun , Jain Prashi , Gilad Yosef , Xia Yan , Sung Nuri , Park Mi Jin , Dean Adam M. , Lanz Rainer B. , Xu Jianming , Dacso Clifford C. , Lonard David M. , O’Malley Bert W.
Published: March 2023

Abstracts

Steroid receptor coactivator 3 (SRC-3) is most strongly expressed in regulatory T cells (Tregs) and B cells, suggesting that it plays an important role in the regulation of Treg function. Using an aggressive E0771 mouse breast cell line syngeneic immune-intact murine model, we observed that breast tumors were ‘permanently eradicated’ in a genetically engineered tamoxifen-inducible Treg-cell specific SRC-3 knockout (KO) female mouse that does not possess a systemic autoimmune pathological phenotype. A similar eradication of tumor was noted in a syngeneic model of prostate cancer. A subsequent injection of additional E0771 cancer cells into these mice showed continued resistance to tumor development without the need for tamoxifen induction to produce additional SRC-3 KO Tregs. SRC-3 KO Tregs were highly proliferative and preferentially infiltrated into breast tumors by activating the Chemokine (C-C motif) ligand (Ccl) 19/Ccl21/ Chemokine (C-C motif) Receptor (Ccr)7 signaling axis, generating antitumor immunity by enhancing the interferon-γ/C-X-C Motif Chemokine Ligand (Cxcl) 9 signaling axis to facilitate the entrance and function of effector T cells and Natural Killer cells. SRC-3 KO Tregs also show a dominant effect by blocking the immune suppressive function of WT Tregs. Importantly, a single adoptive transfer of SRC-3 KO Tregs into wild-type E0771 tumor-bearing mice can completely abolish pre-established breast tumors by generating potent antitumor immunity with a durable effect that prevents tumor reoccurrence. Therefore, treatment with SRC-3 deleted Tregs represents a novel approach to completely block tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.

Significance statement

Tregs are essential in restraining immune responses for immune homeostasis. SRC-3 is a pleiotropic coactivator, the second-most highly expressed transcriptional coactivator in Tregs, and a suspect in Treg function. The disruption of SRC-3 expression in Tregs leads to a ‘complete lifetime eradication’ of tumors in aggressive syngeneic breast cancer mouse models because deletion of SRC-3 alters the expression of a wide range of key genes involved in efferent and afferent Treg signaling. SRC-3KO Tregs confer this long-lasting protection against cancer recurrence in mice without an apparent systemic autoimmune pathological phenotype. Therefore, treatment with SRC-3 deleted Tregs could represent a novel and efficient future target for eliminating tumor growth and recurrence without the autoimmune side-effects that typically accompany immune checkpoint modulators.
A Conserved Switch Controls Virulence, Sporulation, and Motility inC. difficile
Authors: DiCandia Michael A. , Edwards Adrianne N. , Lee Cheyenne D. , Monteiro Marcos P. , Cuebas Germán Vargas , Bagchi Pritha , McBride Shonna M.
Published: March 2023

Spore formation is required for environmental survival and transmission of the human enteropathogenicClostridioides difficile. In all bacterial spore formers, sporulation is regulated through activation of the master response regulator, Spo0A. However, the factors and mechanisms that directly regulateC. difficileSpo0A activity are not defined. In the well-studiedBacillusspecies, Spo0A is directly inactivated by Spo0E, a small phosphatase. To understand Spo0E function inC. difficile, we created a null mutation of thespo0Eortholog and assessed sporulation and physiology. Thespo0Emutant produced significantly more spores, demonstrating Spo0E repressesC. difficilesporulation. Unexpectedly, thespo0Emutant also exhibited increased motility and toxin production, and enhanced virulence in animal infections. We uncovered that Spo0E interacts with both Spo0A and the toxin and motility regulator, RstA. Direct interactions between Spo0A, Spo0E, and RstA constitute a previously unknown molecular switch that coordinates sporulation with motility and toxin production. Reinvestigation of Spo0E function inB. subtilisrevealed that Spo0E induced motility, demonstrating Spo0E regulation of motility and sporulation among divergent species. Further, we found that Spo0E orthologs are widespread among prokaryotes, suggesting that Spo0E performs conserved regulatory functions in diverse bacteria.
Ribosomal protein mutation suppresses gonadal leader cell migration defects inmig-17/ADAMTSmutants inCaenorhabditis elegans
Authors: Kim Hon-Song , Mitsuzumi Kaito , Kondo Shohei , Yamaoka Rie , Ihara Shinji , Otsuka Hiroshi , Kubota Yukihiko , Fujiwara Toshinobu , Shibata Yukimasa , Nishiwaki Kiyoji
Published: March 2023

The migration of the gonadal distal tip cells (DTCs) inCaenorhabditis elegansprovides an excellent model for studying the migration of epithelial tubes during organogenesis. Mutations in themig-17/ADAMTSgene cause misdirected migration of DTCs during gonad formation, resulting in deformed gonad arms. An amino-acid substitution in RPL- 20 corresponding to the mammalian RPL18a/eL20, a component of the 60S ribosomal large subunit, showed a slow growth phenotype and strongly suppressed themig-17gonadal defects. Slow-growing mutantsclk-1andclk-2also suppressedmig-17, although weaker thanrlp-20mutants. MIG-17 recruits FBL-1C/fibulin-1C to the gonadal basement membrane to regulate DTC migration. Reducing the gene dosage offbl-1by half partially compromised the suppressor activity of the mutantrpl-20gene onmig-17. Analysis using the mNeonGreen-FBL-1 reporter revealed that its localization to the gonadal basement membrane was significantly reduced inmig-17, whereas it was recovered to the wild-type levels inmig-17; rpl-20double mutants. These results indicate that therpl-20mutation suppressesmig-17gonadal defects through dual mechanisms: deceleration of growth rate and enhancement of FBL-1C recruitment to the gonadal basement membrane.
Atopic dermatitis and risk of 14 site-specific cancers: a Mendelian randomization study
Authors: Liu Qiang , Chen Li , Wang Yipeng , Wang Xiangyu , Lewis Sarah J , Wang Jing
Published: March 2023

IMPORTANCE

Atopic dermatitis (AD) accounts for a large proportion of the burden of skin disease with a prevalence of around 10% among adults worldwide. In addition, systematic reviews and meta-analyses have found that AD is associated with cancer risk at several sites, if found to be causal this could highlight potential treatment targets to reduce cancer risk.

OBJECTIVE

To assess the potential causative link between AD and 14 site-specific cancers in a two-sample Mendelian randomization study.

EXPOSURE

Atopic dermatitis

DESIGN, SETTING, AND PARTICIPANTS

From the largest genome-wide association study (GWAS) of AD (10,788 cases and 30,047 non-cases), genetic variants highly associated (P < 5E-08) with AD in European population were selected as instrumental variables (IVs). Data from large cancer consortia, as well as the UK Biobank study(n=442,239) and the FinnGen study (n=218,792) were employed to assess genetic associations with 14 site-specific cancers and overall cancer. A set of complementary approaches and sensitivity analyses were carried out to examine the robustness of our results. In addition, associations for the same cancer site from different data sources were combined using meta-analyses.

RESULTS

We discovered no strong causal evidence of AD on the risk of overall cancer, with effect estimates close to zero. After Benjamini–Hochberg correction, the inverse weighted method indicated no association of AD on overall cancer risk in both the UK biobank (OR, 1.00; 95%CI, 0.94-1.06; FDR, 0.98) and FinnGen studies (OR, 0.96; 95%CI, 0.92, 1.02; FDR, 0.68). No strong evidence of association was found between genetically predicted AD and the risk of any other site-specific cancers.

CONCLUSIONS AND RELEVANCE

Our MR investigation does not support a causal effect of AD on cancer risk. This finding has important implications for the prevention and management of both AD and cancer, as it reduces the concern of potential adverse effects of AD on cancer outcomes.
Broad and potent neutralizing mAbs are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection
Authors: Seow Jeffrey , Shalim Zayed A. , Graham Carl , Kimuda Simon , Pillai Aswin , Lechmere Thomas , Kurshan Ashwini , Khimji Atika M. , Snell Luke B. , Nebbia Gaia , Mant Christine , Waters Anele , Fox Julie , Malim Michael H. , Doores Katie J.
Published: March 2023

Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, with the emergence of SARS-CoV-2 variants of concern (VOC) which encode mutations in Spike, and the waning of vaccine induced immunity, there has been an increase in SARS-CoV-2 infections in vaccinated individuals which leads to increased serum neutralization breadth. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two-doses of BNT162b2 vaccine before becoming delta or omicron/BA.1-infected, we show that breadth arises from re-activation and maturation of B cells generated through previous COVID-19 vaccination rather than ade novoresponse specific to the VOC Spike. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5 and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicate the presence of conserved epitopes on RBD and a lesser extent NTD. These findings have implications for selection of Spike antigens for next-generation COVID-19 vaccines.
When the difference between incommensurate and commensurate structures becomes elusive: the case of Bi4BO7
X (X = Cl, Br) oxyhalides
Authors: Volkov Sergey , Arsent'ev Maxim , Ugolkov Valery , Povolotskiy Alexey , Savchenko Yevgeny , Krzhizhanovskaya Maria , Bubnova Rimma , Aksenov Sergey
Published: March 2023

Data are reported on the incommensurately modulated structures of bismuth oxyhalide borates, Bi4BO7
X (X = Cl and Br). Their crystal structure is similar to that of the previously reported oxyiodide and can be described as alternating litharge-related [Bi4O4]4+ layers of edge-sharing OBi4 tetrahedra. The X
− and BO3
3− anions fill the interlayer space; they alternate in the following sequence: ...〈...–BO3–BO3–X–X–...〉–X–X–X–〈...–BO3–BO3–X–X–...〉–BO3–BO3–BO3–..., wherein the 〈...–BO3–BO3–X–X–...〉 part of the sequence is maintained for 152 cells for X = Cl and 56 cells for X = Br. The incommensurate structure is deceptively close to the commensurate fourfold a × b × 4c superstructure due to the extreme closeness of the q vector to (0,0,¼). The incommensurate nature of the structure could be revealed from accurate analysis of single-crystal and Rietveld diffraction data. Fine details of the diffraction pattern are discussed, indicating the incommensurate deviation of the crystal structures. The compound Bi4BO7Br was additionally characterized by thermal analysis and vibrational and UV–Vis–NIR spectroscopy, as well as by density functional theory (DFT) calculations. On the basis of the DFT calculations, it is possible to predict that the a × b × 4c superstructure of Bi4BO7Br is unstable under ambient conditions.
Do customer centricity and innovativeness mediate the relationship between total quality management and the corporate success of SaaS companies?
Authors: Dash Ajitabh
Published: March 2023

Purpose

This research explores the mediating role of a firm's innovativeness and customer orientation on the relationship between commercial success and total quality management (TQM) in the Indian SaaS (Software-as-a-Service) sector.

Design/methodology/approach

The hypotheses suggested for this study were validated using partial least squares-based structural equation modeling on data collected from 189 executives working in SaaS companies in India.

Findings

The findings of this study revealed that a SaaS company's innovativeness fully mediates the relationship between TQM and corporate performance, whereas the customer orientation of SaaS companies partially mediates the relationship between TQM and corporate performance.

Originality/value

Findings of this paper indicate that, in addition to TQM deployment, SaaS companies' innovativeness and customer-focused strategy will improve their corporate performance. With minimal research focusing on India, this study may be considered a pioneer work. It can serve as a basis for SaaS company promoters to improve their corporate performance by implementing TQM processes.
Organization capital and firm risks
Authors: Hasan Mostafa Monzur , Cheung Adrian (Wai Kong)
Published: March 2023

Purpose

This paper aims to investigate how organization capital influences different forms of corporate risk. It also explores how the relationship between organization capital and risks varies in the cross-section of firms.

Design/methodology/approach

To test the hypothesis, this study employs the ordinary least squares (OLS) regression model using a large sample of the United States (US) data over the 1981–2019 period. It also uses an instrumental variable approach and an errors-in-variables panel regression approach to mitigate endogeneity problems.

Findings

The empirical results show that organization capital is positively related to both idiosyncratic risk and total risk but negatively related to systematic risk. The cross-sectional analysis shows that the positive relationship between organization capital and idiosyncratic risk is significantly more pronounced for the subsample of firms with high information asymmetry and human capital. Moreover, the negative relationship between organization capital and systematic risk is significantly more pronounced for firms with greater efficiency and firms facing higher industry- and economy-wide risks.

Practical implications

The findings have important implications for investors and policymakers. For example, since organization capital increases idiosyncratic risk and total risk but reduces systematic risk, investors should take organization capital into account in portfolio formation and risk management. Moreover, the findings lend support to the argument on the recognition of intangible assets in financial statements. In particular, the study suggests that standard-setting bodies should consider corporate reporting frameworks to incorporate the disclosure of intangible assets into financial statements, particularly given the recent surge of corporate intangible assets and their critical impact on corporate risks.

Originality/value

To the best of the authors' knowledge, this is the first study to adopt a large sample to provide systematic evidence on the relationship between organization capital and a wide range of risks at the firm level. The authors show that the effect of organization capital on firm risks differs remarkably depending on the kind of firm risk a particular risk measure captures. This study thus makes an original contribution to resolving competing views on the effect of organization capital on firm risks.
Investigation on dynamic mathematical model and control method of flue gas heat exchange system
Authors: Ma Hongqiang , Xie Yue , Song Xingpeng , Liu Yu , Luo Xinmei , Wang Shengxun
Published: March 2023

Purpose

The purpose of this paper is to recover the waste heat of flue gas heat exchanger (FGHE) as efficiently as possible and avoid the acid dew corrosion of that.

Design/methodology/approach

A novel flue gas waste heat recovery system was proposed in the paper. The dynamic mathematical models of key equipment in that were established based on theory and experiment method. The proportion integration differentiation-differentiation (PID-P) cascade control method based on particle swarm optimization algorithm was used to control the outlet temperature of FGHE. The dynamic characteristics of the flue gas heat exchange system were simulated by the particle swarm optimization algorithm with different fitness functions.

Findings

The PID-P temperature controller parameters can be quickly and effectively obtained by the particle swarm optimization algorithm based on the fitness function of integral time absolute error (ITAE). The overshoot, rise time and adjusting time of the novel system are 2, 83 and 105s, respectively. Compared with the traditional two-step tuning (T-ST) method, the novel system is better in dynamic and steady-state performance. The overshoot and the adjustment time of the system are reduced by 44% and 328s, respectively. ITAE is a performance evaluation index for control system with good engineering practicability and selectivity.

Originality/value

The dynamic mathematical model of key equipment in the new flue gas waste heat recovery system is established and the system's control strategies and methods are explored.
Workers’ mobility across occupations: Complementary insights from the human capital, migration and social stratification literature.
Authors: Cardoso Ben Hur Francisco , Hartmann Dominik
Published: March 2023

Purpose

A growing body of literature shows how intragenerational occupational mobility affects economic dynamics and social stratification. In this article the authors aim to carry out a structured review of this literature, outlining a systemic overview for more comprehensive research and public policies.

Design/methodology/approach

The authors use methods from structured literature reviews and network science to reveal the segmented research landscape of occupational mobility literature. The authors made an in-depth analysis of the most important papers to summarize the main contributions of the literature and identify research gaps.

Findings

The authors reveal a segmented research landscape around three communities: (1) human capital theory, (2) social stratification theory and (3) migration studies. Human capital research uses microfounded mathematical modeling to understand the relationship between skills and mobility. Nevertheless, it cannot explain social segregation and generally does not focus on the importance of local labor demand. Social stratification research can explain the social and institutional barriers to occupational mobility. Migration research studies the relationship between migration, labor demand and social mobility.

Originality/value

This paper is the first literature review that uses network analysis to perform a systematic review of the intragenerational occupational mobility literature. Moreover, this review identifies opportunities for mutual learning and research gaps in the research landscape.