bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of a mouse germ cell tumor model establishes pluripotency-associated miRNAs as conserved serum biomarkers for germ cell cancer detection
Authors: Loehr Amanda R. , Timmerman Dennis M. , Liu Michelle , Gillis Ad J.M. , Matthews Melia , Bloom Jordana C. , Nicholls Peter K. , Page David C. , Miller Andrew D. , Looijenga Leendert H.J. , Weiss Robert S.
Published: September 2023

Malignant testicular germ cells tumors (TGCTs) are the most common solid cancers in young men. Current TGCT diagnostics include conventional serum protein markers, but these lack the sensitivity and specificity to serve as accurate markers across all TGCT subtypes. MicroRNAs (miRNAs) are small non-coding regulatory RNAs and informative biomarkers for several diseases. In humans, miRNAs of the miR-371-373 cluster are detectable in the serum of patients with malignant TGCTs and outperform existing serum protein markers for both initial diagnosis and subsequent disease monitoring. We previously developed a genetically engineered mouse model featuring malignant mixed TGCTs consisting of pluripotent embryonal carcinoma (EC) and differentiated teratoma that, like the corresponding human malignancies, originate in utero and are highly chemosensitive. Here, we report that miRNAs in the mouse miR-290-295 cluster, homologs of the human miR-371-373 cluster, were detectable in serum from mice with malignant TGCTs but not from tumor-free control mice or mice with benign teratomas. miR-291-293 were expressed and secreted specifically by pluripotent EC cells, and expression was lost following differentiation induced by the drug thioridazine. Notably, miR-291-293 levels were significantly higher in the serum of pregnant dams carrying tumor-bearing fetuses compared to that of control dams. These findings reveal that expression of the miR-290-295 and miR-371-373 clusters in mice and humans, respectively, is a conserved feature of malignant TGCTs, further validating the mouse model as representative of the human disease. These data also highlight the potential of serum miR-371-373 assays to improve patient outcomes through early TGCT detection, possibly even prenatally.
Supercharging carbohydrate-binding module alone enhances endocellulase thermostability, binding, and activity on cellulosic biomass
Authors: DeChellis Antonio , Nemmaru Bhargava , Sammond Deanne , Douglass Jenna , Patil Nivedita , Reste Olivia , Chundawat Shishir P. S.
Published: September 2023

Lignocellulosic biomass recalcitrance to enzymatic degradation necessitates high enzyme loadings incurring large processing costs for industrial-scale biofuels or biochemicals production. Manipulating surface charge interactions to minimize non-productive interactions between cellulolytic enzymes and plant cell wall components (e.g., lignin or cellulose) via protein supercharging has been hypothesized to improve biomass biodegradability, but with limited demonstrated success to date. Here we characterize the effect of introducing non-natural enzyme surface mutations and net charge on cellulosic biomass hydrolysis activity by designing a library of supercharged family-5 endoglucanase Cel5A and its native family-2a carbohydrate binding module (CBM) originally belonging to an industrially relevant thermophilic microbeThermobifida fusca. A combinatorial library of 33 mutant constructs containing different CBM and Cel5A designs spanning a net charge range of −52 to 37 was computationally designed using Rosetta macromolecular modelling software. Activity for all mutants was rapidly characterized as soluble cell lysates and promising mutants (containing mutations either on the CBM, Cel5A catalytic domain, or both CBM and Cel5A domains) were then purified and systematically characterized. Surprisingly, often endocellulases with mutations on the CBM domain alone resulted in improved activity on cellulosic biomass, with three top-performing supercharged CBM mutants exhibiting between 2–5-fold increase in activity, compared to native enzyme, on both pretreated biomass enriched in lignin (i.e., corn stover) and isolated crystalline/amorphous cellulose. Furthermore, we were able to clearly demonstrate that endocellulase net charge can be selectively fine-tuned using protein supercharging protocol for targeting distinct substrates and maximizing biocatalytic activity. Additionally, several supercharged CBM containing endocellulases exhibited a 5–10 °C increase in optimal hydrolysis temperature, compared to native enzyme, which enabled further increase in hydrolytic yield at higher operational reaction temperatures. This study demonstrates the first successful implementation of enzyme supercharging of cellulolytic enzymes to increase hydrolytic activity towards complex lignocellulosic biomass derived substrates.
Examining DNA Breathing with pyDNA-EPBD
Authors: Kabir Anowarul , Bhattarai Manish , Rasmussen Kim Ø. , Shehu Amarda , Usheva Anny , Bishop Alan R , Alexandrov Boian S
Published: September 2023

Motivation

The two strands of the DNA double helix locally and spontaneously separate and recombine in living cells due to the inherent thermal DNA motion.This dynamics results in transient openings in the double helix and is referred to as “DNA breathing” or “DNA bubbles.” The propensity to form local transient openings is important in a wide range of biological processes, such as transcription, replication, and transcription factors binding. However, the modeling and computer simulation of these phenomena, have remained a challenge due to the complex interplay of numerous factors, such as, temperature, salt content, DNA sequence, hydrogen bonding, base stacking, and others.

Results

We present pyDNA-EPBD, a parallel software implementation of the Extended Peyrard-Bishop-Dauxois (EPBD) nonlinear DNA model that allows us to describe some features of DNA dynamics in detail. The pyDNA-EPBD generates genomic scale profiles of average base-pair openings, base flipping probability,DNA bubble probability, and calculations of the characteristically dynamic length indicating the number of base pairs statistically significantly affected by a single point mutation using the Markov Chain Monte Carlo (MCMC) algorithm.
Perceptual uncertainty explains activation differences between audiovisual congruent speech and McGurk stimuli
Authors: Dong Chenjie , Noppeney Uta , Wang Suiping
Published: September 2023

Face-to-face communication relies on the integration of acoustic speech signals with the corresponding facial articulations. While the McGurk illusion is widely used as an index of audiovisual speech integration, critics argue that it arises from perceptual processes that differ categorically from natural speech recognition. Conversely, Bayesian theoretical frameworks suggest that both the illusory McGurk and the veridical audiovisual congruent speech percepts result from probabilistic inference based on noisy sensory signals. According to these models, the inter-sensory conflict in McGurk stimuli may only increase observers’ perceptual uncertainty. This functional magnetic resonance imaging (fMRI) study presented participants (20 male and 24 female) with audiovisual congruent, incongruent, and McGurk stimuli along with their unisensory counterparts in a syllable categorization task. Behaviorally, observers’ response entropy was greater for McGurk compared to congruent audiovisual stimuli. At the neural level, McGurk stimuli increased activations in a widespread neural system, extending from the inferior frontal sulci (IFS) to the pre-supplementary motor area (pre-SMA) and insulae, typically involved in cognitive control processes. Crucially, in line with Bayesian theories these activation increases were fully accounted for by observers’ perceptual uncertainty as measured by their response entropy. Our findings suggest that McGurk and congruent speech processing rely on shared neural mechanisms, thereby supporting the McGurk illusion as a valid measure of natural audiovisual speech perception.

Significance Statement

Effective face-to-face communication relies on integrating acoustic speech signals with the corresponding facial articulations. While McGurk illusion is extensively used to study audiovisual speech perception, recent critiques argue that it may be categorically different from typical speech recognition because of the conflict between the audiovisual inputs. This study demonstrates that McGurk stimuli increase activations in a network of regions typically involved in cognitive control. Crucially, the activation differences between McGurk and normal speech stimuli could be fully accounted for by the variation in observers’ perceptual uncertainties. Our results suggest that McGurk and congruent audiovisual speech stimuli rely on shared neural mechanisms – thereby supporting the validity of the McGurk illusion as a tool for studying natural audiovisual speech perception.
Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing
Authors: Bard Angela M. , Clark Lindsay V. , Cosgun Erdal , Aldinger Kimberly A. , Timms Andrew , Quina Lely A. , Lavista Ferres Juan M. , Jardine David , Haas Elisabeth A. , Becker Tatiana M , Pagan Chelsea M , Santani Avni , Martinez Diego , Barua Soumitra , McNutt Zakkary , Nesbitt Addie , Mitchell Edwin A , Ramirez Jan-Marino
Published: September 2023

Purpose

To gain insights into potential genetic factors contributing to the infant’s vulnerability to Sudden Unexpected Infant Death (SUID).

Methods

Whole Genome Sequencing (WGS) was performed on 145 infants that succumbed to SUID, and 576 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences.

Results

Variants of interest were identified in 86 genes, 63.4% of our cohort. Seventy-one of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria (Figure 1).

Conclusion

Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID.
A Bayesian approach to identifying the role of hospital structure and staff interactions in nosocomial transmission of SARS-CoV-2
Authors: Bridgen Jessica R.E. , Lewis Joseph M. , Todd Stacy , Taegtmeyer Miriam , Read Jonathan M. , Jewell Chris P.
Published: September 2023

Nosocomial infections threaten patient safety, and were widely reported during the COVID-19 pandemic. Effective hospital infection control requires a detailed understanding of the role of different transmission pathways, yet these are poorly quantified. Using patient and staff data from a large UK hospital we demonstrate a method to infer unobserved epidemiological event times efficiently and disentangle the infectious pressure dynamics by ward. A stochastic individual-level, continuous-time state-transition model was constructed to model transmission of SARS-CoV-2, incorporating a dynamic staff-patient contact network as time-varying parameters. A Metropolis-Hastings MCMC algorithm was used to estimate transmission rate parameters associated with each possible source of infection, and the unobserved infection and recovery times. We found that the total infectious pressure exerted on an individual in a ward varied over time, as did the primary source of transmission. There was marked heterogeneity between wards; each ward experienced unique infectious pressure over time. Hospital infection control should consider the role of between-ward movement of staff as a key infectious source of nosocomial infection for SARS-CoV-2. With further development, this method could be implemented routinely for real-time monitoring of nosocomial transmission and to evaluate interventions.
Recapturing the Initial Clinical Benefit of TMS in a Major Depressive Episode: a Retrospective Analysis in a Veteran Cohort
Authors: Laufer Jeremy , Olmsted Alisa , Sampair Irina , Madore Michelle , Yoon Jong , Hack Laura , Keller Corey J.
Published: September 2023

Background

Repetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question.

Aims

Following an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course.

Methods

116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response.

Results

Of the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. Exploratory regression analysis predicted change in depression symptoms (PHQ-9) during a second TMS course using initial treatment response, time into treatment, and baseline symptom severity. Together, these factors explained 72% of the variance. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well.

Conclusions

Our findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.
High burden of anti-microbial resistance among neonatal blood stream infections in Southeast Asia: results of the NeoSEAP study
Authors: R Dickson Benjamin F , Putri Nina Dwi , Adrizain Riyadi , Kartina Leny , Villaneuva Uy Maria Esterlita , Gunaratna Gayana , Le Chau , Tran Hoang , Xuân Hương Nguyễn , Sukarja Distayay , Yuniati Tetty , Utomo Martono , Kieu Trinh Nguyen Thi , Thanh Thuy Hoang Nguyen , Cam Tu Tran Thi , Hong Le Tuyet , Fong Siew Moy , Harrison Michelle , M Williams Phoebe C
Published: September 2023

Background

Progress on neonatal sepsis has remained modest in recent decades and is threatened by the global rise of antimicrobial resistance. The Southeast Asian region has a high burden of both neonatal sepsis and antimicrobial resistance. Despite this, their remains a lack of robust epidemiological data on the causes of neonatal sepsis and the prevalence of AMR in the region.

Methods

We evaluated the causes of neonatal sepsis and AMR burden in 10 sites across five countries in South and Southeast Asia (Sri Lanka, Indonesia, The Philippines, Malaysia and Vietnam). Retrospective data on all blood cultures collected from neonates between 1stJanuary 2019 – 31stDecember 2020 were extracted from laboratory records. Data were also collected on the availability of clinical resources, the implementation of infection prevention and control strategies, and antimicrobial prescribing practices.

Findings

A total of 1,528 blood cultures were positive for significant isolates over the study period. Gram-negative pathogens predominated (1,163/1,528, 76.1%) with the most frequently isolated pathogensKlebsiellaspp. (408/1,528, 26.7%) andAcinetobacterspp. (261/1,528, 17.08%) Among Gram-negative Enterobacteriaceae pooled resistance to ampicillin, gentamicin, third-generation cephalosporins (ceftriaxone and/or cefotaxime) and carbapenems was 75% (193/257), 59% (393/665), 67% (441/655) and 18.6% (125/672). For Gram negative non-Enterobacteriaceae resistance to gentamicin and carbapenems was 76.6% (326/282) and 69.7% (207/297).

Interpretation

Neonatal sepsis among study sites was caused predominantly by Gram-negative pathogens and associated with high levels of non-susceptibility to common empirical treatment regimes.
Enhancing Recovery from Gut Microbiome Dysbiosis and Alleviating DSS-Induced Colitis in Mice with a Consortium of Rare Short-Chain Fatty Acid-Producing Bacteria
Authors: Ambat Achuthan , Antony Linto , Maji Abhijit , Ghimire Sudeep , Mattiello Samara , Kashyap Purna C. , More Sunil , Sebastian Vanessa , Scaria Joy
Published: September 2023

The human gut microbiota is a complex community comprising hundreds of species, with a few present in high abundance and the vast majority in low abundance. The biological functions and effects of these low-abundant species on their hosts are not yet fully understood. In this study, we assembled a bacterial consortium (SC-4) consisting ofB. paravirosa, C. comes, M. indica, andA. butyriciproducens, which are low-abundant, short-chain fatty acid (SCFA)-producing bacteria isolated from healthy human gut, and tested its effect on host health using germfree and human microbiota-associated colitis mouse models. The selection also favored these four bacteria being reduced in abundance in either Ulcerative Colitis (UC) or Crohn’s disease (CD) metagenome samples. Our findings demonstrate that SC-4 can colonize germ-free (GF) mice, increasing mucin thickness by activating MUC-1 and MUC-2 genes, thereby protecting GF mice from Dextran Sodium Sulfate (DSS)-induced colitis. Moreover, SC-4 aided in the recovery of human microbiota-associated mice from DSS-induced colitis, and intriguingly, its administration enhanced the alpha diversity of the gut microbiome, shifting the community composition closer to control levels. The results showed enhanced phenotypes across all measures when the mice were supplemented with Inulin as a dietary fiber source alongside SC-4 administration. We also showed a functional redundancy existing in the gut microbiome, resulting in the low abundant SCFA producers acting as a form of insurance, which in turn accelerates recovery from the dysbiotic state upon the administration of SC-4. SC-4 colonization also upregulated iNOS gene expression, further supporting its ability to produce an increasing number of goblet cells. Collectively, our results provide evidence that low-abundant SCFA-producing species in the gut may offer a novel therapeutic approach to IBD.
Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates
Authors: Yang Zi , Yoshii Saori R. , Sakai Yuji , Chino Haruka , Knorr Roland L. , Mizushima Noboru
Published: September 2023

During PINK1 and Parkin-mediated mitophagy, autophagy adaptors are recruited to depolarized mitochondria to promote the selective degradation of mitochondria. Autophagy adaptors such as OPTN and NDP52 bridge mitochondria and autophagosomal membranes by binding to ubiquitinated mitochondrial proteins and autophagosomal ATG8 family proteins. Here, we demonstrate that OPTN and NDP52 form sheet-like phase-separated condensates with liquid-like properties on the surface of ubiquitinated mitochondria. The dynamic and liquid-like feature of OPTN condensates is important for mitophagy activity because reducing the liquidity of OPTN–ubiquitin condensates suppresses the recruitment of ATG9 vesicles and impairs mitophagy. Based on these results, we propose a dynamic liquid-like model of autophagy adaptors, in contrast to a stoichiometric model, to explain their interactions between autophagic membranes (i.e., ATG9 vesicles and isolation membranes) and mitochondrial membranes during Parkin-mediated mitophagy. This model underscores the importance of liquid–liquid phase separation in facilitating membrane– membrane contacts, likely through the generation of capillary forces.
Structural basis for EROS binding to human phagocyte NADPH oxidase NOX2
Authors: Liang Shiyu , Liu Aijun , Liu Yezhou , Wang Fuxing , Zhou Youli , Wang Tao , Liu Zheng , Ren Ruobing , Ye Richard D.
Published: September 2023

EROS (essential for reactive oxygen species) is a recently identified molecular chaperone of NOX2 (gp91phox), the catalytic subunit of phagocyte NADPH oxidase. Deficiency in NOX2 expression or function due to genetic mutations leads to chronic granulomatous disease (CGD) with recurrent bacterial and fungal infections. To delineate how EROS interacts with NOX2, we solved the cryo-EM structure of the EROS-NOX2-p22phoxheterotrimeric complex. EROS binds to NOX2 in plasma membrane through its anti-parallel α-helices H1 and H2, and in cytoplasm through multiple β-strands that form hydrogen bonds with the C terminal fragment of NOX2. EROS binding alters the conformation of the TM2 and TM6 transmembrane helices, increases the distance between the two hemes, and causes dislocation of the binding site for flavin adenine dinucleotide (FAD). EROS colocalizes with NOX2 on cell surface of neutrophil-like HL-60 cells and forms a heterotrimer with mature NOX2-p22phoxin transfected cells. Phorbol myristate acetate, an activator of NOX2, induces dissociation of EROS from NOX2 in a NanoLuc complementation assay with concurrent production of superoxide in reconstituted cells. Taken together, these findings provide a structural basis for EROS-NOX2 interaction and suggest a previously unidentified function of EROS in regulating NOX2 activation.
Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice
Authors: Creisher Patrick S. , Parish Maclaine A. , Lei Jun , Liu Jin , Perry Jamie L. , Campbell Ariana D. , Sherer Morgan L. , Burd Irina , Klein Sabra L.
Published: September 2023

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes, but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2α. Treatment with 17-α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy.

Importance

Pregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. We developed an outbred mouse model of 2009 H1N1 influenza virus infection during pregnancy, with semi-allogenic fetuses. When dams are infected with 2009 H1N1, in addition to pulmonary virus replication, tissue damage, and inflammation, the placenta shows evidence of transient damage and inflammation that is mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone are associated with long-term effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment safe that is safe to use in pregnancy, prevents placental damage and inflammation and adverse fetal outcomes. This provided a novel therapeutic option for treatment of influenza during pregnancy that should be explored clinically.
Influenza A virus activates the unfolded protein response and induces the accumulation of insoluble protein aggregates that are essential for efficient viral propagation
Authors: Marques Mariana , Ramos Bruno , Albuquerque Hélio , Pereira Marisa , Ribeiro Diana Roberta , Nunes Alexandre , Sarabando Jéssica , Brás Daniela , Ferreira Ana Rita , Vitorino Rui , Amorim Maria João , Silva Artur M. S. , Soares Ana Raquel , Ribeiro Daniela
Published: September 2023

Influenza A virus (IAV) is one of the main causes of annual respiratory epidemics in humans. IAV employs multiple strategies to evade host immunity and hijack cellular mechanisms to support proper virion formation and propagation. Some of these strategies encompass the manipulation of pathways involved in protein homeostasis, leading to changes in the host proteome and protein distribution within the cell. In this study, we performed a detailed analysis of the interplay between IAV and the host cells’ proteostasis mechanisms throughout the entire infectious cycle. We reveal that IAV infection induces the activation of the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response (UPR), at an infection stage that coincides with high rates of viral protein translation. This activation is particularly important for infection, as attenuation of virus production was observed upon IRE1 inhibition. Concomitantly to UPR activation, we observed the accumulation of virus-induced insoluble protein aggregates, which contain both viral and host proteins and are associated with a dysregulation of the host cell RNA metabolism. We demonstrate that this accumulation is important for IAV propagation, as its prevention using a quinoline-steroid hybrid compound significantly reduces the number of produced infectious virus particles. Our data suggests that the formation of these insoluble protein aggregates favors the final steps of the infection cycle, more specifically the virion assembly. Our findings reveal additional mechanisms by which IAV disrupts the host cell proteostasis to favor infection and uncover new cellular targets that can be explored for the development of host-directed antiviral strategies.
Row1, a member of a new family of conserved fungal proteins involved in infection, is required for appressoria functionality in Ustilago maydis
Authors: Pejenaute-Ochoa María Dolores , Tomás-Gallardo Laura , Ibeas José I. , Barrales Ramón R.
Published: September 2023

The appressorium of phytopathogenic fungi is a specific structure with a crucial role in plant cuticle penetration. Pathogens with melanized appressoria break the cuticle through cell wall melanization and intracellular turgor pressure. However, in fungi with non-melanized appressorium, the mechanisms governing cuticle penetration are poorly understood. Here we characterize Row1, a previously uncharacterized appressoria-specific protein ofUstilago maydisthat localizes to membrane and secretory vesicles. Deletion ofrow1decrease appressoria formation and plant penetration, thereby reducing virulence. Specifically, the Δrow1mutant has a thicker cell wall that is more resistant to glucanase degradation. We also observed that the Δrow1mutant has secretion defects. Our data suggest that Row1 could modify the glucans that form the fungal cell wall and may be involved in unconventional protein secretion, thereby promoting both appressoria maturation and penetration. We show that Row1 is functionally conserved at least among Ustilaginaceae and belongs to the Row family, which consists of five other proteins that are highly conserved among Basidiomycota fungi and are involved inU. maydisvirulence. We observed similarities in localization between Row1 and Row2, which is also involved in cell wall remodelling and secretion, suggesting similar molecular functions for members of this protein family.
SIRT1 and SIRT3 impact host mitochondrial function and host-SalmonellapH balance during infection
Authors: Hajra Dipasree , Yadav Vikas , Singh Amit , Chakravortty Dipshikha
Published: September 2023

Mitochondria are an important organelle regulating energy homeostasis. Mitochondrial health and dynamics are crucial determinants of the outcome of several bacterial infections. SIRT3, a major mitochondrial sirtuin, along with SIRT1 regulates key mitochondrial functions. This led to considerable interest in understanding the role of SIRT1 and SIRT3 in governing mitochondrial functions duringSalmonellainfection. Here, we show that loss of SIRT1 and SIRT3 function either by shRNA-mediated knockdown or inhibitor treatment led to increased mitochondrial dysfunction with alteration in mitochondrial bioenergetics alongside increased mitochondrial superoxide generation in theSalmonella-infected macrophages. Consistent with dysfunctional mitochondria, mitophagy was induced along with altered mitochondrial fusion-fission dynamics inS.Typhimurium-infected macrophages. Additionally, the mitochondrial bioenergetic alteration promotes acidification of the infected macrophage cytosolic pH. This host cytosolic pH imbalance skewed the intra-phagosomal and intra- bacterial pH in the absence of SIRT1 and SIRT3, resulting in decreased SPI-2 gene expression. Our results suggest a novel role of SIRT1 and SIRT3 in maintaining the intracellularSalmonellaniche by modulating the mitochondrial bioenergetics and dynamics in the infected macrophages.

Graphical Abstract
SCCmectransformation requires living donor cells in mixed biofilms
Authors: Maree Mais , Ushijima Yuri , Higashide Masato , Morikawa Kazuya
Published: September 2023

Methicillin-resistantStaphylococcus aureus(MRSA) is an important human pathogen that has emerged through the horizontal acquisition of the staphylococcus cassette chromosomemec(SCCmec). Previously, we showed that SCCmecfrom heat-killed donors can be transferred via natural transformation in biofilms at frequencies of 10-8-10-7. Here, we show an improved transformation assay of SCCmecwith frequencies up to 10-2using co-cultured biofilms with living donor cells. The Ccr-attB system played an important role in SCCmectransfer, and the deletion ofccrABrecombinase genes reduced the frequency ∼30-fold. SCCmeccould be transferred from either MRSA or methicillin-resistant coagulase-negative staphylococci to some of methicillin-sensitiveS. aureusrecipients. In addition, the transformation of other plasmid or chromosomal genes is enhanced by using living donor cells. This study emphasizes the role of natural transformation as an evolutionary ability ofS. aureusand in MRSA emergence.

Importance

Methicillin-resistantStaphylococcus aureus(MRSA) stands out as the leading contributor to fatalities attributed to antibiotic-resistant infections. To comprehend its emergence and dissemination, it is crucial to understand the mechanisms behind it. MRSA has arisen through the horizontal acquisition of the methicillin resistance genemecA, which is harboured within the staphylococcal cassette chromosome (SCCmec). Our study sheds light on a noteworthy discovery: when methicillin-sensitiveS. aureusrecipient cells are grown alongside viable methicillin-resistant donor cells in co-cultured biofilms, a highly efficient transfer of SCCmecoccurs, both within the same species and between different species. This remarkable transfer process is facilitated by natural transformation, underscoring its pivotal role in the evolution of staphylococci and the emergence of MRSA.
NRF2 pathway activation reverts high-glucose-induced transcriptional memory in endothelial cells
Authors: Wilson-Verdugo Martí , Bustos-García Brandon , Adame-Guerrero Olga , Hersch-González Jaqueline , Cano-Dominguez Nallely , Soto-Nava Maribel , Acosta Carlos A. , Tusie-Luna Teresa , Avila-Rios Santiago , Noriega Lilia G. , Valdes Victor J.
Published: September 2023

Various diabetes complications, including nephropathy, retinopathy, and cardiovascular disease, arise from vascular dysfunction. In this context, it has been observed that past hyperglycaemic events can induce long-lasting transcriptional changes, a phenomenon termed “metabolic memory”. Yet, the underlying mechanisms driving these persistent effects are not fully characterized. In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high glucose exposure in human endothelial cells (ECs). We found that cells exposed to a transient high glucose episode had decreased glycolytic and oxygen consumption rates. Transcriptional profiling indicated that high glucose exposure induced substantial changes in the expression of genes belonging to pathways known to be impaired in diabetes, such as TGF-beta, TNF, FoxO, p53, and NRF2 pathways, many of which were retained after normalization of glucose concentrations. Furthermore, analysis of chromatin accessibility showed that transient hyperglycaemia can induce persistent modifications in the accessibility landscape, with the majority of differentially accessible regions located in non-promoter regions. Some of these regions were identified as putative enhancers with neighbouring genes persistently altered after transient high glucose exposure. Finally, we showed that activation of the NRF2 pathway through either NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, was able to substantially revert the glucose-induced transcriptional memory in ECs. Our findings demonstrate that transient high glucose can induce persistent changes in both the transcriptomic and chromatin accessibility profiles of ECs, and that pharmacological NRF2 pathway activation is able to prevent and revert the high-glucose-induced transcriptional memory.

Abstract Figure
ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules
Authors: Mariani Davide , Setti Adriano , Castagnetti Francesco , Vitiello Erika , Mecarelli Lorenzo Stufera , Timoteo Gaia di , Giuliani Andrea , Perego Eleonora , Zappone Sabrina , Liessi Nara , Armirotti Andrea , Vicidomini Giuseppe , Bozzoni Irene
Published: September 2023

Stress Granules (SG) formation is a cellular protection mechanism, constituting a storage for untranslated mRNAs and RNA-binding proteins (RBPs); however, these condensates can turn into pathological aggregates, related to the onset of neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS). This transition towards cytotoxic inclusions is triggered by ALS-causative mutations in the RBP FUS, which lead to its cytoplasmic mis-localization and accumulation in SG. Here, we describe the SG transcriptome in a neural context and describe several features for RNA recruitment in SG. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of mutant FUS, switching to a more unstructured, AU-rich SG transcriptome. Moreover, we show that mutant FUS, together with its protein interactors and their target RNAs, are responsible for the reshaping of the mutant SG transcriptome with alterations that can be linked to neurodegeneration. Therefore, our data give a comprehensive view of the molecular differences between physiological and pathological SG in ALS conditions, showing how FUS mutations impact the RNA and protein population of these condensates.
Chromatin loop dynamics during cellular differentiation are associated with changes to both anchor and internal regulatory features
Authors: Bond Marielle L. , Davis Eric S. , Quiroga Ivana Y. , Dey Anubha , Kiran Manjari , Love Michael I. , Won Hyejung , Phanstiel Douglas H.
Published: September 2023

Three-dimensional (3D) chromatin structure has been shown to play a role in regulating gene transcription during biological transitions. Although our understanding of loop formation and maintenance is rapidly improving, much less is known about the mechanisms driving changes in looping and the impact of differential looping on gene transcription. One limitation has been a lack of well-powered differential looping data sets. To address this, we conducted a deeply sequenced Hi-C time course of megakaryocyte development comprising four biological replicates and 6 billion reads per time point. Statistical analysis revealed 1503 differential loops. Gained loop anchors were enriched for AP-1 occupancy and were characterized by large increases in histone H3K27ac (over 11-fold) but relatively small increases in CTCF and RAD21 binding (1.26- and 1.23-fold, respectively). Linear modeling revealed that changes in histone H3K27ac, chromatin accessibility, and JUN binding were better correlated with changes in looping than RAD21 and almost as well correlated as CTCF. Changes to epigenetic features between—rather than at—boundaries were highly predictive of changes in looping. Together these data suggest that although CTCF and RAD21 may be the core machinery dictating where loops form, other features (both at the anchors and within the loop boundaries) may play a larger role than previously anticipated in determining the relative loop strength across cell types and conditions.
Puran poli [1] to Purna Bramha: an exemplary entrepreneurial journey
Authors: Maheshwari Kalpana
Published: September 2023

Learning outcomes

This case study aims to understand the role of women entrepreneurship that reconcile the interests of not only business but also the economy as a whole; to map the most common avenues and levers as well as challenges and impediments in entrepreneurship; and to study how women have proved themselves and created value (for company as well as consumer) and driven leadership in business.

Case overview/synopsis

This case study predominantly is an entrepreneurial journey of the protagonist who left her cushy job to follow her dreams and started her own venture in hospitality industry. The case is designed on the basis of rounds of interviews conducted with the owner, hence it is based on primary data. Jayanti Kathale, a technology expert, working with a reputed organization, started Purna Bramha in 2013. The unique selling proposition of her food business was the home-like taste of the Marathi cuisine that she was serving. There were challenges like funding, logistics and pricing just like any other start-up. But Jayanti was determined to excel and her perseverance helped her get through all the challenges. Besides being a successful entrepreneur herself, she played a role in empowering other women also, by offering them franchisees of her restaurant. The food service industry is fast-paced, competitive and constantly evolving. This is taken well into consideration and proper training is organized for the staff. The protagonist's main quandary at this time is her pricing strategy.

Complexity academic level

The case is designed to be taught to the undergraduate and postgraduate management students and any other equivalent course. It can be taught in 2-h class and is expected to require some outside preparation by students. The students should be acquainted with the basic concepts of entrepreneurship and organizational culture in India. The instructor should focus on two aspects in the case. The broader aspect is Entrepreneurship in India and the narrower and more focused ones like Women Leadership.

Subject code

CCS 3: Entrepreneurship

Supplementary materials

Teaching notes are available for educators only.
Dual solutions for general three-dimensional MHD boundary layer stagnation-point flow of hybrid nanofluid and heat transfer
Authors: Zainal Nurul Amira , Khashi'ie Najiyah Safwa , Waini Iskandar , Mohd Kasim Abdul Rahman , Nazar Roslinda , Pop Ioan
Published: September 2023

Purpose

The evaluation of high thermal efficiency has actively highlighted the unique behaviour of hybrid nanofluid. Thus, the purpose of this paper is to emphasize the hybrid nanofluid’s stagnation point in three-dimensional flow with magnetic field.

Design/methodology/approach

The defined ordinary differential equations systems are addressed using the bvp4c solver.

Findings

The results indicate that using dual solutions is possible as long as the physical parameters remain within their specified ranges. Hybrid nanofluid flow has been recognised for its superior heat transfer capabilities in comparison to both viscous flow and nanofluid flow. Furthermore, it has been demonstrated in the current study that augmenting the volume concentration of nanoparticles leads to a corresponding enhancement in the rate of heat transfer. When the velocity gradients ratio is augmented, there is a corresponding reduction in the thermal performance. The separation value grows as the magnetic parameter rises, which signifies the expansion of the boundary layer.

Originality/value

The originality of the paper highlights the general mathematical hybrid model of the three-dimensional problem with the magnetohydrodynamics (MHD) effect in the stagnation point flow. The comprehensive examination of the suggested model has not yet been thoroughly addressed in prior research.
Related party transactions and earnings quality: the moderating role of female directors
Authors: Bona Sánchez Carolina , Elistratova Marina , Pérez Alemán Jerónimo
Published: September 2023

Purpose

This study aims to analyse the effect of related party transactions (RPTs) on earnings quality in a sample of Spanish listed firms, as well as the moderating role played by female directors in the relationship between RPTs and earnings quality.

Design/methodology/approach

The sample includes non-financial Spanish listed firms from 2005 to 2019. The authors use panel data analysis based on the firm fixed-effect estimator. Additionally, the authors use the two-step system generalized method of moments estimator to test the robustness of the results.

Findings

The results show a negative effect of RPTs on earnings quality. Further analysis reveals that the negative effect is mainly driven by transactions between the firm and its directors and major shareholders, as well as by RPTs that are more likely to reflect insiders’ self-interest. Moreover, the authors show that the presence of female directors reduces the negative impact of RPTs on earnings quality.

Practical implications

The study provides practical implications for investors, auditors and policymakers, who should be aware that RPTs might harm earnings quality and adversely affect the flow of financial capital to promising investment opportunities. Additionally, the study evidences the key governance role played by female directors regarding financial reporting policies as RPTs increase.

Social implications

The findings promote the need for a higher representation of women in leadership positions since the authors reveal the key governance role played by female directors regarding financial reporting policies as RPTs increase.

Originality/value

The results to emerge from the study complement available evidence concerning the effect of RPTs on earnings quality in a continental European country. The authors also provide novel evidence vis-à-vis the role of female directors in the relationship between RPTs and earnings quality.
B2C multi- to single-channel: the effect of removing a consumer channel preference on consumer retailer and channel choice
Authors: Ngoh Cheryl-lyn , Mellema Hillary N.
Published: September 2023

Purpose

This paper aims to study how retailers moving from a multi- (in-store and online) to a single- (online) channel impacts consumers’ retailer and channel choices.

Design/methodology/approach

The authors conduct two scenario-based experimental studies to examine consumers’ in-store and online channel shopping preferences and behavioural intentions (i.e. channel and retailer choices) when their preferred focal retailer’s physical store closes.

Findings

The findings show that when a focal retailer removes its physical store location, consumers with a strong preference for shopping online have a greater likelihood of shopping online. Their loyalty towards the retailer explains this relationship but is conditional on low levels of reactance. When reactance is high, consumers with a strong preference for shopping online are more likely to switch to a competitor.

Originality/value

This research paper bridges the intersection between B2B and B2C literature to understand how retailers’ channel-related supply chain decisions affect downstream consumer shopping behaviour.
Key technologies and applications of intelligent dispatching command for high-speed railway in China
Authors: Ding Shuxin , Zhang Tao , Sheng Kai , Chen Yuanyuan , Yuan Zhiming
Published: September 2023

Purpose

The intelligent Central Traffic Control (CTC) system plays a vital role in establishing an intelligent high-speed railway (HSR) system. As the core of HSR transportation command, the intelligent CTC system is a new HSR dispatching command system that integrates the widely used CTC in China with the practical service requirements of intelligent dispatching. This paper aims to propose key technologies and applications for intelligent dispatching command in HSR in China.

Design/methodology/approach

This paper first briefly introduces the functions and configuration of the intelligent CTC system. Some new servers, terminals and interfaces are introduced, which are plan adjustment server/terminal, interface for automatic train operation (ATO), interface for Dynamic Monitoring System of Train Control Equipment (DMS), interface for Power Supervisory Control and Data Acquisition (PSCADA), interface for Disaster Monitoring, etc.

Findings

The key technologies applied in the intelligent CTC system include automatic adjustment of train operation plans, safety control of train routes and commands, traffic information data platform, integrated simulation of traffic dispatching and ATO function. These technologies have been applied in the Beijing-Zhangjiakou HSR, which commenced operations at the end of 2019. Implementing these key intelligent functions has improved the train dispatching command capacity, ensured the safe operation of intelligent HSR, reduced the labor intensity of dispatching operators and enhanced the intelligence level of China's dispatching system.

Originality/value

This paper provides further challenges and research directions for the intelligent dispatching command of HSR. To achieve the objectives, new measures need to be conducted, including the development of advanced technologies for intelligent dispatching command, coping with new requirements with the development of China's railway signaling system, the integration of traffic dispatching and train control and the application of AI and data-driven modeling and methods.