bluuebunny/crossref_metadata_2025 huggingface dataset:
Acetylcholine modulates prefrontal outcome coding during threat learning under uncertainty
Authors: Tu Gaqi , Wen Peiying , Halawa Adel , Takehara-Nishiuchi Kaori
Published: September 2024

Outcomes can vary even when choices are repeated. Such ambiguity necessitates adjusting how much to learn from each outcome by tracking its variability. The medial prefrontal cortex (mPFC) has been reported to signal the expected outcome and its discrepancy from the actual outcome (prediction error), two variables essential for controlling the learning rate. However, the source of signals that shape these coding properties remains unknown. Here, we investigated the contribution of cholinergic projections from the basal forebrain because they carry precisely timed signals about outcomes. One-photon calcium imaging revealed that as mice learned different probabilities of threat occurrence on two paths, some mPFC cells responded to threats on one of the paths, while other cells gained responses to threat omission. These threat- and omission-evoked responses were scaled to the unexpectedness of outcomes, some exhibiting a reversal in response direction when encountering surprising threats as opposed to surprising omissions. This selectivity for signed prediction errors was enhanced by optogenetic stimulation of local cholinergic terminals during threats. The enhanced threat-evoked cholinergic signals also made mice erroneously abandon the correct choice after a single threat that violated expectations, thereby decoupling their path choice from the history of threat occurrence on each path. Thus, acetylcholine modulates the encoding of surprising outcomes in the mPFC to control how much they dictate future decisions.
RNA Polymerase II Degradation Triggered by DNA Repair OccursIn Transand Independently of how the Lesion is Recognised
Authors: Choudhary Ramveer , Muñoz Juan Cristobal , Beckerman Inés , Bastianello Giulia , Bouvier León Alberto , Foiani Marco , Muñoz Manuel J.
Published: September 2024

In response to DNA damage, RPB1, the catalytic subunit of RNA Polymerase II (RNAPII), is degraded by the ubiquitin-proteasome system. Degradation models only consider transcriptionally engaged molecules, where a stalled RNAPII complex functions as a lesion recognition factor and its RPB1 subunit is proposed to be subsequently degraded to facilitate access of core Nucleotide Excision Repair (NER) factors. This Transcription Coupled repair is complemented by the Global Genome repair (GG-NER) system, where lesions are recognized by the XPE and XPC factors. Here we show that RPB1 degradation is controlledin transby a pathway that depends on NER activity, irrespectively of whether the lesion is recognized by RNAPII itself or by GG-NER factors. Incomplete lesion repair due to absence of any core NER factor enhances RPB1 degradation, indicating that the signal controlling RPB1 abundance is started by lesion recognition and continues until DNA repair is completed. Consistent with anin transmechanism, damage-induced RPB1 degradation is not restricted to active nor phosphorylated RPB1 molecules and depends on Cullin-RING ubiquitin ligases. These findings uncover a repair-dependent mechanism controlling RPB1 levels and provide a rationale for the control of gene expression under stress, where more damage implies more repair and less RPB1 levels, hence restricting RNAPII activity.
Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production
Authors: Arafi Parnian , Devkota Sujan , Williams Emily , Maesako Masato , Wolfe Michael S.
Published: September 2024

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer’s disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in aC. elegansmodel of FAD independently of Aβ production. Here we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.
A Novel Approach to Reducing Spinal Implant-Associated Infections
Authors: Nishizawa Mitsuhiro , Hu Diane , Serhan Hassan , Saleh Bahram , Marcucio Ralph S , Morioka Kazuhito
Published: September 2024

Implant-associated infection is a severe complication of instrumented spinal surgery. Preventive measures against biofilm formation, such as chemical modifications of devices with antibiotics or bactericidal substances, have been explored to decrease infection rates and enhance therapeutic outcomes. However, this approach remains challenging, and the safety issues associated with antibiotic resistance and cellular toxicity need to be addressed. Hence, there is an unmet clinical need for implants that resist biofilm formation. Ultrafine-grained material (UFG), which has a nanoscale grain structure, is a novel form of metal with exceptional mechanical and biocompatibility properties that may also have antimicrobial activity. This study investigates the extent to which UFG stainless steel implants resist biofilm formation byStaphylococcus aureus in vitroandin vivo. The results show that the UFG stainless steel wire significantly reduced biofilm formation at early time points after bacterial infection compared to a standard wire. In mouse models of implant-associated infection below the skin or the fascia, the UFG wire had significantly less biofilm formation at early time points. The UFG wire appeared to delay initial bacterial adhesion and biofilm maturation. These findings suggest that UFG implants may resist initial biofilm formation and maturation, leading to promising antibacterial materials for patients.
Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways
Authors: Hickey Kelsey L. , Panov Alexandra , Whelan Enya Miguel , Schäfer Tillman , Mizrak Arda , Kopito Ron R. , Baumeister Wolfgang , Fernández-Busnadiego Rubén , Harper J. Wade
Published: September 2024

A hallmark of neurodegenerative diseases is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. However, studying the underlying cellular pathways and mechanisms has remained a challenge, as formation of many types of protein aggregates is asynchronous, with individual cells displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge a kinetically tractable and synchronous agDD-GFP system for aggregate formation with targeted gene knockdowns, to uncover degradation mechanisms used in response to acute aggregate formation. We find that agDD-GFP forms amorphous aggregates by cryo-electron tomography at both early and late stages of aggregate formation. Aggregate turnover occurs in a proteasome-dependent mechanism in a manner that is dictated by cellular aggregate burden, with no evidence of the involvement of autophagy. Lower levels of misfolded agDD-GFP, enriched in oligomers, utilizes UBE3C-dependent proteasomal degradation in a pathway that is independent of RPN13 ubiquitylation by UBE3C. Higher aggregate burden activates the NRF1 transcription factor to increase proteasome subunit transcription, and subsequent degradation capacity of cells. Loss or gain of NRF1 function alters the turnover of agDD-GFP under conditions of high aggregate burden. Together, these results define the role of UBE3C in degradation of this class of misfolded aggregation-prone proteins and reveals a role for NRF1 in proteostasis control in response to widespread protein aggregation.
Neuronal firing rate diversity lowers the dimension of population covariability
Authors: Tian Gengshuo John , Zhu Ou , Shirhatti Vinay , Greenspon Charles M. , Downey John E. , Freedman David J. , Doiron Brent
Published: September 2024

Populations of neurons produce activity with two central features. First, neuronal responses are very diverse – specific stimuli or behaviors prompt some neurons to emit many action potentials, while other neurons remain relatively silent. Second, the trial-to-trial fluctuations of neuronal response occupy a low dimensional space, owing to significant correlations between the activity of neurons. These two features define the quality of neuronal representation. We link these two aspects of population response using a recurrent circuit model and derive the following relation: the more diverse the firing rates of neurons in a population, the lower the effective dimension of population trial-to-trial covariability. This surprising prediction is tested and validated using simultaneously recorded neuronal populations from numerous brain areas in mice, non-human primates, and in the motor cortex of human participants. Using our relation we present a theory where a more diverse neuronal code leads to better fine discrimination performance from population activity. In line with this theory, we show that neuronal populations across the brain exhibit both more diverse mean responses and lower-dimensional fluctuations when the brain is in more heightened states of information processing. In sum, we present a key organizational principle of neuronal population response that is widely observed across the nervous system and acts to synergistically improve population representation.
Prodrug activation in malaria parasites mediated by an imported erythrocyte esterase, acylpeptide hydrolase (APEH)
Authors: Sundararaman SA , Miller JJ , Daley EC , O’Brien KA , Kasak P , Daniels AM , Edwards RL , Heidel KM , Bague DA , Wilson MA , Koelper AJ , Kourtoglou EC , White AD , August SA , Apple GA , Rouamba RW , Durand AJ , Esteb JJ , Muller FL , Johnson RJ , Hoops GC , Dowd CS , Odom John AR
Published: September 2024

The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite,Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that ofP. falciparumesterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2–4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

Significance

Rising antimalarial drug resistance threatens current gains in malaria control. New antimalarial drugs are urgently needed. Unfortunately, many drug candidates have poor drug-like properties, such as poor absorbability in the gastrointestinal tract, or poor accumulation at the site of action. This can be overcome by prodrugging, the addition of prodrug groups which mask poor drug features until they are removed by an activating enzyme. Here, we show that a red blood cell enzyme, acylpeptide hydrolase, is taken up by malaria parasites and serves as the activating enzyme for multiple lipophilic ester prodrugs. Our findings highlight a novel mechanism for prodrug activation, which could be leveraged to design novel prodrugs with high barriers to drug resistance.
The human hippocampus is involved in implicit motor learning
Authors: Griffa Guillermina , Deleglise Alvaro , Solano Agustín , Jacobacci Florencia , De Pino Gabriela , Della-Maggiore Valeria
Published: September 2024

Recent evidence suggests that the human hippocampus, traditionally associated with declarative memory, plays a role in motor sequence learning (MSL). However, the classic MSL paradigm depends initially on declarative learning. Therefore, it is critical to discern whether the participation of the hippocampus relates to its canonical role or to processing a general aspect of learning that transcends the declarative/non-declarative distinction. To address this issue, here we turn to visuomotor adaptation -a type of motor learning involving skill recalibration-which unlike MSL can be easily manipulated to eliminate the explicit component. Here, we examined the broader involvement of the hippocampus in procedural motor learning by using diffusion MRI to indirectly assess structural plasticity associated with memory consolidation in visuomotor adaptation (VMA) and an implicit-only version (IVMA). We found that both VMA and IVMA engaged the left posterior hippocampus in a learning-specific manner. Remarkably, while VMA induced only transient hippocampal alterations, IVMA elicited structural changes that persisted overnight, underscoring the reliance on implicit learning for enduring neuroplasticity. As expected, training on both visuomotor tasks impacted the microstructure of the cerebellum, the motor and the posterior parietal cortex. Notably, the temporal dynamics of changes in these regions closely paralleled those of the left hippocampus, suggesting that motor and limbic regions operate in a coordinated manner as part of the same neural network. Collectively, our findings support an active role of the hippocampus in procedural motor memory and argue for a unified function in memory encoding regardless of the declarative or non-declarative nature of the task.
Limosilactobacillus reuteripromotes the expression and secretion of enteroendocrine- and enterocyte-derived hormones
Authors: Di Rienzi Sara C. , Danhof Heather A. , Forshee Micah D. , Roberts Ari , Britton Robert A.
Published: September 2024

Observations that intestinal microbes can beneficially impact host physiology have prompted investigations into the therapeutic usage of such microbes in a range of diseases. For example, the human intestinal microbeLimosilactobacillus reuteristrains ATCC PTA 6475 and DSM 17938 are being considered for use for intestinal ailments including colic, infection, and inflammation as well as non- intestinal ailments including osteoporosis, wound healing, and autism spectrum disorder. While many of their beneficial properties are attributed to suppressing inflammatory responses in the gut, we postulated thatL. reuterimay also regulate hormones of the gastrointestinal tract to affect physiology within and outside of the gut. To determine ifL. reuterisecreted factors impact the secretion of enteric hormones, we treated an engineered jejunal organoid line,NGN3-HIO, which can be induced to be enriched in enteroendocrine cells, withL. reuteri6475 or 17938 conditioned medium and performed transcriptomics. Our data suggest that theseL. reuteristrains affect the transcription of many gut hormones, including vasopressin and luteinizing hormone subunit beta, which have not been previously recognized as being produced in the gut epithelium. Moreover, we find that these hormones appear to be produced in enterocytes, in contrast to canonical gut hormones which are produced in enteroendocrine cells. Finally, we show thatL. reutericonditioned media promotes the secretion of several enteric hormones including serotonin, GIP, PYY, vasopressin, and luteinizing hormone subunit beta. These results supportL. reuteriaffecting host physiology through intestinal hormone secretion, thereby expanding our understanding of the mechanistic actions of this microbe.
Programmed ribosomal frameshifting duringPLEKHM2mRNA decoding generates a constitutively active proteoform that supports myocardial function
Authors: Loughran Gary , Pace Raffaella De , Ding Ningyu , Zhang Jianchao , Jungreis Irwin , Carancini Gionmattia , Mudge Jonathan M. , Wang Ji , Kellis Manolis , Atkins John F. , Baranov Pavel V. , Firth Andrew E. , Li Xiaowei , Bonifacino Juan S. , Khan Yousuf A.
Published: September 2024

Programmed ribosomal frameshifting is a process where a proportion of ribosomes change their reading frame on an mRNA1, rephasing the ribosome relative to the mRNA. While frameshifting is commonly employed by viruses2, very few phylogenetically conserved examples are known in nuclear encoded genes and some of the evidence is controversial3,4. Here we report a +1 frameshifting event during decoding of the human genePLEKHM25. This frameshifting occurs at the sequence UCC_UUU_CGG, which is conserved in vertebrates and is similar to an influenza virus sequence that frameshifts with similar efficiency6,7. The new C-terminal domain generated by this frameshift forms an α-helix, which relieves PLEKHM2 from autoinhibition and allows it to move to the tips of cellsviaassociation with kinesin-1 without requiring activation by ARL8. Reintroducing both the canonically-translated and frameshifted protein are necessary to restore normal contractile function ofPLEKHM2-knockout cardiomyocytes, demonstrating the necessity of frameshifting for normal cardiac activity.
Engineering pathogen-inducible promoters for conferring disease resistance in tomato
Authors: Wei Wei , Kim Doogie , Koehler Naio , Bendl Ashley , Cho Myeong-Je , Krasileva Ksenia
Published: September 2024

Plant diseases pose a significant threat to global crop production. Most disease resistance genes used in crop breeding programs encode nucleotide-binding leucine-rich repeat receptors (NLRs) that are limited in pathogen specificity and durability. In this study, we leveraged synthetic biology to develop an inducible broad-spectrum resistance in tomatoes. Constitutive expression of autoactive NLRs in plants leads to robust resistance against multiple pathogens but significantly stunts growth. We expressed autoactive NLRs under the control of pathogen-inducible (PI) promoters to mitigate the fitness costs. Taking advantage of extensive, new genomic and transcriptomic resources, we identified PI promoters that responded to multiple pathogens but not abiotic stress. We further validated functionality of predicted elements through a promoter luciferase assay. We generated significant resistance in transgenic tomatoes but we also encountered unwanted expression induction of the native promoter regions in flowers which led to lethal fruit development. Thus, we pursued promoter engineering for fine-tuning the induction. We identified cis-regulatory regions responsible for pathogen-inducibility through promoter bashing experiments and recombined the native promoter with the inducible part and the core promoter. Furthermore, we rationally created synthetic promoters showing a gradient of expression levels, which will allow for selection for transgenic tomatoes with the best performance. We found that the spacing between functional sequences, repeat number of inducible sequences, and core promoters all influence the outcome of engineering. Our study outlines a framework for developing broad-spectrum synthetic immune constructs with reduced fitness cost and provides examples of pathogen-inducible promoter engineering.
Decreasing ZAP Poly(ADP-ribose) Binding Enhances Antiviral Activity Against Alphaviruses
Authors: Cheng Shang-Jung , Griffin Diane E. , Leung Anthony K. L. , Abraham Rachy
Published: September 2024

Zinc finger antiviral protein (ZAP), also known as PARP13, is an antiviral factor effective against several virus families. ZAP contains three major protein domains: N-terminal zinc fingers, central WWE domains, and a C-terminal inactive ADP-ribosyltransferase domain, which is present only in the longer isoform ZAPL. While both the zinc finger and ADP-ribosyltransferase domains inhibit viral replication, the role of the WWE domains remains unclear. WWE domains bind poly(ADP-ribose) (PAR). In this study, we focus on ZAPS, the shorter isoform comprised of the minimal unit that confers antiviral activity and lacking the ADP-ribosyltransferase domain, to investigate how PAR-binding contributes to antiviral defense against alphaviruses. We identified the Y659 residue on the second WWE domain as essential for PAR-binding both in vitro and in cells. When infected with Chikungunya or Sindbis virus, cells with the Y659A mutant of ZAPS had reduced formation of replication complexes, decreased levels of viral genomic and subgenomic transcripts, and fewer infectious virions released compared to cells with the unmutated ZAPS, suggesting enhanced antiviral activity of the PAR-binding mutant. These findings suggest that inhibiting PAR-binding in ZAPS could potentiate host antiviral functions, offering a novel therapeutic strategy against alphavirus infections.
Binder and monomer valencies determine the extent of collapse and reswelling of chromatin
Authors: Guha Sougata
Published: September 2024

Multivalent DNA-bridging proteins-mediated collapse of chromatin polymer has long been established as one of the driving factors in chromatin organisation inside cells. These multivalent proteins can bind to distant binding sites along the chromatin backbone and bring them together in spatial proximity, leading to collapsed conformations. Recently, it has been suggested that these proteins not only drive collapse of the chromatin polymer, but also reswelling at higher concentrations. In this study, we investigate the physical mechanisms underlying this unexpected reswelling behaviour. We use Langevin dynamics simulation of a coarse-grained homopolymer to investigate the effects of the valencies of both the binders and the monomers on the polymer conformations. We find that while the extent of collapse of the polymer is strongly dependent on the binder valency, the extent of reswelling is largely determined by the monomer valency. Furthermore, we also discover two different physical mechanisms that drive reswelling of the polymer -excluded volume effectsandloss of long-range loops. Finally, we obtain a classification map to determine the regimes in which each of these mechanisms is the dominant factor leading to polymer reswelling.
BayeSMART: Bayesian Clustering of Multi-sample Spatially Resolved Transcriptomics Data
Authors: Guo Yanghong , Zhu Bencong , Tang Chen , Rong Ruichen , Ma Ying , Xiao Guanghua , Xu Lin , Li Qiwei
Published: September 2024

The field of spatially resolved transcriptomics (SRT) has greatly advanced our understanding of cellular microenvironments by integrating spatial information with molecular data collected from multiple tissue sections or individuals. However, methods for multi-sample spatial clustering are lacking, and existing methods primarily rely on molecular information alone. This paper introduces BayeSMART, a Bayesian statistical method designed to identify spatial domains across multiple samples. BayeSMART leverages artificial intelligence (AI)-reconstructed single-cell level information from the paired histology images of multi-sample SRT datasets while simultaneously considering the spatial context of gene expression. The AI integration enables BayeSMART to effectively interpret the spatial domains. We conducted case studies using four datasets from various tissue types and SRT platforms and compared BayeSMART with alternative multi-sample spatial clustering approaches and a number of state-of-the-art methods for single-sample SRT analysis, demonstrating that it surpasses existing methods in terms of clustering accuracy, interpretability, and computational efficiency. BayeSMART offers new insights into the spatial organization of cells in multi-sample SRT data.
Fluctuating chromatin facilitates enhancer-promoter communication by regulating transcriptional clustering dynamics
Authors: Zhu Tao , Li Chunhe , Chu Xiakun
Published: September 2024

Abstract

Enhancers regulate gene expression by forming contacts with distant promoters. Phase-separated condensates or clusters formed by transcription factors (TFs) and co-factors are thought to facilitate these enhancer-promoter (E-P) interactions. Using polymer physics, we developed distinct coarse-grained chromatin models that produce similar ensemble-averaged Hi-C maps but with “stable” and “dynamic” characteristics. Our findings, consistent with recent experiments, reveal a multi-step E-P communication process. The dynamic model facilitates E-P proximity by enhancing TF clustering and subsequently promotes direct E-P interactions by destabilizing the TF clusters through chain flexibility. Our study promotes physical understanding of the molecular mechanisms governing E-P communication in transcriptional regulation.

Graphical TOC Entry
Unravelling the Maturation Pathway of a Eukaryotic Virus through Cryo-EM
Authors: Castells-Graells Roger , Hesketh Emma L. , Matsui Tsutomu , Johnson John E. , Ranson Neil A. , Lawson David M. , Lomonossoff George P.
Published: September 2024

The importance of virus maturation has been appreciated for nearly 70 years1as it provides models for large-scale protein reorganization resulting in functional activation as well as being a target for antiviral therapies2. However, a detailed description of the pathway from the initial assembly product (procapsid) to the mature, infectious particle (virion) has been elusive. This is due to the “in cell” nature of the natural process, the 2- state behavior of maturation (no detectable intermediates) in some virusesin vitro3and heterogeneous populations of particle intermediates that are only partially matured in other systems4. The non-enveloped, T=4, ssRNA-containing,Nudaurelia capensisomega virus (NωV), is a highly accessible model system that exemplifies the maturation process of a eukaryotic virus. During maturation the particle shrinks in outer diameter from 482 Å (pH 7.5) to 428 Å (pH 5.0). It is possible to mimic the maturation processin vitroby lowering the pH of a population of procapsids produced in heterologous systems5. Indeed, by controlling the pHin vitroit is possible to produce homogenous populations of intermediate NωV virus-like particles (VLPs) that occur too fleetingly to be observedin vivo6.

Here we report structural models, based on cryo-electron microscopy (cryo-EM), of five intermediates in the NωV maturation process. The structures of the intermediate particles reveal unique, quaternary position-dependent trajectories and refolding of subunit N and C-terminal regions, including the formation of the autocatalytic cleavage site at N570. The detailed structures reported here, coupled with previously determined structures of the procapsids and mature particles, allows the maturation pathway to be described in detail for the first time for a eukaryotic virus.
Highly pathogenic avian influenza H5 virus exposure in goats and sheep
Authors: Wong Foong Ying , Yaqub Tahir , Zhang Rong , Mukhtar Nadia , Pervaiz Hamda , Hussain Yawar Hafiz Usama , Iqbal Mubashir , bin Aslam Hassaan , Aziz Muhammad Waqar , Akram Maham , Raza Sumbal , Low Jenny G , Cronin Peter , Laing Eric D , Low Dolyce HW , Webby Richard J , Su Yvonne CF , Smith Gavin JD
Published: September 2024

The recent outbreaks of highly pathogenic avian influenza A(H5N1) virus in North and South America, including widespread infection of cattle in the United States, calls for an urgent assessment of the host range of influenza A viruses, particularly for subtypes of pandemic concern. We conducted a serological survey for binding antibodies to influenza A and B viruses in goats (n=452) and sheep (n=329) in Pakistan and found high seropositive rates for the hemagglutinin (HA) of avian influenza A viruses (AIV) H5 (23.9–34.0%), H7 (13.9– 37.1%), and H9 (17.0–34.7%). In contrast, there were low levels of seropositivity against the HA of human and swine pandemic H1N1/pdm09 (0.9–1.8%) in goats and against swine H3 (0.6%) in sheep. Notably, we observed high reactivity to the neuraminidase of human H1N1/2009 (57.8–60.6%) and swine H3N2 (14.0–14.4%), likely due to cross-reactivity with the N1 and N2 proteins of H5N1 and H9N2 AIVs, respectively. Interestingly, we also detected seropositivity against influenza B HA in both goats (7.1%) and sheep (4.6%). The presence of AIV antibodies in goats and sheep suggest these species represent previously unrecognized hosts for viruses of pandemic concern, revealing extensive gaps in our current understanding of the ecology of influenza A and B viruses.
Quantitative physiology and biomass composition ofCyberlindnera jadiniiin ethanol-grown cultures
Authors: Vieira-Lara Marcel A. , Warmerdam Marieke , de Hulster Erik A. F. , van den Broek Marcel , Daran Jean-Marc , Pronk Jack T.
Published: September 2024

Background

Elimination of greenhouse gas emissions in industrial biotechnology requires replacement of carbohydrates by alternative carbon substrates, produced from CO2and waste streams. Ethanol is already industrially produced from agricultural residues and waste gas and is miscible with water, self-sterilising and energy-dense. The yeastC. jadiniican grow on ethanol and has a history in the production of single-cell protein (SCP) for feed and food applications. To address a knowledge gap in quantitative physiology ofC. jadiniiduring growth on ethanol, this study investigates growth kinetics, growth energetics, nutritional requirements, and biomass composition ofC. jadiniistrains in batch, chemostat and fed-batch cultures.

Results

In aerobic, ethanol-limited chemostat cultures,C. jadiniiCBS 621 exhibited a maximum biomass yield on ethanol (Yx/smax) of 0.83 gbiomass(gethanol)-1and an estimated maintenance requirement for ATP (mATP) of 2.7 mmol·(gbiomass)-1·h-1. Even at specific growth rates below 0.05 h-1, a stable protein content of approximately 0.54 gprotein·(gbiomass)-1was observed. At low specific growth rates, up to 17% of the proteome consisted of alcohol dehydrogenase proteins, followed by aldehyde dehydrogenases and acetyl-CoA synthetase. Of 13C. jadiniistrains evaluated, 11 displayed fast growth on ethanol (μmax> 0.4 h-1) in mineral medium without vitamins, and CBS 621 was found to be a thiamine auxotroph. The prototrophic strainC. jadiniiCBS 5947 was grown on an inorganic salts medium in fed-batch cultures (10-L scale) fed with pure ethanol. Biomass concentrations in these cultures increased up to 100 gbiomass·(kgbroth)-1, with a biomass yield of 0.65 gbiomass·(gethanol)-1. Model-based simulation, based on quantitative parameters determined in chemostat cultures, adequately predicted biomass production. A different protein content of chemostat- and fed-batch-grown biomass (54% and 42%, respectively) may reflect the more dynamic conditions in fed-batch cultures.

Conclusions

Analysis of ethanol-grown batch, chemostat and fed-batch cultures provided a quantitative physiology baseline for fundamental and applied research onC. jadinii. Its high maximum growth rate, high energetic efficiency of ethanol dissimilation, simple nutritional requirements and high protein content, makeC. jadiniia highly interesting platform for production of SCP and other products from ethanol.
Noradrenaline causes a spread of association in the hippocampal cognitive map
Authors: Koolschijn Renée S , Parthasarathy Prakriti , Browning Michael , Przygodda Xenia , Clarke William T , Vogels Tim P , O’Reilly Jill X , Barron Helen C
Published: September 2024

The mammalian brain stores relationships between items and events in the world as cognitive maps in the hippocampal system. However, the neural mechanisms that control cognitive map formation remain unclear. Here, using a double-blind study design with a pharmacological intervention in humans, we show that the neuromodulator noradrenaline elicits a significant ‘spread of association’ across the hippocampal cognitive map. This neural spread of association predicts overgeneralisation errors measured in behaviour, and is predicted by physiological markers for noradrenergic arousal, namely an increase in the pupil dilation response and reduced cortical GABAergic tone. Thus, noradrenaline sets the width of the ‘smoothing kernel’ for plasticity across the cognitive map. Elevated noradrenaline can allow disparate memories to become linked, introducing potential for distortions in the cognitive map that deviate from direct experience.

Graphical abstract
The spatiotemporal distribution of LIN-5/NuMA regulates spindle orientation and tissue organization in theC. elegansgerm line
Authors: Zellag Réda M. , Poupart Vincent , Negishi Takefumi , Labbé Jean-Claude , Gerhold Abigail R.
Published: September 2024

Mitotic spindle orientation sets the cell division plane and is thus critical for maintaining tissue organization. TheC. elegansgonad is tube-shaped, with germ cells forming a circumferential monolayer around a shared inner core of cytoplasm called the rachis. Each germ cell is connected to the rachis via a stable cytoplasmic bridge, polarizing germ cells along their rachis-basal axis. How this tissue organization is maintained during development is unclear, as germ cells lack the canonical cell-cell junctions that, in other tissue types, ensure proper spindle orientation. Here we use live-cell imaging ofC. elegansgerm cells, bothin situand in gonad explants, to show that the microtubule force generator dynein and its conserved regulator LIN-5/NuMA regulate spindle orientation inC. elegansgerm cells and are required for germline tissue organization. We uncover a cyclic, polarized pattern of LIN-5/NuMA cortical localization that predicts centriole/centrosome positioning throughout the cell cycle, providing a means to align spindle orientation with the tissue plane. This work reveals a new mechanism by which oriented cell division can be achieved to maintain tissue organization during animal development.
Host and antibiotic jointly select for greater virulence inStaphylococcus aureus
Authors: Su Michelle , Hoang Kim L. , Penley McKenna , Davis Michelle H. , Gresham Jennifer D. , Morran Levi T. , Read Timothy D.
Published: September 2024

Widespread antibiotic usage has resulted in the rapid evolution of drug-resistant bacterial pathogens and poses significant threats to public health. Resolving how pathogens respond to antibiotics under different contexts is critical for understanding disease emergence and evolution going forward. The impact of antibiotics has been demonstrated most directly throughin vitropathogen passaging experiments. Independent from antibiotic selection, interactions with hosts have also altered the evolutionary trajectories and fitness landscapes of pathogens, shaping infectious disease outcomes. However, it is unclear how interactions between hosts and antibiotics impact the evolution of pathogen virulence. Here, we evolved and re-sequencedStaphylococcus aureus,a major bacterial pathogen, varying exposure to host and antibiotics to tease apart the contributions of these selective pressures on pathogen adaptation. After 12 passages,S. aureusevolving inCaenorhabditis elegansnematodes exposed to a sub-minimum inhibitory concentration of antibiotic (oxacillin) became highly virulent, regardless of whether the ancestral pathogen was methicillin-resistant (MRSA) or methicillin-sensitive (MSSA). Host and antibiotic exposure selected for reduced drug susceptibility in MSSA lineages while increasing MRSA total growth outside hosts. We identified mutations in genes involved in complex regulatory networks linking virulence and metabolism, includingcodY,agr, andgdpP, suggesting that rapid adaptation to infect hosts may have pleiotropic effects. In particular, MSSA populations under selection from host and antibiotic accumulated mutations in the global regulator genecodY, which controls biofilm formation inS. aureus.These populations had indeed evolved more robust biofilms—a trait linked to both virulence and antibiotic resistance—suggesting evolution of one trait can confer multiple adaptive benefits. Despite evolving in similar environments, MRSA and MSSA populations proceeded on divergent evolutionary paths, with MSSA populations exhibiting more similarities across replicate populations. Our results underscore the importance of considering multiple and concurrent selective pressures as drivers of pervasive pathogen traits.
Dispersal of influenza virus populations within the respiratory tract shapes their evolutionary potential
Authors: Ferreri Lucas M. , Seibert Brittany , Caceres C. Joaquin , Patatanian Kayle , Holmes Katie E. , Gay L. Claire , Faccin Flavio Cargnin , Cardenas Matias , Carnaccini Silvia , Shetty Nishit , Rajao Daniela , Koelle Katia , Marr Linsey C. , Perez Daniel R. , Lowen Anice C.
Published: September 2024

Viral infections are characterized by dispersal from an initial site to secondary locations within the host. How the resultant spatial heterogeneity shapes within-host genetic diversity and viral evolutionary pathways is poorly understood. Here we show that dispersal within and between the nasal cavity and trachea maintains diversity and is therefore conducive to adaptive evolution, whereas dispersal to the lungs is stochastic and gives rise to population heterogeneity. We infected ferrets either intranasally or by aerosol with a barcoded influenza A/California/07/2009 (H1N1) virus. At 1, 2 or 4 days post infection, dispersal was assessed by collecting 52 samples from throughout the respiratory tract of each animal. Irrespective of inoculation route, barcode compositions across the nasal turbinates and trachea were similar and highly diverse, revealing little constraint on the establishment of infection in the nasal cavity and descent through the trachea. By comparison, infection of the lungs produced genetically distinct viral populations. Lung populations were pauci-clonal, suggesting that each seeded location received relatively few viral genotypes. While aerosol inoculation gave distinct populations at every lung site sampled, within-host dispersal after intranasal inoculation produced larger patches, indicative of local expansion following seeding of the lungs. Throughout the respiratory tract, barcode diversity declined over time, but new diversity was generated through mutation. De novo variants were often unique to a given location, indicating that localized replication following dispersal resulted in population divergence. In summary, dispersal within the respiratory tract operates differently between regions and contributes to the potential for viral evolution to proceed independently in multiple within-host subpopulations.
“The dark spiral: exploring the impact of employee exploitation on cutting corners, unraveling the link through negative emotions and moral disengagement”
Authors: Burhan Qurat-ul-Ain , Malik Muhammad Faisal
Published: September 2024

Purpose

The pervasive issue of employee exploitation has surfaced as a salient ethical quandary within the context of modern-day workplaces, thereby demanding expeditious and imperative deliberation and redressal. This research endeavor aims to meticulously investigate the ramifications of employee exploitation on the proclivity to partake in the act of cutting corners within the workplace. This analysis encompasses the sequential mediating variables of negative emotions, namely resentment, anger, and frustration, as well as moral disengagement.

Design/methodology/approach

A purposive sampling technique and self-administered questionnaires were utilized in this study of 132 SME sector personnel. The current study is time-lagged in nature and uses the Amos software, the data were analyzed using exploratory and confirmatory factor analyses, as well as structural equation modeling.

Findings

According to the results, employee exploitation has a strong positive impact on cutting corners. This effect is mediated progressively by negative emotions (resentment, anguish, frustration), as well as moral disengagement. According to the findings, organizations should prioritize addressing employee exploitation to build a healthy work environment that promotes employee well-being and encourages employee voice.

Originality/value

This study’s novelty comes from its analysis of the sequential mediation of negative emotions, as well as moral disengagement, in the relationship between employee exploitation and cutting corners. The study’s findings add to the body of literature concerning management development, conflict handling, and employees’ attitudes and behaviors by offering a thorough grasp of the detrimental effects of employee exploitation on cutting corners as well as useful recommendations for businesses looking to promote productive workplaces.
A new level of refinement at Sirah Heritage Holdings
Authors: Sahim Ahmad Izzat Fauzan , Raja Yusof Raja Nerina
Published: September 2024

Learning outcomes

At the end of the case study exercise, students will be able to evaluate a company’s competitive standing and formulate business growth strategies based on internal and external environment analysis, develop business strategies for a company to strategise product offerings and recommend promotional strategies for a company to best market new product offerings.

Case overview/synopsis

This case study is about the Central Production Unit (CPU), a wholly owned subsidiary of Sirah Heritage Holdings Sdn. Bhd. (owner of the popular restaurant brand “Tuuu […] Dia Pak Tam”), which was initially set up to standardise production for the whole company. However, ever since the subsidiary was set up, the management realised a few pertinent issues that needed their attention. Firstly, the CPU was underutilised even with the large number of Tuuu […] Dia Pak Tam restaurants across Peninsular Malaysia. Furthermore, the CPU was also tasked to introduce new products and services that could attract consumers and increase the visibility of their restaurants, but the company had no idea how to promote its new products. This study aims to look at the issues faced by the CPU by applying analytical tools such as SWOT analysis, Ansoff matrix and promotion mix.

Complexity academic level

This case study is designed for undergraduate and postgraduate students who are taking courses such as strategic management, marketing management and business development. This case study can also be used by training departments, corporate trainers and other relevant managers to improve growth strategies using business theories.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 8: Marketing
Mechanism design and mechanical analysis of pipeline inspection robot
Authors: Wang Yongming , Wang Jinlong , Zhou Qi , Feng Sai , Wang Xiaomin
Published: September 2024

Purpose

This study aims to address the issues of limited pipe diameter adaptability and low inspection efficiency of current pipeline inspection robots, a new type of pipeline inspection robot capable of adapting to various pipe diameters was designed.

Design/methodology/approach

The diameter-changing mechanism uses a multilink elastic telescopic structure consisting of telescopic rods, connecting rods and wheel frames, driven by a single motor with a helical drive scheme. A geometric model of the position relationships of the hinge points was established based on the two extreme positions of the diameter-changing mechanism.

Findings

A pipeline inspection robot was designed using a simple linkage agency, which significantly reduced the weight of the robot and enhanced its adaptive pipe diameter ability. The analysis determined that the robot could accommodate pipe diameters ranging from 332 mm to 438 mm. A static equilibrium equation was established for the robot in the hovering state, and the minimum pressing force of the wheels against the pipe wall was determined to be 36.68 N. After experimental testing, the robots could successfully pass a height of 15 mm, demonstrating the good obstacle capacity of the robot.

Practical implications

This paper explores and proposes a new type of multilink elastic telescopic variable diameter pipeline inspection robot, which has the characteristics of strong adaptability and flexible operation, which makes it more competitive in the field of pipeline inspection robots and has great potential market value.

Originality/value

The robot is characterized by the innovative design of a multilink elastic telescopic structure and the use of a single motor to drive the wheel for spiral motion. On the basis of reducing the weight of the robot, it has good pipeline adaptability, climbing ability and obstacle-crossing ability.
Eringen’s nonlocal elasticity theory for the analysis of two temperature generalized thermoelastic interactions in an anisotropic medium with memory
Authors: Seth Tanmoy , Mallik Sadek Hossain
Published: September 2024

Purpose

The purpose of this paper is to investigate the thermoelastic interactions in a homogeneous, transversely isotropic infinite medium with a spherical cavity in the context of two temperature Lord-Shulman (2TLS) generalized theory of thermoelasticity considering Eringen’s nonlocal theory and memory dependent derivative (MDD). Memory-dependent derivative is found to be better than fractional calculus for reflecting the memory effect which leads us to the current investigation.

Design/methodology/approach

The governing field equations of the problem are solved analytically using the eigenvalue approach in the transformed domain of Laplace when the cavity’s boundary is being loaded thermomechanically. Using MATLAB software the numerical solution in real space-time domain is obtained by Stehfest method.

Findings

Numerical results for the different thermophysical quantities are presented in graphs and the effects of delay time parameter, non-local parameter and two temperature parameters are studied thereafter. The outcomes of this study convince that the displacement u, conductive temperature ϕ, thermodynamic temperature θ are concave upward whereas radial stress τrr is concave downward for every choice of delay time parameter ω, two temperature parameter η and non-local parameter “ζ”. As a specific instance of our findings, the conclusions of an equivalent problem involving integer order thermoelasticity theory can be obtained, and the corresponding results of this article can be readily inferred for isotropic materials.

Originality/value

The novelty of this research lies in the adoption of generalized thermoelastic theory with memory dependent derivative and Eringen’s nonlocality for analyzing the thermoelastic interactions in an infinite body with spherical cavity by employing eigenvalue approach. It has applications to many thermo-dynamical systems.