bluuebunny/crossref_metadata_2025 huggingface dataset:
A Public Health Hackathon for Medical Students in Africa: Process, Outcome and Recommendations
Authors: Babatunde Abdulhammed Opeyemi , Brimmo Farida Oluwabukola , Arama Umulkhairah Onyioiza , Onyinyechi Madu Gloria , Josephat Kasule Aiden , Osiene Austine Oluwatobi
Published: January 2023

Africa has a dual burden of disease, which causes preventable morbidities and fatalities. This is a result of our healthcare system’s deficiencies, which has suffered a serious decline since the COVID-19 pandemic. However, this opened up the possibilities for digital health interventions, which innovators could utilize to provide solutions to these public health issues. Health hackathons, which offer an environment for innovators to brainstorm and collaborate, are rare in Africa. This paper outlines the planning and execution of a virtual hackathon and explores its implications for the promotion of public health in Africa.

Over the course of a month, we collaborated with innovation hubs in Africa to hold an open call, a training session, a design sprint, as well as a 48-hour virtual hackathon. We received 68 submissions from 13 African nations. Following the selection of 10 teams, design thinking was employed to develop solutions to a public health problem in Africa. The theme for the hackathon was ‘Promoting Health Equity with Digital Technology in Africa’ and areas of focus were non-communicable diseases; infectious disease epidemiology and surveillance; and health information and data management. All ten teams developed prototypes, the top three teams were offered the opportunity to continue on to the start-up accelerator program, while the winning team also received a cash prize.

In conclusion, the public health hackathon challenged African medical students to develop innovations for healthcare problems. There is a need for further study to evaluate the solutions developed.
SURGICALLY IMPORTANT ANATOMIC VARIATIONS OF EXTRAHEPATIC BILIARY SYSTEM AMONG BLACK KENYAN CADAVERS AT MOI UNIVERSITY HUMAN ANATOMY LABORATORY
Authors: Ndiwa Dan , Wandera Andrew , Njoroge Anthony , Lwande Gerald , El-Badawi Mohamed
Published: January 2023

Background

Anatomical variations of the human body including the extra hepatic biliary system exist across various individuals. Understanding the variant anatomy of the extrahepatic biliary system aids surgeons in avoiding iatrogenic injuries. This is important in resource limited settings where it is not possible to perform adequate radiological investigations of the hepatobiliary system prior to surgery. This study described the anatomic variation of the extrahepatic biliary system among Kenyans.

Methods

This was a cross-sectional study conducted at Moi University’s Anatomy Laboratories among 42 adult cadaveric specimens. Specimen dissections were conducted as per the fifteenth edition of Cunningham’s manual of Practical Anatomy. The variant anatomy data collected were filled in a structured data collection form, analysed and presented using descriptive statistics.

Study Findings

Of the 42 cadavers sampled, 62% (n=26) were male while 38% (n=16) were female. All had a gall bladder being drained by the cystic duct. The length of the cystic duct ranged between 7-35 mm joining the common hepatic duct to form the common bile duct in 98% (n=41) of all the cadavers sampled. This confluence was to the left in 7.1% (n=3), right 42.9% (n=18), anteriorly in 14.3% (n=6) and posteriorly 35.7% (n=14). A single cadaver (2%) had the cystic duct drain into the right hepatic duct. Two thirds (66.7%; n=28) of the cadavers sampled had the confluence of the right and the left hepatic duct outside the liver. There were no cholecystohepatic ducts in this study.

Conclusion

The study determined the existence of surgically important variant anatomy of the extrahepatic biliary system. There is need for greater appreciation of the extrahepatic biliary system variant anatomy by both surgeons and radiologists so as to decrease morbidity and improve on surgical outcomes.
Inter-step Variations of Stairways and Associations of High-Contrast Striping and Fall-related Event Observations
Authors: Brown Chayston B. , Poulsen Shandon L. , Barrett Tyson S. , Dakin Christopher J. , Harper Sara A.
Published: January 2023

Background

Variability in the riser and depth of each step in a stairway can decrease step predictability, and increase users’ fall risk. Unfortunately, inconsistencies in inter-step riser height and depth are common, but their impact may be lessened by adding high-contrast tread edges and vertical, monochrome striping applied to the bottom and top steps’ faces. Such contrast enhancement may draw greater attention to the steps’ edges or enhance the precision of the edge’s estimated location.

Purpose

To determine if greater inconsistency in inter-step riser height and depth are associated with more frequent slips, trips, and falls, and if these events are reduced in flights of stairs with contrast-enhanced step edges.

Methods

Stair users were videotaped on two public stairways. One stairway had black vinyl strips applied to the steps’ edges and black-and-white vertical stripes on the first and last steps’ faces. The intervention stairway was switched halfway through data collection. Stair users were coded for whether they experienced a fall-related event. A Monte Carlo simulation was used to determine the probability of observing a range of plausible distributions of fall-related events.

Results

Flights of stairs with riser height variability of 14 mm and tread depth variability of 38 mm were associated with 80% of the observed fall-related events. 13 of 16 (81%) fall-related events occurred on the control stairway compared to 3 of 16 (19%) on the intervention stairway. The distribution of fall-related events observed between conditions had a probability of occurring by random chance of less than 0.04.

Conclusion

These data suggest a vision-based strategy (i.e., striping) may counteract fall risk associated with inter-step riser height and depth inconsistencies. While the mechanisms of its action remain unclear, the high-contrast striping appears to reduce the incidence of fall-related events in the presence of inter-step riser height and depth inconsistencies.
Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
Authors: Tadros Rafik , Zheng Sean L , Grace Christopher , Jordà Paloma , Francis Catherine , Jurgens Sean J , Thomson Kate L , Harper Andrew R , Ormondroyd Elizabeth , West Dominique M , Xu Xiao , Theotokis Pantazis I , Buchan Rachel J , McGurk Kathryn A , Mazzarotto Francesco , Boschi Beatrice , Pelo Elisabetta , Lee Michael , Noseda Michela , Varnava Amanda , Vermeer Alexa MC , Walsh Roddy , Amin Ahmad S , van Slegtenhorst Marjon A , Roslin Nicole , Strug Lisa J , Salvi Erika , Lanzani Chiara , de Marvao Antonio ,   Hypergenes InterOmics Collaborators, Roberts Jason D , Tremblay-Gravel Maxime , Giraldeau Genevieve , Cadrin-Tourigny Julia , L’Allier Philippe L , Garceau Patrick , Talajic Mario , Pinto Yigal M , Rakowski Harry , Pantazis Antonis , Baksi John , Halliday Brian P , Prasad Sanjay K , Barton Paul JR , O’Regan Declan P , Cook Stuart A , de Boer Rudolf A , Christiaans Imke , Michels Michelle , Kramer Christopher M , Ho Carolyn Y , Neubauer Stefan ,   HCMR Investigators, Matthews Paul M , Wilde Arthur A , Tardif Jean-Claude , Olivotto Iacopo , Adler Arnon , Goel Anuj , Ware James S , Bezzina Connie R , Watkins Hugh
Published: January 2023

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) as sociated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene,SVIL, which encodes the actin-binding protein supervillin, showing that rare truncatingSVILvariants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.
The parasubthalamic nucleus refeeding ensemble delays feeding initiation
Authors: Dunning Jeffery L , Lopez Catherine , Krull Colton , Kreifeldt Max , Angelo Maggie , Ramakrishnan Charu , Deisseroth Karl , Contet Candice
Published: January 2023

The parasubthalamic nucleus (PSTN) is responsive to refeeding after food deprivation and PSTN subpopulations can suppress feeding. However, no study directly addressed the role of PSTN neurons activated upon food access resumption. Here we show that the ensemble of refeeding-activated PSTN neurons drastically increases the latency to initiate refeeding with both familiar and novel food but exerts limited control over the amount of food consumed by hungry mice. This ensemble also delays sucrose consumption but accelerates water consumption in thirsty mice. We next sought to identify which subpopulations of PSTN neurons might be driving these effects. We discovered that PSTNTac1neurons projecting to the CeA selectively suppress feeding initiation while PSTNCrhneurons surprisingly promote the consumption of novel, palatable substances. Our results demonstrate the key role of endogenous PSTN activity in the control of feeding initiation and identify PSTN subpopulations counteracting each other’s influence on consummatory behaviors.
Myeloperoxidase promotes a tumorigenic microenvironment in non-small cell lung cancer
Authors: Valadez-Cosmes Paulina , Maitz Kathrin , Kindler Oliver , Mujkanovic Nejra Cosic , Lueger Anna , Raftopoulou Sofia , Kienzl Melanie , Mihalic Zala Nikita , Santiso Ana , Sarsembayeva Arailym , Brcic Luka , Lindenmann Jörg , Sattler Wolfgang , Heinemann Akos , Schicho Rudolf , Marsche Gunther , Houghton A. McGarry , Kargl Julia
Published: January 2023

Myeloperoxidase (MPO) is a heme peroxidase that is mainly expressed and secreted by neutrophils. MPO’s role in inflammatory diseases has been highlighted in recent years, but its role in tumor development remains unclear. Therefore, we investigated the role of MPO in non-small cell lung cancer (NSCLC).In silicoanalysis revealed a survival benefit in patients with NSCLC and low MPO expression. Furthermore, a syngeneic tumor model using MPO knockout (KO) mice revealed that mice lacking MPO had lower tumor growth than controls. The reduction in tumor size was accompanied by an increase in lymphoid populations, including natural killer cells and CD8+T cells, suggesting a shift to a more anti-tumorigenic immune environment in MPO-KO mouse tumors. The T cell induced interferon-gamma (IFN-γ) expression was increased in MPO-KO tumors, indicating increased tumoricidal activity. CD8 depletion abolished the previously observed reduction in tumor size in MPO-KO mice, indicating that CD8+T cells play an important role.In vitro, T cells treated with MPO showed reduced proliferation and IFN-γ expression. Furthermore, MPO could be internalized into T cells. Heparin pretreatment of T cells blocked MPO binding and internalization into T cells and reversed MPO-induced proliferation reduction. Interestingly, MPO+lymphocytes were found in tumor samples from patients with NSCLC. Our findings suggest that MPO plays an immunosuppressive role in NSCLC.

One Sentence Summary

High myeloperoxidase (MPO) expression in non-small cell lung cancer patients is a predictor for adverse outcome and mice lacking MPO showed enhanced anti-tumorigenic leukocyte infiltration, suggesting a pro-tumorigenic role of MPO.
HTLV-1 Splice Sites in Prevalent Gene Vectors Cause Splicing Perturbations in Transgenic Human Cells
Authors: Miskey Csaba , Prommersberger Sabrina , Mestermann Katrin , Hudecek Michael , Ivics Zoltán
Published: January 2023

The use of any semi-randomly integrating gene vector in a therapeutic setting is associated with genotoxic risks. The two major mechanisms of genotoxicity are disruption of a coding sequence (loss-of-function) or transcriptional upregulation of genes (gain-of-function) in the cellular genome where the genetic modifications are executed. A third, less widely recognized genotoxic risk stems from splice sites and polyadenylation sites within the vector sequences. These transcriptional elements may drive aberrant splicing and/or polyadenylation between transgene-contained and genomic sequences. A widely used promoter/enhance element present in gene vectors to ensure high transgene expression levels in mammalian cells is composed of a hybrid EF1α/HTLV-1 LTR, in which the retroviral LTR contains an intron. We assessed aberrant splicing initiated from the splice donor (SD) element present in the HTLV-1 LTR in CAR-T cells that had been engineered by either lentiviral vector (LV) orSleeping Beauty(SB) transposon-mediated gene transfer. We establish that the vector-contained canonical SD site gives rise to aberrantly spliced RNA species and thereby can cause misexpression of host gene segments that are involved in various host cell functions. This, potentially genotoxic, effect could be abrogated by mutating or completely eliminating the SD (or the entire intron) from the HTLV-1 LTR segment. CAR-T cells generated by the modified vectors are equally potent in efficiency of CAR-T cell manufacturing and in functionality. The simple genetic modifications that we describe here affecting vector design therefore enhance genomic safety while maintaining efficacy of gene-modified therapeutic cells.
PPAD: A deep learning architecture to predict progression of Alzheimer’s disease
Authors: Al Olaimat Mohammad , Martinez Jared , Saeed Fahad , Bozdag Serdar ,   Alzheimer's Disease Neuroimaging Initiative
Published: January 2023

Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Mild cognitive impairment (MCI) is an intermediary stage between cognitively normal (CN) state and AD. Not all people who have MCI convert to AD. The diagnosis of AD is made after significant symptoms of dementia such as short-term memory loss are already present. Since AD is currently an irreversible disease, diagnosis at the onset of disease brings a huge burden on patients, their caregivers, and the healthcare sector. Thus, there is a crucial need to develop methods for the early prediction AD for patients who have MCI. Recurrent Neural Networks (RNN) have been successfully used to handle Electronic Health Records (EHR) for predicting conversion from MCI to AD. However, RNN ignores irregular time intervals between successive events which occurs common in EHR data. In this study, we propose two deep learning architectures based on RNN, namely Predicting Progression of Alzheimer’s Disease (PPAD) and PPAD-Autoencoder (PPAD-AE). PPAD and PPAD-AE are designed for early predicting conversion from MCI to AD at the next visit and multiple visits ahead for patients, respectively. To minimize the effect of the irregular time intervals between visits, we propose using age in each visit as an indicator of time change between successive visits. Our experimental results conducted on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Alzheimer’s Coordinating Center (NACC) datasets showed that our proposed models outperformed all baseline models for most prediction scenarios in terms of F2 and sensitivity. We also observed that the age feature was one of top features and was able to address irregular time interval problem.
Biosimilarity of GBPD002 compared with Eprex®through clinical evaluation in human
Authors: Nag Kakon , Mohiuddin Mohammad , Mahtab Mamun Al , Bachar Sitesh Chandra , Rahim Abdur , Uddin Helal , Kumar Samir , Khan Maksudur Rahman , Sarker Enamul Haq , Chowdhury Mashfiqur Rahman , Roy Rony , Chakraborty Sourav , Biswas Bipul Kumar , Bappi Emrul Hasan , Roy Ratan , Barman Uttam , Sultana Naznin
Published: January 2023

Background

The biosimilarity for erythropoietin (EPO) functionality of GBPD002 (test candidate) and Eprex®(comparator) has been evaluated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties following subcutaneous injection.

Methods

This was a randomized, double-blinded, two-sequence, crossover clinical trial. Subjects were randomly assigned and received a dose (4,000 IU) of either the test or comparator EPO, and received the alternative formulations after 4-weeks of washout period.

Results

The PK parameters,viz., maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-inf), were calculated with the serum EPO concentrations from blood samples and were found comparable for both formulations. The geometric mean ratios (at 90% CI) of the Cmaxand AUCinfwere 0.89 and 1.16, respectively, which were within the regulatory range of 0.80 – 1.25. The time-matched serum EPO concentrations and PD markers (reticulocyte, hematocrit, hemoglobin, and red blood cell) denoted a counterclockwise hysteresis, suggesting a time delay between the observed concentration and the response. ANOVA-derivedP-values (>0.05) for the effectors clearly revealed the similarity between effects on PD markers for the test and comparator drugs. Both formulations were found tolerated well, and anti-drug antibodies were not observed.

Conclusions

Thus, the two formulations are projected to be used interchangeably in clinical settings.
The artemisinin-induced dormant stages ofPlasmodium falciparumexhibit hallmarks of cellular senescence and drug resilience
Authors: Tripathi Jaishree , Stoklasa Michal , Nayak Sourav , Low Kay En , Lee Erica Qian Hui , Rénia Laurent , Malleret Benoit , Bozdech Zbynek
Published: January 2023

Recrudescent infections with human malaria parasite,Plasmodium falciparum, presented traditionally the major setback of artemisinin-based monotherapies. Although introduction of artemisinin combination therapies (ACT) largely solved the problem, the ability of artemisinin to induce dormant parasites still poses major obstacle for current as well as future malaria chemotherapeutics. Here, we developed a robust laboratory model for induction of dormantP. falciparumparasites and characterized their transcriptome, drug sensitivity profile and cellular ultrastructure. We show thatP. falciparumdormancy requires a ~5-days maturation process during which the genome-wide gene expression pattern gradually transitions from the ring-like state to a highly unique form. The transcriptome of the mature dormant stage carries hallmarks of cellular senescence with downregulation of most cellular functions associated with growth and development, but upregulation of selected metabolic functions and DNA repair. Moreover, theP. falciparumdormant stage is considerably more resistant to essentially all antimalaria drugs compared to the fast-growing asexual stages. Finally, the unique cellular ultrastructure further suggests unique properties of this new developmental stage of theP. falciparumlife cycle that should be taken into consideration by new malaria control strategies.
An orally bioavailable 4-phenoxy-quinoline compound as a potent AURKB relocation blocker for cancer treatment
Authors: Li Jinhua , Zhang Ting , Shi Qiong , Lv Gang , Zhou Xiaohu , Choudhry Namrta , Kalashova Julia , Yang Chenglu , Li Hongmei , Long Yan , Sakthivel Balasubramaniyan , Nimishetti Naganna , Liu Hong , Allen Thaddeus D. , Zhang Jing , Yang Dun
Published: January 2023

We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, AURKB. Here, we evaluated the impact of halogen substitutions (F, Cl, Br, I) on this scaffold with respect to various drug parameters. Br-substitutedLXY18was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations.LXY18prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activityin vitro. With a favorable PK profile, it shows widespread tissue distribution including the blood-brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action ofLXY18may eliminate some drawbacks of direct catalytic inhibition of AURKs. Successful development ofLXY18as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.
Phosphorylation of the inner core oligosaccharide of lipopolysaccharide mediates recognition and phagocytosis of Gram-negative bacteria by Brain Angiogenesis Inhibitor 1 (BAI1)
Authors: Billings Emily A. , Columbus Linda , Casanova James E.
Published: January 2023

Recognition of lipopolysaccharide (LPS) is critical for host defense against Gram-negative bacteria and the regulation of local inflammatory responses at the host-microbial interface. We have previously shown that the adhesion G-protein-coupled receptor (aGPCR) BAI1 acts as a phagocytic pattern recognition receptor (PRR) that selectively recognizes Gram-negative bacteria through a series of five Type I thrombospondin repeats (TSRs) in its extracellular domain. Unlike Toll-like receptor 4 (TLR4), which recognizes the hydrophobic lipid A region of LPS, the BAI1 TSRs bind the core oligosaccharide of canonical LPS structures (1). In this study, we report that BAI1 requires the phosphorylated inner core L-glycero-d-manno-heptose moiety of LPS for recognition, in the context of intact, live bacteria. Mutant strains ofSalmonella entericaserovar Typhimurium orE. coliBW25113 K-12 that fail to phosphorylate the inner core oligosaccharide, specifically heptose I, are not recognized by BAI1. Phosphorylation of inner core oligosaccharides is critical for membrane stability and function and is conserved across most Gram-negative species, thus allowing BAI1 to recognize a broad range of organisms.
Deletion of genes linked to the C1-fixing gene cluster affects growth, by-products, and proteome ofClostridium autoethanogenum
Authors: Nwaokorie Ugochi Jennifer , Reinmets Kristina , de Lima Lorena Azevedo , Pawar Pratik Rajendra , Shaikh Kurshedaktar Majibullah , Harris Audrey , Köpke Michael , Valgepea Kaspar
Published: January 2023

Gas fermentation has emerged as a sustainable route to produce fuels and chemicals by recycling inexpensive one-carbon (C1) feedstocks from gaseous and solid waste using gas-fermenting microbes. Currently, acetogens that utilise the Wood-Ljungdahl pathway to convert carbon oxides (CO and CO2) into valuable products are the most advanced biocatalysts for gas fermentation. However, our understanding of the functionalities of the genes involved in the C1-fixing gene cluster and its closely-linked genes is incomplete. Here, we investigate the role of two genes with unclear functions – hypothetical protein (hp;LABRINI_07945) and CooT nickel binding protein (nbp;LABRINI_07950) – directly adjacent and expressed at similar levels to the C1-fixing gene cluster in the gas-fermenting model-acetogenClostridium autoethanogenum. Targeted deletion of either thehpornbpgene using CRISPR/nCas9, and phenotypic characterisation in heterotrophic and autotrophic batch and autotrophic bioreactor continuous cultures revealed significant growth defects and altered by-product profiles for both Δhpand Δnbpstrains. Variable effects of gene deletion on autotrophic batch growth on rich or minimal media suggest that both genes affect the utilisation of complex nutrients. Autotrophic chemostat cultures showed lower acetate and ethanol production rates and higher carbon flux to CO2and biomass for both deletion strains. Additionally, proteome analysis revealed that disruption of either gene affects the expression of proteins of the C1-fixing gene cluster and ethanol synthesis pathways. Our work contributes to a better understanding of genotype-phenotype relationships in acetogens and offers engineering targets to improve carbon fixation efficiency in gas fermentation.
Dual RNA-seq identifies proteins and pathways modulated duringClostridioides difficilecolonisation
Authors: Frost Lucy R. , Stark Richard , Anonye Blessing , Ferreira Ludmila R. P. , Unnikrishnan Meera
Published: January 2023

The gastrointestinal pathogen,Clostridioides difficile, is the most common cause of hospital-acquired diarrhoea. Bacterial interactions with the gut mucosa are crucial for colonisation and establishment ofC. difficileinfection, however, key infection events like bacterial attachment and gut penetration are still poorly defined. To better understand the initial events that occur when this anaerobic pathogen interacts with human gut epithelial cells, we employed a dual RNA-sequencing approach to study the bacterial and host transcriptomic profiles duringC. difficileinfection in a dual-environmentin vitrohuman gut model. Temporal changes in gene expression during infection were studied in the bacterium and the host cells over the course of 3-24 hours. While there were several common differentially expressed bacterial genes across the different times after infection, mammalian transcriptional profiles were quite distinct with little overlap. Interestingly, an induction of colonic receptors forC. difficiletoxins was observed, along with the expression downregulation of genes encoding immune response markers. Several cell wall associated proteins were downregulated inC. difficilewhen in association with host cells, includingslpA, which encodes the main S-layer protein. Gene function and pathway enrichment analyses revealed a potential modulation of the purine/pyrimidine synthesis pathways both in the mammalian and the bacterial cells. We observed that proline-proline endopeptidase, a secreted metalloprotease responsible for cell surface protein cleavage, is downregulated during infection, and a mutant lacking this enzyme demonstrated enhanced adhesion to epithelial cells during infection. This study provides new insight into the host and bacterial pathways based on gene expression modulation during the initial contact ofC. difficilewith gut cells.

Importance

The initial interactions between the colonic epithelium and the bacterium are likely critical in the establishment ofClostridioides difficileinfection, one of the major causes of hospital acquired diarrhoea worldwide. Molecular interactions betweenC. difficileand human gut cells have not been well defined mainly due to the technical challenges of studying cellular host-pathogen interactions with this anaerobe. Here we have examined transcriptional changes occurring in the pathogen and host cells during the initial 24 hours of infection. Our data indicate several changes in metabolic pathways and virulence-associated factors during the initial bacterium-host cell contact and early stages of infection. We describe canonical pathways enriched based on the expression profiles of a dual RNAseq in the host and the bacterium, and functions of bacterial factors modulated during infection. This study provides insight into the early infection process at a molecular level.
Identification of functionalNpuDnaE and gp41-1 inteins split in three fragments
Authors: Weis Daniel , Palanisamy Navaneethan , Ballestin Jara Ballestin , Öztürk Mehmet Ali , Di Ventura Barbara
Published: January 2023

Inteins are special proteins that auto-catalytically carry out a protein splicing reaction. Due to their ability to post-translationally modify target proteinsin vitroandin vivo, they are used in different applications, ranging from protein purification to the construction of Boolean logic gates. So far inteins have been found to be either encoded by a single gene (contiguous inteins) or by two separate ones (split inteins). Previously, it has been shown that the contiguousSspandRmaDnaB inteins and the splitNpuDnaE intein could be artificially split in three fragments and retain functionality. Here we report the identification of novel split sites within the N-terminal fragments of theNpuDnaE and gp41-1 split inteins that lead to synthetic functional three-piece versions of these inteins. These variants contribute to the toolkit of three-piece inteins that could be used in biotechnological applications based on highly-fragmented inteins.
Adaptive and maladaptive consequences of deregulation in a bacterial gene regulatory network
Authors: Vinchhi Rhea , Yelpure Chetna , Balachandran Manasvi , Matange Nishad
Published: January 2023

The archetypal PhoQP two-component system from Enterobacteria regulates crucial pathways like magnesium homeostasis inEscherichia coliand virulence factor expression inSalmonella enterica. Previously we had reported that a laboratory strain ofE. colirapidly accumulated loss-of-function mutations in themgrBgene, a negative feedback regulator of PhoQP, when evolved in the presence of the antibiotic trimethoprim. Hyperactive PhoQP enhanced the expression of dihydrofolate reductase (folA), target of trimethoprim, resulting in antibiotic tolerance. Here we ask, firstly, how important are mutations inmgrBfor trimethoprim resistance? Using laboratory evolution, we show that trimethoprim resistance evolves by different mutational trajectories under condition of high and low PhoQP activity. Mutations inmgrBare only fixed when PhoQP is active. Importantly, loss of functional MgrB, though itself only mildly beneficial, enhances the fixation probability of trimethoprim-resistant bacteria under selection and this can be explained by epistasis betweenmgrBandfolAloci. As a result, the activation status of PhoQP directly impacts how fast resistance is acquired by evolving populations ofE. coli. Secondly, we investigate why negative feedback may be needed in the PhoQP system. We show that under drug-free conditions MgrB is required to mitigate the fitness costs of pervasive gene dysregulation by hyperactive PhoQP. Using RNA-seq transcriptomics and genetic analyses, we demonstrate that PhoQP-hyperactivation perturbs the balance of RpoS and RpoD-regulated transcriptional programs, and spontaneous mutations inrpoSrectify this imbalance. We propose that deregulation can be adaptive or maladaptive depending on the environmental context and this explain the evolution of negative feedback in bacterial gene regulatory networks.
Structure of a Membrane Tethering Complex Incorporating Multiple SNAREs
Authors: DAmico Kevin A. , Stanton Abigail E. , Shirkey Jaden D. , Travis Sophie M. , Jeffrey Philip D. , Hughson Frederick M.
Published: January 2023

Most membrane fusion reactions in eukaryotic cells are mediated by membrane tethering complexes (MTCs) and SNARE proteins. MTCs are much larger than SNAREs and are thought to mediate the initial attachment of two membranes. Complementary SNAREs then form membrane-bridging complexes whose assembly draws the membranes together for fusion. Here, we present a cryo-EM structure of the simplest known MTC, the 255-kDa Dsl1 complex, bound to the two SNAREs that anchor it to the endoplasmic reticulum. N-terminal domains of the SNAREs form an integral part of the structure, stabilizing a Dsl1 complex configuration with remarkable and unexpected similarities to the 850-kDa exocyst MTC. The structure of the SNARE-anchored Dsl1 complex and its comparison with exocyst reveal what are likely to be common principles underlying MTC function. Our structure also implies that tethers and SNAREs can work together as a single integrated machine.
Human Amylin in the Presence of SARS-COV-2 Protein Fragments
Authors: Chesney Andrew D. , Maiti Buddhadev , Hansmann Ulrich H. E.
Published: January 2023

Covid-19 can lead to the onset of type-II diabetes which is associated with aggregation of islet amyloid polypeptides, also called amylin. Using molecular dynamics simulations, we investigate how the equilibrium, between amylin monomers in its functional form and fibrils associated with diabetes, is altered in presence of SARS-COV-2 protein fragments. For this purpose, we study the interaction between the fragment SFYVYSRVK of the Envelope protein or the fragment FKNIDGYFKI of the Spike protein with the monomer and two amylin fibril models. Our results are compared with earlier work studying such interactions for two different proteins.
Fitness effects of mutations to SARS-CoV-2 proteins
Authors: Bloom Jesse D. , Neher Richard A.
Published: January 2023

Knowledge of the fitness effects of mutations to SARS-CoV-2 can inform assessment of new variants, design of therapeutics resistant to escape, and understanding of the functions of viral proteins. However, experimentally measuring effects of mutations is challenging: we lack tractable lab assays for many SARS-CoV-2 proteins, and comprehensive deep mutational scanning has been applied to only two SARS-CoV-2 proteins. Here we develop an approach that leverages millions of publicly available SARS-CoV-2 sequences to estimate effects of mutations. We first calculate how many independent occurrences of each mutation are expected to be observed along the SARS-CoV-2 phylogeny in the absence of selection. We then compare these expected observations to the actual observations to estimate the effect of each mutation. These estimates correlate well with deep mutational scanning measurements. For most genes, synonymous mutations are nearly neutral, stop-codon mutations are deleterious, and amino-acid mutations have a range of effects. However, some viral accessory proteins are under little to no selection. We provide interactive visualizations of effects of mutations to all SARS-CoV-2 proteins (https://jbloomlab.github.io/SARS2-mut-fitness/). The framework we describe is applicable to any virus for which the number of available sequences is sufficiently large that many independent occurrences of each neutral mutation are observed.
Evaluating workforce needs for higher specialist training for psychiatry of intellectual disability in Kent, Surrey and Sussex: a workforce scoping service evaluation
Authors: Mukherjee Raja A.S. , Ondrusz Mary
Published: January 2023

Purpose

Whilst recruitment and retention of high-quality staff is vital to providing a good service, at the time of the evaluations, Kent, Surrey and Sussex (KSS) was the only area of the UK without a Higher Specialist Training (HST) scheme in intellectual disability (ID). The purpose of this project was to identify barriers to recruitment and support the need for change.

Design/methodology/approach

This evaluation included conducting interviews with 16 practitioners in the region with links to ID to consider the gaps in training and find solutions.

Findings

Four themes were identified, namely, good experiences are important to recruiting people into the ID field; bad experiences or lack of exposure to people with ID are likely to prevent engagement with this field; there is an ongoing need for specialist psychiatrists in ID services; and there is a developing need for specialists in neurodevelopmental disorders. Finally, the challenge means we need to think differently about developing a workforce. Seven recommendations to support workforce delivery in KSS were developed.

Originality/value

This paper highlights an important rationale for ongoing need for HST in ID work and also reasons to engage people in this field. This has not been undertaken in the ID field in this way previously.
“My contract is breached, and I want to leave, but I am embedded!” how do reluctant stayers respond?
Authors: Singh Riann
Published: January 2023

Purpose

This study takes a unique perspective on the role of psychological contract breach, turnover intentions and off-the-job embeddedness in influencing the behavior of reluctant stayers. More specifically, reluctant stayers are defined as employees who are high on turnover intentions and off-the-job embeddedness. It proposes that employees who perceive psychological contract breaches are more likely to develop turnover intentions. Such breaches are expected to indirectly spur organizational deviance, with turnover intentions as the mediator. Finally, a moderated-mediation model is proposed where off-the-job embeddedness is expected to moderate the relationship between turnover intentions and organizational deviance.

Design/methodology/approach

Data were collected from 231 employees across the energy sector within the Caribbean nation of Trinidad, using a two-wave research design and a path-analytic approach.

Findings

The findings provide support for the propositions that perceived psychological contract breach predicts turnover intentions and that turnover intentions mediate the contract breach–organizational deviance relationship. Further, the proposition that off-the-job embeddedness moderates the relationship between turnover intentions and organizational deviance was supported by the sample data. Consequently, reluctant stayers (employees with high turnover intentions and high off-the-job embeddedness) responded to perceived psychological contract breach with higher levels of organizational deviance when they were more deeply embedded.

Originality/value

Limited studies have explored the behaviors of reluctant stayers, and hence this study adds to research on this emerging classification of employees. Furthermore, no study has yet explored the role of high turnover intentions and off-the-job embeddedness in creating reluctant stayers.
Critical project management success factors analysis for the construction industry of Bangladesh
Authors: Datta Shuvo Dip , Sobuz Md. Habibur Rahman , Nafe Assafi Mohammad , Sutan Norsuzailina Mohamed , Islam Md. Nazrul , Mannan Maria Binte , Akid Abu Sayed Mohammad , Hasan Noor Md. Sadiqul
Published: January 2023

Purpose

This paper aims to identify the critical project management success factors and analyze those factors to achieve a sustainable construction industry in Bangladesh.

Design/methodology/approach

This study identified 41 major problematic factors from the related literature. In this research, a detailed questionnaire survey was conducted among the experts and stakeholders of the construction industry of Bangladesh. The survey was carried out on a Likert scale and ranked the critical factors using the relative importance index (RII). The 41 problematic factors were divided into five group factors and ranked by the RII index to prioritize the factors. Finally, stakeholders' opinions were analyzed with the critical assessed factors, which was a very effective technique to eliminate the risks and uncertain occurrences in the construction industry of Bangladesh.

Findings

The factors analysis revealed that cost overrun, traffic jam, low wedges, slow payment for completed works and financial issues of the owner were leading critical factors in construction projects. Moreover, the critical factors are divided into five-factor groups, namely, financial management, monitoring and feedback, competency management, communication and coordination management, and risk management, which exhibit 0.767, 0.720, 0.711, 0.710 and 0.658 RII values. After all, the stakeholders' opinion suggested that implementing modern tools and techniques can help to avoid the critical situation in the construction industry of Bangladesh.

Practical implications

The construction industry of Bangladesh is moving away from stable construction work day by day. Previously, the potential CSFs were discussed unstructured way. Hence, detecting early warning signals in a structured way has become necessary for the building firm's survival.

Originality/value

Though some scattered critical issues are discussed in different literature, the critical issues of the Bangladeshi construction industry were not investigated extensively. Therefore, this study finds out the potential critical issues of the construction industry of Bangladesh to accumulate such harmful construction issues in a single platform so that the construction industry can have an overview of them with the help of innovative technologies.
Breaking out of the expatriate bubble in Denmark: insights from the challenge of making connections with local Danes
Authors: van Bakel Marian , Vance Charles M.
Published: January 2023

Purpose

The social context of expatriation is crucial for expatriate success, including for building local host country national (HCN) social network support that can facilitate effective adjustment through information exchange. However, expatriates have particular difficulties in breaking out of the expatriate bubble and building social ties with HCNs in certain countries, especially in Scandinavia. This paper focuses on the case of Denmark and explains why many expatriates find it difficult to make social connections with Danes.

Design/methodology/approach

This study involves a meta-ethnography of literature on Danish culture, as well as semistructured interviews with a total of 16 expatriates in Denmark.

Findings

Three main cultural elements are identified as crucial for explaining the difficulty expatriates face in connecting with Danes, namely homogeneity, the value placed on equality and the public–private divide. The homogeneity and inward-looking mentality make it more difficult for outsiders to break into the social circle. Outsiders have to earn the trust that is difficult to obtain, reflecting Denmark's high score on GLOBE's institutional collectivism.

Practical implications

In light of the challenges that many expatriates face in creating a new social network abroad, organizations can support them in several ways. The authors discuss context-specific strategies for making new social connections in Denmark, which may be usefully applied in other countries.

Originality/value

This study focuses on the context of expatriate social network formation and shows that cultural differences in socializing affect the ease with which expatriates can make connections with HCNs, who can have a positive impact on expatriate adjustment and performance success.
Risk analysis of the rice supply chain in Cambodia
Authors: Rath Bunhorng , Wonginta Thitima , Amchang Chompoonut
Published: January 2023

Purpose

This paper aims to analyze the risks faced by the Cambodian rice supply chain (RSC), including risk identification, risk investigation and risk management.

Design/methodology/approach

The first qualitative area of exploration from this exploratory sequential design is to identify the potential risks, in which the authors conduct in-depth interviews with ten different experts in Cambodia. Using the structural equation model (SEM) in AMOS and descriptive statistics analysis, this study investigates the risks that affect the RSC performance on an environmental, social and economic basis and subsequently proposes risk management strategies. The authors collect quantitative data from 200 Cambodian farmers through interviews and surveys.

Findings

The results illustrate that the farm households face 18 risk factors. The researchers consolidate 18 risk factors into four classifications: supply risks, production risks, demand risks and environmental risks. Nine experts out of the ten who were interviewed (90%) consider themselves “highly vulnerable” (with a rating of 4 or 5 on the Likert scale), while only one expert has a “neutral” stance (with a rating of 3 on the Likert scale); these results concerning risk identification are visualized in the likelihood effect matrix of the RSC. After investigating the risks, the authors found that RSC performance is significantly affected by the RSC risks. In particular, four groups are created, representing two different approaches to mitigate, avoid, transfer and cope with agricultural risks, i.e. ex ante and ex post risk management strategies.

Originality/value

This study fully answers research questions regarding risk identification, risk investigation and risk management.
His, hers and theirs: comparative narratives from young people who use violence
Authors: Rak Louise , Warton Timothy
Published: January 2023

Purpose

This paper aims to explore narratives of violence in the lives of young men and young women in Australia. Through partnering with young people to understand and make meaning of their stories, the authors highlight similarities and differences in gendered experiences of violence, and the implications of these for cross-disciplinary practice.

Design/methodology/approach

This article presents the synthesis of narrative data from two separate studies that worked with justice-involved young men and young women, who had both experienced and used violence. Study 1 used a thematic analysis of practitioner narratives and qualitative data from in-session narratives. Study 2 used a thematic analysis of interview data using grounded approach and peer review to promote trustworthiness and inter-rater reliability.

Findings

Insights on the experiences of young people who use violence are notably absent in most forms of violence discourse, practice and research. Findings demonstrate that understandings of youth violence are linked to identity, but also situated within contexts of trauma, place, gender, relationality and community. This conceptualisation of violence is particularly important to understandings of young female violence.

Originality/value

Through collaborative approaches of co-design and co-production, the paper outlines that a stronger understanding of the experiences of young men and young women (often an over-looked cohort) in the justice system can help improve the trauma-informed and gender responsiveness of interventions across practice settings. The authors highlight that exploring gendered differences in narratives of youth violence is necessary and seeking lived experiences of youth justice young people is instructive to academia, policy and practice.
Psychometric attributes associated with attrition within a prison-based democratic therapeutic community
Authors: Pointon Victoria Jade , Roberts Rachel
Published: January 2023

Purpose

The purpose of this paper is to examine the psychometric characteristics of male offenders who joined a democratic therapeutic community and their relationship to attrition.

Design/methodology/approach

Residents who left therapy prematurely during the assessment phase (N = 46) and residents who left therapy prematurely during core therapy (N = 202) were compared to residents who completed therapy (N = 52) on two psychometric measures: Raven’s Standard Progressive Matrices and The Blame Attribution Inventory.

Findings

A multinomial logistic regression analysis showed higher levels of external blame can predict attrition during therapy; those with higher levels of external attribution are significantly more likely to leave therapy prematurely, including both during the assessment phase and during core therapy. Raven's Standard Progressive Matrices score did not significantly predict whether an individual left therapy prematurely.

Originality/value

Support was found for existing research within the academic evidence base. The findings have both empirical and clinical utility, suggesting during the assessment phase of therapy, practitioners can identify residents that may require additional support to maintain engagement, minimising the potential for premature departure. The implications of the findings are discussed, with suggestions made for future research.