bluuebunny/crossref_metadata_2025 huggingface dataset:
State-Level Excess Mortality in US Adults During the Delta and Omicron Waves of COVID-19
Authors: Renton Benjamin , Du Chengan , Chen Alexander Junxiang , Li Shu-Xia , Lin Zhenqiu , Krumholz Harlan M. , Faust Jeremy Samuel
Published: March 2023

Introduction

The US has continued to see excess mortality through the Delta and Omicron periods. We sought to quantify excess mortality on a state level and calculate potential deaths averted if all states matched the excess mortality rates of those with the 10 lowest excess mortality rates.

Methods

Observational cohort, US and state-level data. Expected monthly deaths were modeled using pre-pandemic US and state-level data (2015-2020). Mortality data was accessed from CDC public reporting.

Results

We find that during the Delta and Omicron waves, the US recorded over 596,000 excess deaths. 60% of the nation’s total excess mortality during these periods could have been averted if all states had excess mortality rates equal to those with the 10 lowest excess mortality rates.

Conclusion

With large differences in excess mortality across US states in this 15-month study period, we note that a significant portion of deaths could have been averted with higher vaccination rates, improved mitigation policies, and adherence to other behaviors.
Spatial and Amplitude Dynamics of Neurostimulation: Insights from the Acute Intrahippocampal Kainate Seizure Mouse Model
Authors: Foutz Thomas J. , Rensing Nicholas , Han Lirong , Durand Dominique M. , Wong Michael
Published: March 2023

Objective

Neurostimulation is an emerging treatment for patients with medically refractory epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model.

Methods

We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of temporal lobe epilepsy. We evaluated combinations of six anatomic targets and three stimulus amplitudes.

Results

We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation.

Significance

These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy.

Key Points

Evaluated spatial and temporal parameters of neurostimulation in a mouse model of acute seizures

Brief bursts of high-frequency (100 Hz) stimulation effectively interrupted epileptiform activity.

The suppressive effect was highly dependent on stimulation amplitude and was maximal at the ipsilateral CA1 and CA3 regions.

Pro-excitatory effects were identified with high-amplitude high-frequency stimulation at the ventral hippocampal commissure and contralateral CA1.
Early transcriptional responses of human nasal epithelial cells to infection with Influenza A and SARS-CoV-2 virus differ and are influenced by physiological temperature
Authors: Resnick Jessica D. , Beer Michael A. , Pekosz Andrew
Published: March 2023

Influenza A (IAV) and SARS-CoV-2 (SCV2) viruses represent an ongoing threat to public health. Both viruses target the respiratory tract, which consists of a gradient of cell types, receptor expression, and temperature. Environmental temperature has been an un-derstudied contributor to infection susceptibility and understanding its impact on host responses to infection could help uncover new insights into severe disease risk factors. As the nasal passageways are the initial site of respiratory virus infection, in this study we investigated the effect of temperature on host responses in human nasal epithelial cells (hNECs) utilizing IAV and SCV2in vitroinfection models. We demonstrate that temperature affects SCV2, but not IAV, viral replicative fitness and that SCV2 infected cultures are slower to mount an infection-induced response, likely due to suppression by the virus. Additionally, we show that that temperature not only changes the basal transcriptomic landscape of epithelial cells, but that it also impacts the response to infection. The induction of interferon and other innate immune responses were not drastically affected by temperature, suggesting that while the baseline antiviral response at different temperatures remains consistent, there may be metabolic or signaling changes that affect how well the cultures are able to adapt to new pressures such as infection. Finally, we show that hNECs respond differently to IAV and SCV2 infection in ways that give insight into how the virus is able to manipulate the cell to allow for replication and release. Taken together, these data give new insight into the innate immune response to respiratory infections and can assist in identifying new treatment strategies for respiratory infections.
Structural insights into the allosteric inhibition of P2X4 receptors
Authors: Shen Cheng , Cui WenWen , Zhang Yuqing , Zhao Yimeng , Sheng Danqi , Teng Xinyu , Wang Jin , Hattori Motoyuki
Published: March 2023

P2X receptors are ATP-activated cation channels involved in a variety of physiological functions. Among the seven subtypes of P2X receptors, the P2X4 subtype plays important roles in both the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets, and several P2X4 subtype-specific inhibitors have been developed. However, the mechanism of allosteric inhibition of P2X4 receptors remains largely unclear due to the lack of structural information.

Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors.

Interestingly, in the previously reported apo structure, the binding pocket is closed and too narrow to accommodate allosteric modulators. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.

Overall, the present work provides structural insights into the allosteric inhibition mechanism of P2X4 receptors, facilitating the design and optimization of specific modulators for P2X4 receptors.
Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
Authors: Stener-Victorin E , Eriksson G , Shrestha M Mohan , Paris V Rodriguez , Lu H , Banks J , Samad M , Perian C , Jude B , Engman V , Boi R , Nilsson E , Ling C , Nyström J , Asterholm I Wernstedt , Turner N , Lanner J T , Benrick A
Published: March 2023

Background

Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function.

Methods

To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation.

Results

Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue.

Conclusions

Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.

Funding

A.B. holds funding from the Swedish Research Council (2020-02485), E.SV. holds funding from the Swedish Research Council (2022-00550), the Novo Nordisk Foundation (NNF22OC0072904), and I.W.A. holds funding from the Swedish Research Council (2020-01463), Mary von Sydow Foundation, Diabetes Wellness Sverige, and EFSD//European Research Programme on ‘New Targets for Diabetes or Obesity-related Metabolic Diseases’ supported by MSD 2022, and J.N. holds funding from IngaBritt and Arne Lundberg Research Foundation.
Pithoviruses are invaded by repeats that contribute to their evolution and divergence from cedratviruses
Authors: Rigou Sofia , Schmitt Alain , Alempic Jean-Marie , Lartigue Audrey , Vendloczki Peter , Abergel Chantal , Claverie Jean-Michel , Legendre Matthieu
Published: March 2023

Pithoviridaeare amoeba-infecting giant viruses possessing the largest viral particles known so far. Since the discovery ofPithovirus sibericum, recovered from a 30,000-y-old permafrost sample, other pithoviruses, and related cedratviruses, were isolated from various terrestrial and aquatic samples. Here we report the isolation and genome sequencing of twoPithoviridaefrom soil samples, in addition to three other recent isolates. Using the 12 available genome sequences, we conducted a thorough comparative genomics study of thePithoviridaefamily to decipher the organization and evolution of their genomes. Our study reveals a non-uniform genome organization in two main regions: one concentrating core genes, and another gene duplications. We also found thatPithoviridaegenomes are more conservative than other families of giant viruses, with a low and stable proportion (5% to 7%) of genes originating from horizontal transfers. Genome size variation within the family is mainly due to variations in gene duplication rates (from 14% to 28%) and massive invasion by inverted repeats. While these repeated elements are absent from cedratviruses, repeat-rich regions cover as much as a quarter of the pithoviruses genomes. These regions, identified using a dedicated pipeline, are hotspots of mutations, gene capture events and genomic rearrangements, that contribute to their evolution.
Genomic determinants of soil depth niche partitioning in Gagatemarchaeaceae, a novel family of deeply-rooted Thaumarchaeota
Authors: Sheridan Paul O. , Meng Yiyu , Williams Tom A. , Gubry-Rangin Cécile
Published: March 2023

Knowledge of deeply-rooted non-ammonia oxidising Thaumarchaeota lineages from terrestrial environments is scarce, despite their abundance in acidic soils. Here, 15 new deeply-rooted thaumarchaeotal genomes were assembled from acidic topsoils (0-15cm) and subsoils (30-60 cm), most of them corresponding to two genera of terrestrially prevalent Gagatemarchaeaceae (previously known as thaumarchaeotal Group I.1c). Unlike previous predictions, metabolic annotations suggest Gagatemarchaeaceae perform aerobic respiration and use various organic carbon sources. Evolutionary speciation between topsoil and subsoil lineages happened early in Gagatemarchaeaceae history, with significant metabolic and genomic trait differences. Reconstruction of the evolutionary mechanisms showed that the genome expansion in topsoil Gagatemarchaeaceae resulted from extensive early lateral gene acquisition, followed by progressive gene duplication throughout evolutionary history. Ancestral trait reconstruction using the expanded genomic diversity also refuted the previous hypothesis of a Thaumarchaeota thermophilic ancestor. Ultimately, this study provides an attractive model for studying mechanisms driving niche partitioning between spatially related ecosystems.
The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates
Authors: Lees John , Pèrtille Fábio , Løtvedt Pia , Jensen Per , Bosagna Carlos Guerrero
Published: March 2023

The mitochondria are central in the cellular response to changing environmental conditions resulting from disease states, environmental exposures or normal physiological processes. Although the influences of environmental stressors upon the nuclear epigenome are well characterized, the existence and role of the mitochondrial epigenome remains contentious. Here, by quantifying the mitochondrial epigenomic response of pineal gland cells to circadian stress, we confirm the presence of extensive cytosine methylation within the mitochondrial genome. Furthermore, we identify distinct epigenetically plastic regions (mtDMRs) which vary in cytosinic methylation, primarily in a non CpG context, in response to stress and in a sex-specific manner. Motifs enriched in mtDMRs contain recognition sites for nuclear-derived DNA-binding factors (ATF4, HNF4A) important in the cellular metabolic stress response, which we found to be conserved across diverse vertebrate taxa. Together, these findings suggest a new layer of mito-nuclear interaction in which the nuclear metabolic stress response directly alters mitochondrial transcriptional dynamics.
ENKIE: A package for predicting enzyme kinetic parameter values and their uncertainties
Authors: Gollub Mattia G. , Backes Thierry , Kaltenbach Hans-Michael , Stelling Jörg
Published: March 2023

Relating metabolite and enzyme abundances to metabolic fluxes requires reaction kinetics, core elements of dynamic and enzyme cost models. However, kinetic parameters have been measured only for a fraction of all known enzymes, and the reliability of the available values is unknown. The ENzyme KInetics Estimator (ENKIE) uses Bayesian Multilevel Models to predict value and uncertainty ofKMandkcatparameters. Our models use five categorical predictors and achieve prediction performances comparable to deep learning approaches that use sequence and structure information. They provide accurate uncertainty predictions and interpretable insights into the main sources of uncertainty. We expect our tool to simplify the construction of priors for Bayesian kinetic models of metabolism.
COVID-19 as a continuous-time stochastic process
Authors: Lone Irfan , Jan Pir Muzaffar
Published: March 2023

In this article a mathematical treatment of Covid-19 as a stochastic process is discussed. The chance of extinction and the consequences of introducing new Covid-19 infectives into the population are evaluated by using certain approximate arguments. It is shown, in general terms, that the stochastic formulation of a recurrent epidemic like Covid-19 leads to the prediction of a permanent succession of undamped outbreaks of disease. It is also shown that one is able to derive certain useful conclusions about Covid-19 without consideration of immune individuals in a population.
“Disruption of Golgi markers by two RILP-directed shRNAs in neurons: a new role for RILP or a neuron-specific off-target phenotype?”
Authors: Yap Chan Choo , Digilio Laura , McMahon Lloyd , Winckler Bettina
Published: March 2023

In neurons, degradation of dendritic cargos requires RAB7 and dynein-mediated retrograde transport to somatic lysosomes. In order to test if the dynein adaptor RILP (RAB-interacting lysosomal protein) mediated the recruitment of dynein to late endosomes for retrograde transport in dendrites, we obtained several knockdown reagents which had been previously validated in non-neuronal cells. We found that striking endosomal phenotypes elicited by one shRILP plasmid were not reproduced by another one. Furthermore, we discovered a profound depletion of Golgi/TGN markers for both shRILP plasmids. This Golgi disruption was only observed in neurons and could not be rescued by re-expression of RILP. This Golgi phenotype was also not found in neurons treated with siRILP or gRILP/Cas9. Lastly, we tested if a different RAB protein that interacts with RILP, namely the Golgi-associated RAB34, might be responsible for the loss of Golgi markers. Expression of a dominant-negative RAB34 did indeed cause changes in Golgi staining in a small subset of neurons but manifested as fragmentation rather than loss of markers. Unlike in non-neuronal cells, interference with RAB34 did not cause dispersal of lysosomes in neurons. Based on multiple lines of experimentation, we conclude that the neuronal Golgi phenotype observed with shRILP is likely off-target in this cell type specifically. Any observed disruptions of endosomal trafficking caused by shRILP in neurons might thus be downstream of Golgi disruption. Different approaches will be needed to test if RILP is required for late endosomal transport in dendrites. Cell type-specific off-target phenotypes therefore likely occur in neurons, making it prudent to re-validate reagents that were previously validated in other cell types.
Molecular characterization of the N-terminal half of TasA during functional amyloid assembly and its contribution toBacillus subtilisbiofilm formation
Authors: Cámara-Almirón Jesús , Domínguez-García Laura , Mammeri Nadia El , Lends Alons , Habenstein Birgit , Vicente Antonio de , Loquet Antoine , Romero Diego
Published: March 2023

Biofilms are bacterial communities that result from a cell differentiation process that leads to the secretion of an extracellular matrix (ECM) by part of the bacterial population. InBacillus subtilis,the main protein component of the ECM is the functional amyloid TasA, which forms a fiber-based scaffold that confers structure to the ECM. The N-terminal half of TasA is strongly conserved amongBacillusspecies and contains a protein domain, the amyloid core (AcTasA), which is critical for the formation of the amyloid architecture. In this study, we demonstrate that recombinantly purified AcTasAin vitroretains biochemical properties previously observed for the entire protein. Further analysis of the AcTasA amino acid sequence revealed two amyloidogenic stretches and a region of imperfect amino acid repeats, which are known to contribute to functional amyloid assembly. Biochemical characterization of these amyloidogenic stretches found in AcTasA revealed their amyloid capacityin vitro, contributing to the amyloid nature of AcTasA. Moreover, the study of the imperfect amino acid repeats revealed the critical role of residues D64, K68 and D69 in the structural function of TasA.In vivoandin vitroexperiments with versions of TasA carrying the substitutions D64A, K68A, and D69A demonstrated a partial loss of function of the protein either in the assembly of the ECM or in the stability of the core and amyloid polymerization. Taken together, our findings allow us to better understand the polymerization process of TasA during biofilm formation and provide knowledge into the sequence determinants that promote the molecular behavior of functional amyloids.
Chromosomal organization of biosynthetic gene clusters suggests plasticity of myxobacterial specialized metabolism including descriptions for nine novel species:Archangium lansiniumsp. nov.,Myxococcus landrumussp. nov.,Nannocystis bainbridgeasp. nov.,Nannocystis poenicansasp. nov.,Nannocystis radixulmasp. nov.,Polyangium mundeleiniumsp. nov.,Pyxidicoccus parkwaysissp. nov.,Sorangium ateriumsp. nov.,Stigmatella ashevillenasp. nov
Authors: Ahearne Andrew , Phillips Kayleigh , Knehans Thomas , Hoing Miranda , Dowd Scot E. , Stevens D. Cole
Published: March 2023

Natural products discovered from bacteria provide critically needed therapeutic leads for drug discovery, and myxobacteria are an established source for metabolites with unique chemical scaffolds and biological activities. Myxobacterial genomes accommodate an exceptional number and variety of biosynthetic gene clusters (BGCs) which encode for features involved in specialized metabolism. Continued discovery and sequencing of novel myxobacteria from the environment provides BGCs for the genome mining pipeline. Herein, we describe the collection, sequencing, and genome mining of 20 myxobacteria isolated from rhizospheric soil samples collected in North America. Nine isolates where determined to be novel species of myxobacteria including representatives from the generaArchangium, Myxococcus, Nannocystis, Polyangium, Pyxidicoccus, Sorangium, andStigmatella. Growth profiles, biochemical assays, and descriptions are provided for all proposed novel species. We assess the BGC content of all isolates and observe differences between Myxococcia and Polyangiia clusters. Utilizing complete or near complete genome sequences we compare the chromosomal organization of BGCs of related myxobacteria from various genera and suggest spatial proximity of hybrid, modular clusters contributes to the metabolic adaptability of myxobacteria.
GABAergic synaptic scaling is triggered by changes in spiking activity rather than AMPA receptor activation
Authors: Gonzalez-Islas Carlos , Sabra Zahraa , Fong Ming-fai , Bülow Pernille , Yong Nicholas Au , Engisch Kathrin , Wenner Peter
Published: March 2023

Homeostatic plasticity represents a set of mechanisms that are thought to recover some aspect of neural function. One such mechanism called AMPAergic scaling was thought to be a likely candidate to homeostatically control spiking activity. However, recent findings have forced us to reconsider this idea as several studies suggest AMPAergic scaling is not directly triggered by changes in spiking. Moreover, studies examining homeostatic perturbationsin vivohave suggested that GABAergic synapses may be more critical in terms of spiking homeostasis. Here we show results that GABAergic scaling can act to homeostatically control spiking levels. We found that perturbations which increased or decreased spiking in cortical cultures triggered multiplicative GABAergic upscaling and downscaling, respectively. In contrast, we found that changes in AMPAR or GABAR transmission only influence GABAergic scaling through their indirect effect on spiking. We propose that GABAergic scaling represents a stronger candidate for spike rate homeostat than AMPAergic scaling.

Significance Statement

The nervous system maintains excitability in order to perform network behaviors when called upon to do so. Networks are thought to maintain spiking levels through homeostatic synaptic scaling, where compensatory multiplicative changes in synaptic strength are observed following alterations in cellular spike rate. Although we demonstrated that AMPAergic synaptic scaling does not appear meet these criteria as a spike rate homeostat, we now show that GABAergic scaling could play this role. Here we present evidence that the characteristics of GABAergic scaling place it in an excellent position to be a spiking homeostat. This work highlights the importance of inhibitory circuitry in the homeostatic control of excitability. Further, it provides a point of focus into neurodevelopmental disorders where excitability is impaired.
RPL26/uL24 UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum
Authors: Scavone Francesco , Gumbin Samantha C. , DaRosa Paul A. , Kopito Ron R.
Published: March 2023

Ribosomes that stall while translating cytosolic proteins are incapacitated by incomplete nascent chains, termed “arrest peptides” (APs) that are destroyed by the ubiquitin proteasome system (UPS) via a process known as the ribosome-associated quality control (RQC) pathway. By contrast, APs on ribosomes that stall while translocating secretory proteins into the endoplasmic reticulum (ER-APs) are shielded from cytosol by the ER membrane and the tightly sealed ribosome-translocon junction (RTJ). How this junction is breached to enable access of cytosolic UPS machinery and 26S proteasomes to translocon- and ribosome-obstructing ER-APs is not known. Here, we show that UPS and RQC-dependent degradation of ER-APs strictly requires conjugation of the ubiquitin-like (Ubl) protein UFM1 to 60S ribosomal subunits at the RTJ. Therefore, UFMylation of translocon-bound 60S subunits modulates the RTJ to promote access of proteasomes and RQC machinery to ER-APs.

Significance Statement

UFM1 is a ubiquitin-like protein that is selectively conjugated to the large (60S) subunit of ribosomes bound to the endoplasmic reticulum (ER), but the specific biological function of this modification is unclear. Here, we show that UFMylation facilitates proteasome-mediated degradation of arrest polypeptides (APs) which are generated following splitting of ribosomes that stall during co-translational translocation of secretory proteins into the ER. We propose that UFMylation weakens the tightly sealed ribosome-translocon junction, thereby allowing the cytosolic ubiquitin-proteasome and ribosome-associated quality control machineries to access ER-APs.
Generation of a SARS-CoV-2 reverse genetics system and novel human lung cell lines that exhibit high virus-induced cytopathology
Authors: Khan Juveriya Qamar , Rohamare Megha , Rajamanickam Karthic , Bhanumathy Kalpana K , Lew Jocelyne , Kumar Anil , Falzarano Darryl , Vizeacoumar Franco J , Wilson Joyce A
Published: March 2023

The global COVID-19 pandemic continues with an increasing number of cases worldwide and the emergence of new SARS-CoV-2 variants. In our study, we have developed novel tools with applications for screening antivirals, identifying virus-host dependencies, and characterizing viral variants. Using reverse genetics, we rescued SARS-CoV-2 Wuhan1 (D614G variant) wild type (WTFL) and reporter virus (NLucFL) using molecular BAC clones. The replication kinetics, plaque morphology and titers were comparable between rescued molecular clones and a clinical isolate (VIDO-01 strain), thus providing confidence that the rescued viruses can be used as effective replication tools. Furthermore, the reporter SARS-CoV-2 NLucFL virus exhibited robust luciferase values over the time course of infection and was used to develop a rapid antiviral assay using remdesivir as proof-of-principle. In addition, as a tool to study lung-relevant virus-host interactions, we established novel human lung cell lines that support SARS-CoV-2 infection with high virus-induced cytopathology. Six lung cell lines (NCI-H23, A549, NCI-H1703, NCI-H520, NCI-H226, and HCC827) and HEK293T cells, were transduced to stably express ACE2 and tested for their ability to support virus infection. A549ACE2B1 and HEK293TACE2A2 cell lines exhibited more than 70% virus-induced cell death and a novel lung cell line NCI-H23ACE2A3 showed about ∼99% cell death post-infection. These cell lines are ideal for assays relying on live-dead selection and are currently being used in CRISPR knockout and activation screens in our lab.

Importance

We used a reverse genetics system to generate a wild type as well as a nanoluciferase-expressing reporter clone of SARS-CoV-2. The reporter virus allows for rapid transient replication assays and high throughput screens by detection of virus replication using luciferase assays. In addition, the reverse genetic system can be used to generate mutant viruses to study phenotypes of variant mutations. Additionally, unique human lung cell lines supporting SARS-CoV-2 replication will aid in studying the virus in a lung-relevant environment and based on high cytopathology induced in some cell lines, will be useful for screens that rely on virus-induced cell death for selection. Our study aims to enhance and contribute to the current replication tools available to study SARS-CoV-2 by providing rapid methods, virus clones and novel lung cell lines.
Infections in biological and targeted synthetic drug use in rheumatoid arthritis: where do we stand? A scoping review and meta-analysis
Authors: Bergmans BJM , Gebeyehu BY , van Puijenbroek EP , Van Deun K , Kleinberg B , Murk JL , de Vries E
Published: March 2023

Objectives

The advent of biological and targeted synthetic therapies has revolutionised rheumatoid arthritis (RA) treatment. However, this has come at the price of an increased risk of infections. The aim of this study was to present an integrated overview of both serious and non-serious infections, and to identify potential predictors of infection risk in RA patients using biological or targeted synthetic drugs.

Design

We systematically reviewed available literature from PubMed and Cochrane and performed multivariate meta-analysis with meta-regression on the reported infections. Randomised controlled trials and prospective and retrospective observational studies including patient registry studies were analysed, combined as well as separately. We excluded studies focusing on viral infections only.

Results

Infections were not reported in a standardised manner. Meta-analysis showed significant heterogeneity that persisted after forming subgroups by study design and follow-up duration. Overall, the pooled proportions of patients experiencing an infection during a study were 0.30 (95%CI, 0.28-0.33) and 0.03 (95%CI, 0.028-0.035) for any kind of infections or serious infections only, respectively. We found no potential predictors that were consistent across all study subgroups.

Conclusions

The high heterogeneity and the inconsistency of potential predictors between studies show that we do not yet have a complete picture of infection risk in RA patients using biological or targeted synthetic drugs. Besides, we found non-serious infections outnumbered serious infections by a factor 10:1, but only few studies have focused on their occurrence. Future studies should apply a uniform method of infectious adverse event reporting and also focus on non-serious infections and their impact on treatment decisions and quality of life.
Functional and regulatory diversification ofPeriodgenes responsible for circadian rhythm in vertebrates
Authors: Kwak Jun Soung , León-Tapia M. Ángel , Diblasi Celian , Manousi Domniki , Grønvold Lars , Sandvik Guro Katrine , Saitou Marie
Published: March 2023

The Period genes (Per) play essential roles in modulating the molecular circadian clock timing in a broad range of species, which regulates the physiological and cellular through the transcription-translation feedback loop. While thePeriodgene paralogs are widely observed among vertebrates, the evolutionary history and the functional diversification ofPergenes across vertebrates are not well known. In this study, we comprehensively investigated the evolution ofPergenes, including de novo binding motif discovery by comparative genomics. We also determined the lineage-specific transcriptome landscape across tissues and developmental stages and phenotypic effects in public RNA-seq data sets of model species. We observed multiple lineage-specific gain and loss events ofPergenes, though no simple association was observed between ecological factors andPergene numbers in each species. Among salmonid fish species, theper3gene has been lost in the majority, whereas those retaining the per3 gene exhibit not a signature of relaxed selective constraint but rather a signature of intensified selection. We also determined the signature of adaptive diversification of the CRY-binding region inPer1andPer3, which modulates the circadian rhythm. We also discovered putative regulatory sequences, which are lineage-specific, suggesting that these cis-regulatory elements may have evolved rapidly and divergently across different lineages. Collectively, our findings revealed the evolution ofPergenes and their fine-tuned contribution to the plastic and precise regulation of circadian rhythms in various vertebrate taxa.

Significance

ThePeriod(Per) genes play essential roles in the circadian rhythm in animals. In this study, we comprehensively investigated the evolutionary diversification of the three types ofPeriodgenes in vertebrates. As a result, we observed a rapid evolution and sub-functionalization of these genes, especially adaptive diversification signatures in the protein-binding region, which plays a crucial role in regulating circadian rhythms. This underscores the fine-tuned contribution ofPergenes in the biological clock’s precision and adaptability across various vertebrate taxa.
Tetracycline-dependent inhibition of mitoribosome protein elongation in mitochondrial disease mutant cells suppresses IRE1α to promote cell survival
Authors: Ronayne Conor T. , Bennett Christopher F. , Perry Elizabeth A. , Kantorovic Noa , Puigserver Pere
Published: March 2023

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations are redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. Depending on the type of mitochondrial mutation, certain mechanisms can efficiently rescue cell death vulnerability. One method is the inhibition of mitochondrial translation elongation using tetracyclines, potent suppressors of cell death in mitochondrial disease mutant cells. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that in mitochondrial mutant disease cells, tetracycline-mediated inhibition of mitochondrial ribosome (mitoribosome) elongation promotes survival through suppression of the ER stress IRE1α protein. Tetracyclines increased levels of the splitting factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) at the mitochondria with recruitment to the mitoribosome large subunit. MALSU1, but not other quality control factors, was required for tetracycline-induced cell survival in mitochondrial disease mutant cells during glucose starvation. In these cells, nutrient stress induced cell death through IRE1α activation associated with a strong protein loading in the ER lumen. Notably, tetracyclines rescued cell death through suppression of IRE1α oligomerization and activity. Consistent with MALSU1 requirement, MALSU1 deficient mitochondrial mutant cells were sensitive to glucose-deprivation and exhibited increased ER stress and activation of IRE1α that was not reversed by tetracyclines. These studies show that inhibition of mitoribosome elongation signals to the ER to promote survival, establishing a new interorganelle communication between the mitoribosome and ER with implications in basic mechanisms of cell survival and treatment of mitochondrial diseases.
X-ray scattering study of GaN nanowires grown on Ti/Al2O3 by molecular beam epitaxy
Authors: Kaganer Vladimir M. , Konovalov Oleg V. , Calabrese Gabriele , van Treeck David , Kwasniewski Albert , Richter Carsten , Fernández-Garrido Sergio , Brandt Oliver
Published: March 2023

GaN nanowires (NWs) grown by molecular beam epitaxy on Ti films sputtered on Al2O3 are studied by X-ray diffraction (XRD) and grazing-incidence small-angle X-ray scattering (GISAXS). XRD, performed both in symmetric Bragg reflection mode and at grazing incidence, reveals Ti, TiN, Ti3O, Ti3Al and Ga2O3 crystallites with in-plane and out-of-plane lattice parameters intermediate between those of Al2O3 and GaN. These topotaxial crystallites in the Ti film, formed as a result of interfacial reactions and N exposure, possess little misorientation with respect to Al2O3. As a result, GaN NWs grow on the top TiN layer, possessing a high degree of epitaxial orientation with respect to the substrate. The measured GISAXS intensity distributions are modelled by the Monte Carlo method, taking into account the orientational distributions of NWs, the variety of their cross-sectional shapes and sizes, and the roughness of their side facets. The cross-sectional size distributions of the NWs and the relative fractions of the {1100} and {1120} side facets are determined.
Mitigation strategies of public–private partnership (PPP) barriers in Palestinian construction projects
Authors: Mousa Kawther , Zhang Zhenglian , Sumarliah Eli
Published: March 2023

Purpose

The scarcity of literature related to the PPP (public-private partnership) barriers in construction projects within war areas, and hence the dearth of information to deliver viable and effective strategies to those barriers, are the primary causes for the failures of PPP schemes in such areas, particularly in Palestine. Financial and non-financial investments are more problematic in war zones than non-war nations and may escalate barrier for projects' success. The investigation purposes to discover proper answers to the barriers of PPP infrastructure schemes and highlight the execution of barrier reactions.

Design/methodology/approach

Specialists were asked to deliver approaches to alleviate 21 barriers and recommend the period needed for applying them. Later, the relevance of alleviation events was examined through prioritization according to the results attained from three elements, i.e. the impact of every barrier and the strategy's viability and efficacy.

Findings

While the most unfavorable barrier was finalized to be the unfeasibility of delivering physical security, the most valid answer was associated with the lack of government cohesiveness and responsibility to perform its duties. The discovered barriers are typical within warring nations, but the paper concentrated on Palestine.

Originality/value

This study is an initial effort to examine PPP barriers in Palestinian infrastructure projects. The presented strategies can be applied as a novel set for barrier reaction improvement in occupied nations such as Palestine. Moreover, the results can develop the usage of PPP and enhance the barrier sharing in this scheme.
Adopting quality management (QM) principles in managing facilities management service delivery
Authors: Myeda Nik Elyna , Chua Shirley Jin Lin , Aqillah Nur Syafiqatul
Published: March 2023

Purpose

This paper aims to assess the quality management (QM) principles in facilities management (FM) service delivery for office buildings. This is to create a quality culture that will enhance the performance of FM service delivery towards meeting the users' requirements and needs.

Design/methodology/approach

This study adopts a quantitative methodology via a questionnaire survey for the data collection. In total, 24.41% of respondents from the registered FM companies in Malaysia attended the survey. SPSS 27.0 was used to interpret the collected data, which were then reviewed through descriptive and inferential analysis.

Findings

The study signifies that customer focus, leadership, improvement, evidence-based decision-making and relationship management indicate positive connections with FM service delivery in ensuring a cost-effective working process and meeting both user requirements and legal and regulatory corporate compliance. There are 18 elements of strategic, people and structural barriers that may hinder the implementation of QM in the FM service delivery. Correspondingly, the five main key enablers suggested being teamwork and participation, leadership, continuous improvement, process management and resources and competency development-based enablers.

Research limitations/implications

The study was conducted during the pandemic crisis with limited access and response from participants. However, this in-depth study was still able to synthesize the imperative QM practice in FM among FM practitioners in Malaysia.

Originality/value

This study provides insight into the implementation of QM principles to cultivate a quality culture that will enhance the performance and productivity in FM service delivery specifically for office buildings in Malaysia. Prior to this study, there was a lack of research pertaining to these two themes: QM and FM.
Exploring how institutional trajectories and political controversies influence policymaking for SE: the case of Norway
Authors: Sætre Hilde Svrljuga , Hauge Hans Abraham
Published: March 2023

Purpose

This study aims to analyse how top-level policymakers across the political left-right spectrum in a social-democratic welfare state understand social enterprise (SE), its relation to existing welfare institutions and their intentions of policymaking towards SE.

Design/methodology/approach

This study conducted in-depth interviews explicitly focused on SE with policymakers at the national level in Norway. The informants collectively represented most political parties in Norway’s Parliament in 2017–2021. Data were analysed using a historical institutional perspective.

Findings

Centre-right wing policymakers predominantly consider SE as commercial enterprises not requiring specific policies. Left wing policymakers prefer that SEs operate like voluntary organizations and advocate policies preventing extraction of profit and competition with public service providers. Hence, policymakers positioned SE within an overarching political debate on the privatization of welfare services. They expressed little interest in developing policies aimed at strengthening SE opportunity structures.

Research limitations/implications

Policy inaction impedes recognition of SEs as different from commercial and voluntary organizations, as well as their ability to compete for tenders. Thus, SE will likely remain a rather marginal phenomenon in Norway. Further research is needed to establish whether and how Norway’s universal welfare state inhibits social entrepreneurship on the society-wide level.

Originality/value

This article details how SE is understood within a social democratic welfare regime and the likely consequences thereof for SEs. It contributes with new knowledge of why policymakers may be reluctant to develop policy dedicated to further SE, across different political party affiliations. To the best of the authors’ knowledge, this is the first study in Norway to analyse how existing institutions and political controversies influence how policymakers at the national level approach SE.
Efficacy and safety of baricitinib treatment for moderate to severe atopic dermatitis in real‐world practice in Japan
Authors: Hagino Teppei , Saeki Hidehisa , Fujimoto Eita , Kanda Naoko
Published: March 2023

The authors evaluated the efficacy and safety of baricitinib, a Janus kinase 1/2 inhibitor, for atopic dermatitis (AD) in real‐world practice. From August 2021 to September 2022, 36 patients aged ≥15 years with moderate to severe AD were treated with oral baricitinib 4 mg/day plus topical corticosteroids. Baricitinib improved clinical indexes; the percent reduction at weeks 4 and 12 was a median of 69.19% and 69.98% for the Eczema Area and Severity Index (EASI), 84.52% and 76.33% for the Atopic Dermatitis Control Tool, and 76.39% and 64.58% for Peak Pruritus Numerical Rating Score, respectively. The achievement rate of EASI 75 was 38.89% and 33.33% at weeks 4 and 12, respectively. The percent reduction of EASI in the head and neck, upper limbs, lower limbs, and trunk was 56.9%, 68.3%, 80.7%, and 62.5% at week 12, respectively, with a significant difference between the head and neck versus the lower limbs. Baricitinib decreased thymus and activation‐regulated chemokine, lactate dehydrogenase, and total eosinophil count at week 4. Baseline EASI of the head and neck negatively correlated with percent reduction of EASI at week 4, while baseline EASI of the lower limbs positively correlated with percent reduction of EASI at week 12. Treatment‐emergent adverse events included elevation of creatine phosphokinase (11.1%), herpes labialis (5.6%), furuncle (8.3%), and exacerbation of AD (1%), without serious treatment‐emergent adverse events. In this real‐world study, baricitinib was well tolerated for patients with AD and achieved therapeutic effects comparable to those in clinical trials. High baseline EASI of the lower limbs might predict good treatment response at week 12, while high baseline EASI of the head and neck might predict poor treatment response at week 4 in baricitinib treatment for AD.
Diagnostic spectrum and therapeutic efficiency in teledermatology–Results of the largest cohort study to date
Authors: Lindemann Hanna , Bonetzki Tim , Frank Jorge
Published: March 2023

Timely and comprehensive dermatological care is a major challenge. Digitized medical consultation offers a possibility to overcome this problem. Here, we studied the diagnostic spectrum and treatment success in teledermatology in the largest cohort to date. Over 12 months, 21 725 individuals received a diagnosis and therapeutic advice using the asynchronous image‐text method. In the context of quality management, 1802 individuals (~10%) of both sexes with a mean age of 33.7 years (SD 15.36) received a follow‐up 3 months after the initial consultation to assess the treatment outcome. Of these, 81.2% did not require a face‐to‐face consultation. Therapeutic efficiency could be ascertained in 83.3% of the patients, whereas 10.9% did not improve, and 5.8% did not provide an information on the course of therapy. Teledermatology is a useful tool in digitalized medicine and complements the classical in‐person dermatological examination, as shown by the high degree of treatment efficacy in this study. Although face‐to‐face consultations can not and should not be completely substituted by teledermatology it reflects a significant contribution to patient care and justifies the further expansion of digital structures in dermatological care.