bluuebunny/crossref_metadata_2025 huggingface dataset:
A PRACTICAL MODEL FOR EARLY IDENTIFICATION OF PROSPECTIVE HIGH NEED HIGH COST PATIENTS
Authors: Cohen Avivit Golan , Vinker Shlomo , Isaacson Adi , Avramovich Eva , Merzon Eugene
Published: February 2022

Background

High Need-High Cost (HNHC) patients are those who experience poor health outcomes and high health care costs. Early identification may improve outcomes and lower costs.

Aim

Development of a model using retrospective data to identify patients at risk for becoming HNHC patients, in order to efficaciously plan interventions.

Methods

Data from a large Israeli Health Maintenance Organization (HMO) that includes 488,615 clients above the age of 21 were examined. Multivariate linear regression models were developed using 2012–2016 health expenditure as a dependent variable.

Results

The number of yearly purchases of medications for chronic disorders, yearly outpatient visits, yearly emergency department and hospital admissions and the last measured HgA1c level were highly predictive of increased expenditure over a five-year period. Each of these indicators has a different coefficient of influence.

Conclusions

We developed a predictive model, based on easily obtained data from electronic medical records that enabled us to identify a population at risk for becoming HNHC in the next five years, a time window allows for intervention. Further research is needed to evaluate whether this is an early enough stage to implement pro-active intervention in the primary care setting.

Trial registration

retrospectively registered.

HIGHLIGHTS

In this study, we developed a numerical point system calculator, to indicate a risk score for health deterioration within 5 years of patients, by using numerical indicators existing in standard EMR data.

The indicators introduced into this calculated risk can guide healthcare providers to the needed areas of intervention. The display of indicators also promotes optimization of care management and continuity of care.

This risk score is expected to focus the attention of primary care teams on the population that will benefit most from it, as well as to evaluate the effectiveness of specific interventions.
Emulation of a target trial from observational data to compare effectiveness of Casirivimab/Imdevimab and Bamlanivimab/Etesevimab for early treatment of non-hospitalized patients with COVID-19
Authors: Mazzotta V , Cozzi Lepri A , Colavita F , Lanini S , Rosati R , Lalle E , Mastrorosa I , Cimaglia C , Vergori A , Bevilacqua Nazario , Daniele Lapa , Andrea Mariano , Bettini Aurora , Agrati C , Piselli P , Girardi E , Castilletti C , Garbuglia AR , Vaia F , Nicastri E , Antinori A
Published: February 2022

Objectives

Comparative analysis between different monoclonal antibodies (mAbs) against SARS-CoV-2 are lacking. We present an emulation trial from observational data to compare effectiveness of Bamlanivimab/Etesevimab (BAM/ETE) and Casirivimab/Imdevimab (CAS/IMD) in outpatients with early mild-to-moderate COVID-19 in a real-world scenario of variants of concern (VoCs) from Alpha to Delta.

Methods

Allocation to treatment was subject to mAbs availability, and the measured factors were not used to determine which combination to use. Patients were followed through day 30. Viral load was measured by cycle threshold (CT) on D1 (baseline) and D7.

Primary outcome was time to COVID-19-related hospitalization or death from any cause over days 0-30. Weighted pooled logistic regression and marginal structural Cox model by inverse probability weights were used to compare BAM/ETE vs. CAS/IMD. ANCOVA was used to compare mean D7 CT values by intervention. Models were adjusted for calendar month, MASS score and VoCs. We evaluated effect measure modification by VoCs, vaccination, D1 CT levels and enrolment period.

Results

COVID19-related hospitalization or death from any cause occurred in 15 of 237 patients in the BAM/ETE group (6.3%) and in 4 of 196 patients in the CAS/IMD group (2.0%) (relative risk reduction [1 minus the relative risk] 72%; p=0.024). Subset analysis carried no evidence that the effect of the intervention was different across stratification factors. There was no evidence in viral load reduction from baseline through day 7 across the two groups (+0.17, 95% −1.41;+1.74, p=0.83). Among patients who experienced primary outcome, none showed a negative RT-PCR test in nasopharingeal swab (p=0.009) and 82.4% showed still high viral load (p<0.001) on D7.

Conclusions

In a pre-Omicron epidemiologic scenario, CAS/IMD reduced risk of clinical progression of COVID-19 compared to BAM/ETE. This effect was not associated with a concomitant difference in virological response.
The Relevance of Lactate Levels in Acute Seizure
Authors: Sop Jessica , Rogers Jessica , Opara Nnennaya , Tager Alfred , Dean Scott , Gustafson Mark L
Published: February 2022

Introduction

Seizures can result in profound elevations of serum lactate. A paucity of investigation into whether lactate levels in these patients is associated with increased mortality. We sought to evaluate the significance in patients presenting with a seizure and elevated lactate.

Methods

This is a retrospective study involving patients presenting to the Emergency Department (ED) with a diagnosis of seizure from September 1st, 2016 until March 31st, 2018. Those with normal serum lactate (< 2mmol/L) were compared with patients that had an elevated serum lactate (≥ 2mmol/L).

Results

Patients with normal serum lactate levels had a significantly longer length of stay in the ED (60 minutes p = 0.04) when compared to those with elevated serum lactate levels. Additionally, a higher percentage of patients with elevated serum lactate received intravenous fluids in the ED (54.69% vs. 35.4%, P=0.01). There was no significant difference in other measured variables.

Conclusion

This study illustrates that serum lactate levels do not directly correlate with indicators of disease severity or outcomes when elevated secondary to seizure. However, patients with normal serum lactate levels had a longer length of stay in the ED.
Optimal Deployment of Automated External Defibrillators in a Long and Narrow Environment
Authors: Lin Chih-Hao , Chu Kuan-Chao , Lee Jung-Ting , Kao Chung-Yao
Published: February 2022

Aim of the study

Public access to automated external defibrillators (AEDs) plays a key role in increasing survival outcomes for patients with out-of-hospital cardiac arrest. Based on the concept of maximizing “rescue benefit” of AEDs, we aimed to develop strategies for optimal deployment of AEDs for long and narrow spaces.

Methods

We classified the effective coverage of an AED in hot, warm, and cold zones. The AEDs were categorized, according to their accessibility, as fixed, summonable, or patrolling types. The overall rescue benefit of the AEDs were evaluated by the weighted size of their collective hot zones. The optimal strategies for the deployment of AEDs were derived mathematically and numerically verified by computer programs.

Results

To maximize the overall rescue benefit of the AEDs, the AEDs should avoid overlapping with each other’s coverage as much as possible. Specific rules for optimally deploying one, two, or multiple AEDs, and various types of AEDs are summarized and presented.

Conclusion

A methodology for assessing the rescue benefit of deployed AEDs was proposed, and deployment strategies for maximizing the rescue benefit of AEDs along a long, narrow, corridor-like, finite space were derived. The strategies are simple and readily implementable. Our methodology can be easily generalized to search for optimal deployment of AEDs in planar areas or three-dimensional spaces.
Polycomb-mediated repression of paternal chromosomes maintains haploid dosage in diploid embryos of Marchantia
Authors: Montgomery Sean A. , Hisanaga Tetsuya , Wang Nan , Axelsson Elin , Akimcheva Svetlana , Sramek Milos , Liu Chang , Berger Frédéric
Published: February 2022

Complex mechanisms regulate gene dosage throughout eukaryotic life cycles. Mechanisms controlling gene dosage have been extensively studied in animals, however it is unknown how generalizable these mechanisms are to diverse eukaryotes. Here, we use the haploid plant Marchantia polymorpha to assess gene dosage control in its short-lived diploid embryo. We show that throughout embryogenesis, paternal chromosomes are repressed resulting in functional haploidy. The paternal genome is targeted for genomic imprinting by the Polycomb mark H3K27me3 starting at fertilization, rendering the maternal genome in control of embryogenesis. Maintaining haploid gene dosage by this new form of imprinting is essential for embryonic development. Our findings illustrate how haploid-dominant species can regulate gene dosage through paternal chromosome inactivation and initiates the exploration of the link between life cycle history and gene dosage in a broader range of organisms.
Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy
Authors: Hurbain Julien , Thommen Quentin , Anquez Francois , Pfeuty Benjamin
Published: February 2022

Living cells use signaling and regulatory mechanisms to adapt to environmental stresses. In the case of oxidative stress due for instance to hydrogen peroxide exposure, the adaptation response relies on co-regulation of enzymes in both glycolysis and pentose phosphate pathways (PPP), so as to support PPP-dependentNADPHand redox homeostasis. To understand the regulatory logic underlying early oxidative stress response, available metabolomics and13C fluxomics dataset are used to infer a probabilistic ensemble of kinetic models. Model ensemble properties of parameter distributions, transient dynamics, dose-response curves and loss-of-function phenotypes all highlights significant and cooperative effects of allosteric regulations of G6PD, PGI and GAPD in early oxidative response. Indeed, efficient flux rerouting into PPP is shown to require dose-dependent coordination between upregulated G6PD enzyme and increased G6P metabolite, the latter requiring fine-tuned inhibition of upper and lower glycolytic enzymes. This set of allosteric regulation also combines negative and positive feedback loops in a subtle manner prone to generate paradoxical perturbation phenotypes for instance related to 6PGD modulation.
Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD
Authors: Abenza Juan F. , Rossetti Leone , Mouelhi Malèke , Burgués Javier , Andreu Ion , Kennedy Keith , Roca-Cusachs Pere , Marco Santiago , García-Ojalvo Jordi , Trepat Xavier
Published: February 2022

Circadian rhythms are a key survival mechanism that dictates biological activity according to the day-night cycle. In animals, cell-autonomous circadian clocks can be found in nearly every cell type and are subjected to multi-layered regulation. Although these peripheral clocks are remotely controlled by the master clock in the brain, they are also sensitive to their immediate mechano-chemical microenvironment. Whereas the mechanisms by which biochemical signalling controls the circadian clock at the single cell level are increasingly well understood, mechanisms underlying regulation by mechanical cues are still unknown. Here we show that the circadian clock in fibroblasts is regulated mechanically through YAP/TAZ and TEAD. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted concomitantly with the translocation of YAP/TAZ to the nucleus. By targeted mutations and tuning expression levels of YAP we identify TEAD as the transcriptional effector of this mechanosensitive regulatory pathway. Our findings establish a mechanism that links cell mechanobiology and the circadian clock, which could contribute to explain the circadian impairment observed in cancer and ageing, where the regulation of the mechanical environment and YAP/TAZ is lost.
ZNF598 responds to mitochondrial stress to abort stalled translation on mitochondrial outer membrane and maintain tissue homeostasis
Authors: Geng Ji , Li Yu , Wu Zhihao , Ohja Rani , Li Shuangxi , Lu Bingwei
Published: February 2022

Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination and its level is upregulated upon mitochondrial stress in mammalian cells andDrosophila. Overexpression of ZNF598 protects against mitochondrial stress. InDrosophilamodels of neurodegenerative diseases and patient cells, ZNF598 overexpression aborted stalled translation of mitochondrial outer membrane-associated mRNAs and removed faulty translation products causal of disease. These results shed lights on the regulation of ZNF598 and its important role in mitochondrial homeostasis.
Effect of compound Tinglizi Decoction on non-classical pathway of pyroptosis in rats with chronic obstructive pulmonary disease related pulmonary hypertension
Authors: Wang Qizhi , Liu Min , Liu Yu , Bai Zhengping
Published: February 2022

Objective

To observe the effect of compound Tinglizi Decoction on non-classical pathway of cell death in rats with pulmonary hypertension, and to explore its mechanism of action in the treatment of COPD-related pulmonary hypertension.

Methods

60 male SD rats were randomly divided into Western group, normal group, model group, high-dose group, medium dose group and low-dose group, with 10 rats per group. We detected the protein expression levels of caspase-11, GSDMD and IL-6 by Western blot, detected serum TNF-α by ELISA, and observed the morphology of lung tissue by hematoxylin and eosin (HE) staining.

Results

In the expression of caspase11, GSDMD, IL-6 mRNA and protein in lung tissue, the model group was significantly higher than the normal group (P < 0.01), and the high-dose group, middledose group, low-dose group and western medicine group were significantly lower than the model group (P < 0.01). The levels of serum TNF-α and serum creatinine in the model group were significantly higher than those in the normal group (P < 0.01); and those in the high-dose group, middle-dose group, low-dose group and western medicine group were significantly lower than those in the model group (P < 0.05).

Conclusion

The mechanism of compound Tinglizi Decoction in the intervention of COPD-related pulmonary hypertension rats is related to the inhibition of non-classical pathway of cell death.
Dynamic gain decomposition reveals functional effects of dendrites, ion channels and input statistics in population coding
Authors: Zhang Chenfei , Revah Omer , Wolf Fred , Neef Andreas
Published: February 2022

Modern, high-density neuronal recordings reveal at ever higher precision how information is represented by neural populations. Still, we lack the tools to understand these processes bottom-up, emerging from the biophysical properties of neurons, synapses, and network structure. The concept of the dynamic gain function, a spectrally resolved approximation of a population’s coding capability, has the potential to link cell-level properties to network-level performance. However, the concept is not only useful but also very complex because the dynamic gain’s shape is co-determined by axonal and somatodendritic parameters and the population’s operating regime. Previously, this complexity precluded an understanding of any individual parameter’s impact. Here, we decomposed the dynamic gain function into three components corresponding to separate signal transformations. This allowed attribution of network-level encoding features to specific cell-level parameters. Applying the method to data from real neurons and biophysically plausible models, we found: 1. The encoding bandwidth of real neurons, approximately 400 Hz, is constrained by the voltage dependence of axonal currents during early action potential initiation. 2. State-of-the-art models only achieve encoding bandwidths around 100 Hz and are limited mainly by subthreshold processes instead. 3. Large dendrites and low-threshold potassium currents modulate the bandwidth by shaping the subthreshold stimulus-to-voltage transformation. Our decomposition provides physiological interpretations when the dynamic gain curve changes, for instance during spectrinopathies and neurodegeneration. By pinpointing shortcomings of current models, it also guides inference of neuron models best suited for large-scale network simulations.

Significant Statement

The dynamic gain function quantifies how neurons can engage in collective, network-level activity, shape brain rhythms and information encoding. Its shape results from a complex interaction between properties of different molecules (ion channels) and cell compartments (morphology, resistance), and is so far only understood for the simplest neuron models. Here we provide an interpretable analysis, decomposing the dynamic gain based on the stimulus transformation steps in individual neurons. We apply the decomposition to data from real neurons and complex models, and attribute changes of the dynamic gain to specific sub- and suprathreshold processes. Using this decomposition method, we reveal the relevance of subthreshold potassium channels for ultrafast information encoding and expose the shortcomings of even the state-of-the-art neuron models.
Minimal RNA replicons for targeted gene silencing based on an asymptomatic viroid
Authors: Marquez-Molins Joan , Urrutia-Perez María , Hernandez-Azurdia Andrea Gabriela , Pallas Vicente , Gomez Gustavo
Published: February 2022

Gene silencing for functional studies in plants has been largely facilitated by manipulating viral genomes with inserts from host genes to trigger virus induced gene silencing (VIGS) against the corresponding mRNAs. However, viral genomes encode multiple proteins and disrupt plant homeostasis by interfering with endogenous cell mechanisms. To circumvent this issue, we have developed a silencing method based on the minimal autonomously-infectious nucleic acids currently known: viroids. In particular,Eggplant latent viroid(ELVd), an asymptomatic viroid, was manipulated with insertions between 21 to 42 nucleotides and our results show that larger insertions are tolerated but secondary structure is critical for their stability. Additionally, these ELVd constructs are able of local and systemic spread and can silence a target gene in eggplant. Inspired by the design of artificial microRNAs, we have developed a standardized procedure to generate stable insertions into the ELVd genome capable of silencing the desired target gene. Analogously to VIGS, we have termed our approach Viroid Induced Gene Silencing (VdIGS) and demonstrate that is a promising tool for dissecting gene functions in eggplant. Overall, this represents the use of minimal circular replicating RNAs able to spread systemically combined with the production of a tailored sRNA for targeted silencing.
Chimeric a-subunit isoforms generate functional yeast V-ATPases with altered regulatory properties in vitro and in vivo
Authors: Tuli Farzana , Kane Patricia M.
Published: February 2022

V-ATPases are highly regulated, multi-subunit proton pumps that acidify organelles. The V-ATPase a-subunit is a two-domain protein containing a C-terminal transmembrane domain that participates in proton transport and a N-terminal cytosolic domain (aNT) that acts as a regulatory hub, integrating environmental inputs to regulate assembly, localization, and V-ATPase activity. Tissue- and organelle-specific a-subunit isoforms exist in most organisms, but how regulatory inputs are decoded by aNT isoforms is unknown. The yeast S. cerevisiae encodes only two organelle-specific a-isoforms, Stv1 in the Golgi and Vph1 in the vacuole. Based on recent structures, we designed chimeric yeast aNTs in which the globular proximal and distal ends are exchanged. The Vph1 proximal-Stv1 distal (VPSD) aNT chimera binds to the glucose-responsive RAVE assembly factor in vitro but exhibits little binding to phosphoinositide lipids that activate V-ATPases. The Stv1 proximal-Vph1 distal (SPVD) aNT lacks RAVE binding but binds more tightly to phosphoinositides than Vph1 or Stv1. When attached to the Vph1 C-terminal domain in vivo, both chimeras complement growth defects of a vph1Δ mutant, but only the SPVD chimera exhibits wild-type V-ATPase activity. Cells containing the SPVD chimera adapt more slowly to a poor carbon source than wild-type cells but grow more rapidly than wild-type after a shift to alkaline pH. This is the first example of a “redesigned” V-ATPase with altered regulatory properties and adaptation to specific stresses.
Targeted nanocarriers coopting pulmonary leukocytes for drug delivery to the injured brain
Authors: Glassman Patrick M. , Nong Jia , Myerson Jacob W. , Zuluaga-Ramirez Viviana , Rodriguez-Garcia Alba , Mukalel Alvin , Omo-Lamai Serena , Walsh Landis R. , Kiseleva Raisa Y. , Villa Carlos H. , Greineder Colin F. , Kasner Scott E. , Weissman Drew , Mitchell Michael J. , Muro Silvia , Persidsky Yuri , Brenner Jacob S. , Muzykantov Vladimir R. , Marcos-Contreras Oscar A.
Published: February 2022

Selective drug delivery to injured regions of the brain is an elusive, but biomedically important, goal. It is tempting to co-opt migrating white blood cells (WBC) to carry drugs to the injured brain, using natural WBC tropism. Current approaches to load cargoes to WBC have limited utility, particularly in acute conditions, due to the need for time consuming ex vivo manipulation and loading of cells. Physiological, in vivo loading of WBC may be advantageous in this scenario. Here we devised such a strategy, capitalizing on the unique features of the direct blood exchange between brain and lungs. Mediators emanating from the injured brain directly travel to the pulmonary vasculature via venous flow. In response to these mediators, WBCs, transiently residing in the pulmonary microvascular lumen, disembark and flow with arterial blood to the brain microvasculature, where they adhere and transmigrate to the brain parenchyma via the local chemoattractant gradient. We posited that direct in vivo targeting of cargoes to the pulmonary WBC pool may provide drug transfer to brain via this natural mechanism. To test this, we intravenously injected agents targeted to intercellular adhesion molecule 1 (ICAM) in mice with acute brain inflammation caused by direct injection of tumor necrosis factor alpha (TNF-α). We found that: A) At 2 hours, >20% of ICAM/NP accumulated in lungs, predominantly in WBCs; B) At 6 and 22 hours, ICAM/NP pulmonary uptake markedly decreased; C) In contrast, ICAM/NP uptake in brain increased ~5-fold in this time interval, concomitantly with migration of WBCs to the brain. Cranial window fluorescent microscopy confirmed WBC transport of ICAM/NP to the brain in TNF-α-challenged mice beyond the BBB. Importantly, demonstrating the pharmacologic relevance of this strategy, dexamethasone-loaded ICAM/liposomes abrogated brain edema in this model. In sum, coopting the natural homing of WBC from the lungs via ICAM-targeting to injured brain is an attractive strategy for precise interventions for treatment of acute brain injuries.

VISUAL ABSTRACT
Interactions between evolved pesticide resistance and pesticide exposure influence immunity against pathogens
Authors: Birnbaum Stephanie S.L. , Schulz Nora K.E. , Tate Ann T.
Published: February 2022

Pesticide resistance readily evolves in natural insect populations and often coopts the same stress, detoxification, and immune pathways involved in physiological responses against primary pathogen and pesticide exposure. As a result, resistance evolution can alter antagonism or facilitation among chemical and biological pest control strategies in directions that remain difficult to predict. To investigate the interactive effects of chemical pesticide resistance, exposure, and bacterial infection on insect phenotypes, we experimentally evolved resistance to two different classes of pesticides (organophosphates and pyrethroids) in the red flour beetle,Tribolium castaneum. We exposed pesticide susceptible and resistant lines to pesticides, the entomopathogen and biocontrol agentBacillus thuringiensis(Bt), or both. Pesticide resistance and Bt exposure were individually associated with slower development, indicating sub-lethal fitness costs of resistance and infection, respectively. After organophosphate exposure, however, beetles developed more quickly and were more likely to survive if also exposed to Bt. We used RNAseq to examine the interactive effects of pesticide resistance, pesticide exposure, and Bt exposure on gene expression. Pyrethroid-resistant insects exhibited dampened immune responses to Bt infection relative to susceptible ones. In a similar vein, simultaneous exposure to organophosphates and Bt resulted in muted stress-associated transcriptional responses compared to exposure with only one factor. Our results suggest that direct and host-mediated indirect interactions among pathogens and pesticides may buffer the cost of exposure to host fitness-associated traits within generations but exacerbate trade-offs over evolutionary time.
Oligomerization processes limit photoactivation and recovery of the Orange Carotenoid Protein
Authors: Andreeva Elena A. , Nizinski Stanislaw , Wilson Adjélé , Levantino Matteo , De Zitter Elke , Munro Rory , Muzzopappa Fernando , Thureau Aurélien , Zala Ninon , Burdzinski Gotard , Sliwa Michel , Kirilovsky Diana , Schirò Giorgio , Colletier Jacques-Philippe
Published: February 2022

The Orange Carotenoid Protein (OCP) is a photoactive protein involved in cyanobacterial photoprotection, by quenching of the excess of light harvested energy. The photoactivation mechanism remains elusive, in part due to absence of data pertaining to the timescales over which protein structural changes take place. It also remains unclear whether or not oligomerization of the dark-adapted and light-adapted OCP could play a role in the regulation of its energy quenching activity. Here, we probed photo-induced structural changes in OCP by a combination of static and time-resolved X-ray scattering and steady-state and transient optical spectroscopy in the visible range. Our results suggest that oligomerization partakes in regulation of the OCP photocycle, with different oligomers slowing down the overall thermal recovery of the dark-adapted state of OCP. They furthermore reveal that upon non-photoproductive excitation, a numbed-state forms, which remains in a non-photoexcitable structural state for at least ∼0.5 µs after absorption of a first photon.

Significance Statement

The orange carotenoid protein (OCP) is a photoactivatable protein involved in cyanobacterial photoprotection. Upon photoactivation, OCP becomes able to quench the excess of energy uptaken by the light-harvesting antennae, thereby evading damage to the cells. It remains unclear, however, what is the exact OCP photoactivation mechanism, and whether or not oligomerization partakes in the regulation of the OCP function. Here, we investigated these issues by combining static and time-resolved (TR) X-ray scattering and optical spectroscopy. Our results show that OCP oligomerizes in both the dark-adapted inactive and light-adapted active states, suggesting a functional role for oligomerization. TR scattering data furthermore reveal that the first large-scale conformational changes associated with OCP photoactivation take place on the µs time scale.
Tau forms dynamic hot spots that are resistant to microtubule perturbations and cholesterol depletion
Authors: Padmanabhan Pranesh , Kneynsberg Andrew , Gonzalez Esteban Cruz , Amor Rumelo , Sibarita Jean-Baptiste , Götz Jürgen
Published: February 2022

Accumulation of Tau aggregates is a pathological hallmark of Alzheimer’s disease, but little is known about where these aggregates assemble and how stable these assemblies are. Using quantitative, single-molecule imaging, we show that Tau exhibits spatial and kinetic heterogeneity near the plasma membrane, resulting in the formation of nanometer-sized hot spots smaller than the diffraction limit. The hot spots lasted tens of seconds, much longer than the short dwell time (~40 ms) of Tau on microtubules. Pharmacological and biochemical disruption of Tau/microtubule interactions did not affect hot spot formation, suggesting that these are different from the reported Tau condensation on microtubules. Although cholesterol removal has been shown to reduce Tau pathology, its depletion did not affect Tau hot spot dynamics. Our study identifies an intrinsic dynamic property of Tau near the plasma membrane that may facilitate the formation of assembly sites for Tau to assume its physiological and pathological functions.
Progerin triggers a phenotypic switch in vascular smooth muscle cells that causes replication stress and an aging-associated secretory signature
Authors: Coll-Bonfill Nuria , Mahajan Urvashi , Lin Chien-Jung , Mecham Robert P. , Gonzalo Susana
Published: February 2022

Hutchinson Gilford Progeria Syndrome is a premature aging disease caused byLMNAgene mutation and the production of a truncated lamin A protein “progerin” that elicits cellular and organismal toxicity. Progerin accumulates in the vasculature, being especially toxic for vascular smooth muscle cells (VSMC). Patients’ autopsies show that vessel stiffening, and aortic atherosclerosis is accompanied by VSMC depletion in the medial layer, altered extracellular matrix (ECM), and thickening of the adventitial layer. Mechanisms whereby progerin causes massive VSMC loss and vessel alterations remain poorly understood. Mature VSMC retain phenotypic plasticity and can switch to a synthetic/proliferative phenotype. Here we show that progerin expression in human and mouse VSMC causes a switch towards the synthetic/proliferative phenotype. This switch elicits some level of replication stress in normal cells, which is exacerbated in the presence of progerin, leading to telomere fragility, genomic instability, and ultimately VSMC death. Importantly, calcitriol prevents replication stress, telomere fragility, and genomic instability, reducing VSMC death. In addition, RNAseq analysis shows induction of a profibrotic and proinflammatory aging-associated secretory phenotype upon progerin expression in human primary VSMC. Our data suggest that phenotypic switch-induced replication stress might be an underlying cause of VSMC loss in progeria, which together with loss of contractile features and gain of profibrotic and proinflammatory signatures contribute to vascular stiffness in HGPS. Preventing the phenotypic switch-induced replication stress with compounds such as calcitriol might ameliorate CVD in HGPS patients.
DNA opening during transcription initiation by RNA polymerase II in atomic detail
Authors: Lapierre Jeremy , Hub Jochen S.
Published: February 2022

RNA polymerase II (RNAP II) is a macro-molecular complex that synthesizes RNA by reading the DNA code, a process called transcription. During transcription initiation, RNAP II opens the double-stranded DNA to expose the DNA template to the active site. The molecular interactions driving and controlling the DNA opening are not well understood. We used all-atom molecular dynamics (MD) simulations to obtain a continuous atomistic pathway for the DNA opening process in human RNAP II. To achieve such large-scale and highly nonlinear transition, we steered the MD simulations along a combination of collective variables involving a guided DNA rotation and a set of path collective variables. The simulations reveal extensive interactions of the DNA with three protein loops near the active site, namely the rudder, fork loop 1, and fork loop 2. According to the simulations, these DNA–protein interactions support DNA opening by attacking Watson-Crick hydrogen bonds, and they stabilize the open DNA bubble by the formation of a wide set of DNA–protein salt bridges.
Janus Kinase 3 phosphorylation and the JAK/STAT pathway are positively modulated by follicle-stimulating hormone (FSH) in bovine granulosa cells
Authors: Zareifard Amir , Beaudry Francis , Ndiaye Kalidou
Published: February 2022

JAK3 is a member of the JAK family of tyrosine kinase proteins involved in cytokine receptor-mediated intracellular signal transduction through the JAK/STAT signaling pathway. JAK3 was shown as differentially expressed in granulosa cells (GC) of bovine pre-ovulatory follicles suggesting that JAK3 could modulate GC function and activation/inhibition of downstream targets. We used JANEX-1, a JAK3 inhibitor, and FSH treatments and analyzed proliferation markers, steroidogenic enzymes and phosphorylation of target proteins including STAT3, CDKN1B/p27Kip1 and MAPK8IP3/JIP3. GC were treated with or without FSH in the presence or not of JANEX-1. Expression of steroidogenic enzyme CYP11A1, but not CYP19A1, was upregulated in GC treated with FSH and both were significantly decreased when JAK3 was inhibited. Proliferation markers CCND2 and PCNA were reduced in JANEX-1-treated GC and upregulated by FSH. Western blots analyses showed that JANEX-1 treatment reduced pSTAT3 amounts while JAK3 overexpression increased pSTAT3. Similarly, FSH treatment increased pSTAT3 even in JANEX-1-treated GC. UHPLC-MS/MS analyses revealed phosphorylation of specific amino acid residues within JAK3 as well as CDKN1B and MAPK8IP3 suggesting possible activation or inhibition post-FSH or JANEX-1 treatments. We show that FSH activates JAK3 in GC, which could phosphorylate target proteins and likely modulate other signaling pathways involving CDKN1B and MAPK8IP3.
Interference with lipoprotein maturation sensitizes methicillin-resistantStaphylococcus aureusto human group IIA secreted phospholipase A2and daptomycin
Authors: Kuijk Marieke M. , Wu Yongzheng , van Hensbergen Vincent P. , Shanlitourk Gizem , Payré Christine , Lambeau Gérard , Herrmann Jennifer , Müller Rolf , van Strijp Jos A.G. , Pannekoek Yvonne , Touqui Lhousseine , van Sorge Nina M.
Published: February 2022

Methicillin-resistantStaphylococcus aureus(MRSA) has been classified as a high priority pathogen by the World Health Organization underlining the high demand for new therapeutics to treat infections. Human group IIA secreted phospholipase A2(hGIIA) is among the most potent bactericidal proteins against Gram-positive bacteria, includingS. aureus. To determine hGIIA-resistance mechanisms of MRSA we screened the Nebraska Transposon Mutant Library using a sublethal concentration of recombinant hGIIA. We identified and confirmed the role oflspA, encoding the lipoprotein signal peptidase LspA, as a new hGIIA resistance gene in bothin vitroassays and an infection model in hGIIA-transgenic mice. Increased susceptibility of thelspAmutant was associated with faster and increased cell wall penetration of hGIIA. Moreover,lspAdeletion also increased susceptibility to daptomycin, a last-resort antibiotic to treat MRSA infections. Exposure of MRSA wild-type to the LspA-specific inhibitors globomycin and myxovirescin A1 induced alspAmutant phenotype with regard to hGIIA and daptomycin killing. Analysis of >26,000S. aureusgenomes showed that LspA is highly sequence-conserved, suggesting that LspA inhibition could be applied universally. The role of LspA in hGIIA resistance was not restricted to MRSA sinceStreptococcus mutansandEnterococcus faecaliswere also more hGIIA-susceptible afterlspAdeletion or LspA inhibition, respectively. Overall, our data suggest that pharmacological blocking of LspA may disarm Gram-positive pathogens, including MRSA, to enhance clearance by innate host defense molecules and clinically-applied antibiotics.
Forecasting blockchain adoption in supply chains based on machine learning: evidence from Palestinian food SMEs
Authors: Hamdan Ihab K. A. , Aziguli Wulamu , Zhang Dezheng , Sumarliah Eli , Usmanova Kamila
Published: February 2022

Purpose

This paper seeks to discover whether the technical, organisational and technology acceptance model (TAM) factors will significantly affect the adoption of blockchain technology (ABT) amongst SMEs.

Design/methodology/approach

The research employs structural equation modelling (SEM) and a machine learning approach to identify factors influencing the ABT behaviour that leaders can use to predict the prospect of the ABT in their enterprises. Information was collected from 255 respondents representing 166 SMEs in the food industry, Palestine.

Findings

The analyses reveal that the ABT is positively and significantly shaped by TAM factors: (1) perceived benefits and (2) perceived ease of using blockchain. Simultaneously, the former is significantly influenced by compatibility and upper management support, while the latter is affected by complexity. Finally, education and training affect both factors.

Originality/value

This paper is amongst the first attempts to examine the ABT behaviour in the food industry using the integration of SEM and machine learning approach.
Does the cost of energy matter for innovation? The effects of energy prices on SME innovation in Sub-Saharan Africa
Authors: Hussain Javed , Karimu Amin , Salia Samuel , Owen Robyn
Published: February 2022

Purpose

Energy and environment has gained traction within the field of entrepreneurship literature, but a comprehensive empirical study that examines the relationship between the cost of energy and small- and medium-sized enterprise (SME) innovation is an omission. Therefore, this novel study aims to examine the relationship between the cost of energy and SMEs innovation in Sub-Saharan Africa (SSA) by first examining the differential impact of the various generation sources on the price of electric energy. This research has enabled us to investigate and understand the transmission mechanism of increasing/decreasing electricity price on innovation decisions and activities of SMEs in SSA.

Design/methodology/approach

Using quantitative approach, with the data from the World Bank Enterprise and Innovation Follow-up Surveys, the study utilises a Tobit model to test whether the generation mix (renewable and non-renewable generation sources) increases or decreases electricity prices and examine the impact of the cost of electric energy on SMEs innovation in SSA.

Findings

The findings of this study shows that the cost of electricity affects negatively on SMEs innovation decision and activities of SMEs in SSA. The impact of renewables on the price of electricity has a larger magnitude relative to that of non-renewables. This finding has implications for policy makers promoting renewable energy without a policy design to tackle the unintended price effect of promoting renewable energy.

Originality/value

This is the first study to introduce cost of energy into an innovation model and to empirically examine the role of cost of energy for innovation activities of SMEs in SSA. Further, it examines the sources of generation on electricity price in SSA. The study contributes towards the empirical literature, and the findings also have implication for policy makers regarding the unintended consequences of promoting the transition to low-carbon electricity generation sources on SMEs via the cost of doing business implication.
Quality disclosure in sharing economy platform with network externality under consumer risk aversion
Authors: Fan Haowen , Zhang Yulin
Published: February 2022

Purpose

This work aims to examine the quality disclosure strategy of sharing economy platforms with network externality, considering consumer risk aversion.

Design/methodology/approach

The game theory, sensitive analysis and numerical study are used herein. The equilibria are derived from the game theory. The quality disclosure strategy is analyzed by profit comparison. To further understand the characteristics of the optimal disclosure strategy, sensitive analysis and numerical studies are conducted to detail the analytical results.

Findings

Regardless of market structure, the quality disclosure decision problem is a trade-off between information effect and cost effect. Consumer risk aversion is a factor that can incentivize low-quality platforms to disclose quality. Both consumer risk aversion and network externality influence the quality disclosure strategy through information effect. Interestingly, for different competition intensities, consumer risk aversion and network externality could lead to positive or negative information effects of removing uncertainty. The authors show that under certain conditions, consumer risk aversion and network externality could induce more quality concealment.

Research limitations/implications

The quality is set exogenous herein, and the integrated process of quality investment and information disclosure is an interesting direction for future research.

Practical implications

This work provides managerial insights for sharing economy platforms regarding how to wisely consider consumer risk aversion and network externality when sharing quality information.

Originality/value

This work identifies two effects that determine quality disclosure strategy and specifies the role of each factor on quality disclosure.
Automated service assistances to the visually impaired people using android application
Authors: Hemalatha S. , Das Nripendra Narayan , Ramasamy Jayanthy , Madan Suman , Mahesh P.C. Senthil
Published: February 2022

Purpose

Internet of Things (IoT) involves connecting physical objects to the internet to provide opportunities to build smart systems or applications. IoT paradigm assumes many devices connected over a conventional intent network. These devices usually have restricted resources, so moving part of the service implementation to a cloud infrastructure is a prominent solution. This study aims to proposes in this project human voice as a potential interface for one or more devices in IoT ecosystem enabling issuing commands and receiving information.

Design/methodology/approach

System design is the process of defining the elements of a system such as the architecture, modules and components, the different interfaces of those components and the data that goes through that system. It is meant to satisfy specific needs and requirements of a business or organization through the engineering of a coherent and well-running system.

Findings

The main aim of this proposed work is to develop a ticket booking application that performs all the operations by speech recognition. Hence, visually impaired people can make use of this application. There are several applications that help visually impaired people. This application adds extra features to those available soft wares. Using this, visually impaired people can book the tickets without the help of personal assistants. For future research, this study hopes to extend this application to perform various other operations that will help visually impaired people to do their daily activities like normal people without the help of personal assistants. For example, making a phone call, sending text messages, booking a taxi, easy navigation, etc.

Originality/value

System design involves the identification of classes, their relationship as well as their collaboration. In objector, classes are divided into entity classes and control classes.
Phylogenomics, epigenomics, virulome and mobilome of Gram‐negative bacteria co‐resistant to carbapenems and polymyxins: a One Health systematic review and meta‐analyses
Authors: Ramaloko Winnie Thabisa , Osei Sekyere John
Published: February 2022

Gram‐negative bacteria (GNB) continue to develop resistance against important antibiotics including last‐resort ones such as carbapenems and polymyxins. An analysis of GNB with co‐resistance to carbapenems and polymyxins from a One Health perspective is presented. Data of species name, country, source of isolation, resistance genes (ARGs), plasmid type, clones and mobile genetic elements (MGEs) were deduced from 129 articles from January 2016 to March 2021. Available genomes and plasmids were obtained from PATRIC and NCBI. Resistomes and methylomes were analysed using BAcWGSTdb and REBASE whilst Kaptive was used to predict capsule typing. Plasmids and other MEGs were identified using MGE Finder and ResFinder. Phylogenetic analyses were done using RAxML and annotated with MEGA 7. A total of 877 isolates, 32 genomes and 44 plasmid sequences were analysed. Most of these isolates were reported in Asian countries and were isolated from clinical, animal and environmental sources. Colistin resistance was mostly mediated by mgrB inactivation (37%; n = 322) and mcr‐1 (36%; n = 312), while OXA‐48/181 was the most reported carbapenemase. IncX and IncI were the most common plasmids hosting carbapenemases and mcr genes. The isolates were co‐resistant to other antibiotics, with floR (chloramphenicol) and fosA3 (fosfomycin) being common; E. coli ST156 and K. pneumoniae ST258 strains were common globally. Virulence genes and capsular KL‐types were also detected. Type I, II, III and IV restriction modification systems were detected, comprising various MTases and restriction enzymes. The escalation of highly resistant isolates drains the economy due to untreatable bacterial infections, which leads to increasing global mortality rates and healthcare costs.
Naked‐eye detection strategies coupled with isothermal nucleic acid amplification techniques for the detection of human pathogens
Authors: Garrido‐Maestu Alejandro , Prado Marta
Published: February 2022

Nucleic acid amplification‐based techniques have gained acceptance by the scientific, and general, community as reference methodologies for many different applications. Since the development of the gold standard of these techniques, polymerase chain reaction (PCR), back in the 1980s many improvements have been made, and alternative techniques emerged reporting improvements over PCR. Among these, isothermal amplification approaches resulted of particular interest as could overcome the need of specialized equipment to accurately control temperature changes, but it was after year 2000 that these techniques have flourished in a huge number of novel alternatives with many different degrees of complexities and requirements. An added value is their possibility to be combined with many different naked‐eye detection strategies, simplifying the resources needed, allowing to reduce cost, and serving as the basis for novel developments of lab‐on‐chip systems, and miniaturized devices, for point‐of‐care testing. In this review, we will go over different types of naked‐eye detection strategies, combined with isothermal amplification. This will provide the readers up‐to‐date information for them to select the most appropriate strategies depending on the particular needs and resources for their experimental setup.