bluuebunny/crossref_metadata_2025 huggingface dataset:
From emergence to endemicity: highly pathogenic H5 avian influenza viruses in Taiwan
Authors: Li Yao-Tsun , Ko Hui-Ying , Hughes Joseph , Liu Ming-Tsan , Lin Yi-Ling , Hampson Katie , Brunker Kirstyn
Published: June 2024

A/goose/Guangdong/1/96-like (GsGd) highly pathogenic avian influenza (HPAI) H5 viruses cause severe outbreaks in poultry when introduced. Since emergence in 1996, control measures in most countries have suppressed local GsGd transmission following introductions, making persistent transmission in domestic birds rare. However, geographical expansion of clade 2.3.4.4 sublineages has raised concern about establishment of endemic circulation, while mechanistic drivers leading to endemicity remain unknown. We reconstructed the evolutionary history of GsGd sublineage, clade 2.3.4.4c, in Taiwan using a time-heterogeneous rate phylogeographic model. During Taiwan’s initial epidemic wave (January 2015 - August 2016), we inferred that localised outbreaks had multiple origins from rapid spread between counties/cities nationwide. Subsequently, outbreaks predominantly originated from a single county, Yunlin, where persistent transmission harbours the trunk viruses of the sublineage. Endemic hotspots determined by phylogeographic reconstruction largely predicted the locations of re-emerging outbreaks in Yunlin. The transition to endemicity involved a shift to chicken-dominant circulation, following the initial bidirectional spread between chicken and domestic waterfowl. Our results suggest that following their emergence in Taiwan, source-sink dynamics from a single county have maintained GsGd endemicity, pointing to where control efforts should be targeted to eliminate the disease.
Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression
Authors: Vlasschaert Caitlyn , Pan Yang , Chen Jianchun , Akwo Elvis , Rao Varun , Hixson James E. , Chong Michael , Uddin Md Mesbah , Yu Zhi , Jiang Mengdi , Peng Fenfen , Cao Shirong , Wang Yinqiu , Kim Do-Kyun , Hung Adriana M. , He Jing , Tamura Manjula Kurella , Cohen Debbie L. , He Jiang , Li Changwei , Bhat Zeenat , Rao Panduranga , Xie Dawei , Bick Alexander G. , Kestenbaum Bryan , Paré Guillaume , Rauh Michael J. , Levin Adeera , Natarajan Pradeep , Lash James P. , Zhang Ming-Zhi , Harris Raymond C. , Robinson-Cohen Cassianne , Lanktree Matthew B. , Kelly Tanika N. ,   the CRIC Study Investigators
Published: June 2024

Background

Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other thanDNMT3A(non-DNMT3ACHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes.

Methods

In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulatingTet2-CHIP compared to controls transplanted wild-type bone marrow.

Results

Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m2, and 24% had CHIP. Upon meta-analysis, non-DNMT3ACHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non-DNMT3ACHIP carriers, relative to non-carriers (β -0.61 ± 0.31 ml/min/1.73m2, p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD,Tet2-CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis.

Conclusion

Non-DNMT3ACHIP is a potentially targetable novel risk factor for CKD progression.
Predictors of Clinical Outcomes among People with HIV and Tuberculosis Symptoms after Rapid Treatment Initiation in Haiti
Authors: Richterman Aaron , Dorvil Nancy , Rivera Vanessa , Bang Heejung , Severe Patrice , Lavoile Kerylyne , Pierre Samuel , Apollon Alexandra , Dumond Emelyne , Forestal Guyrlaine Pierre Louis , Rouzier Vanessa , Joseph Patrice , Cremieux Pierre-Yves , Pape Jean W , Koenig Serena P
Published: June 2024

Introduction

Few studies have evaluated baseline predictors of clinical outcomes among people with HIV starting antiretroviral therapy (ART) in the modern era of rapid ART initiation.

Methods

We conducted a secondary analysis of a randomized controlled trial of two rapid treatment initiation strategies for people with treatment-naïve HIV and tuberculosis symptoms at an urban clinic in Haiti. We used logistic regression models to assess associations between baseline characteristics and (1) retention in care at 48 weeks, (2) HIV viral load suppression at 48 weeks (among participants who underwent viral load testing), and (3) all-cause mortality.

Results

500 participants were enrolled in the study 11/2017-1/2020. Eighty-eight (18%) participants were diagnosed with tuberculosis, and ART was started in 494 (99%). After adjustment, less than secondary education (adjusted odds ratio [AOR] 0.21, 95% CI 0.10-0.46), dolutegravir initiation (AOR 2.57, 95% CI 1.22-5.43), age (AOR 1.42 per 10-year increase, 95% CI 1.01-1.99), and tuberculosis diagnosis (AOR 3.92, 95% CI 1.36-11.28) were significantly associated with retention. Age (AOR 1.36, 95% CI 1.05-1.75), dolutegravir initiation (AOR 1.75, 95% CI 1.07-2.85), and tuberculosis diagnosis (AOR 0.50, 95% CI 0.28-0.89) were associated with viral suppression. Higher CD4 cell count at enrollment (unadjusted odds ratio [OR] 0.69, 95% CI 0.55-0.87) and anemia (OR 4.86, 95% CI 1.71-13.81) were associated with mortality.

Conclusions

We identified sociodemographic, treatment-related, clinical, and laboratory-based predictors of clinical outcomes. These characteristics may serve as markers of sub- populations that could benefit from additional interventions to support treatment success after rapid treatment initiation.
Community pharmacists’ referrals to General Practice with suspected need of antibiotics: a national prospective pilot
Authors: Stehlik Paulina , Moles Rebekah , Jones Mark , Murray Amanda , El-Den Sarira , Morgan Mark , Del Mar Chris
Published: June 2024

Background

Interventions to minimise community antibiotic use have focused on the GP and patient behaviour rather than the community pharmacist. Patient expectations are a known driver for antibiotic prescribing, and pharmacists may be inveterately contributing to these expectations by referring patients for GPs for suspected antibiotic-requiring infections (S-ARI). We sought to quantify these referral rates.

Method

Pharmacists and GPs were recruited independently using convenience sampling and completed prospective data collection on 20 minor ailment encounters and consecutive consultations respectively. Pharmacists recorded patient gender, age, referral reason and comments (if any). GPs recorded patient age, gender, reason for visit, and origin of patient referral including self-referral.

All data were analysed descriptively. Generalised estimating equations, multivariable logistic regression was used to investigate factors that may be associated with pharmacist referral rates.

Results

Nineteen pharmacists representing 466 minor ailments encounters, and 19 GPs representing 394 consultations were recruited.

Pharmacists referred 16.5% (77/466) of all minor ailments encounters for S-ARI. Comments suggested that reasons included upper-respiratory tract, ear nose and throat, and urinary tract infections. Most of S-ARI referrals were to a GP (62/466).

None of the 88 consultations for infection in GP data were documented as being referred by a pharmacist; majority were self-referred (77.3%; 68/88).

Discussion

Pharmacists referred 1 in 8 minor ailments encounters to the GP for S-ARI, with some indication they were for conditions that do not require antibiotics. Most GP consultations for infection were documented as self-referrals. Both provide potential points of intervention to minimise antibiotic use.
The Effects of Lamin B Receptor knockdown on a Myeloid Leukemia Cell
Authors: Mark Welch David B. , Olins Ada L. , Olins Donald E.
Published: June 2024

In an effort to extend our understanding of the genetic functions of the nuclear envelope protein Lamin B Receptor (LBR), we examined the effect of a stable short hairpin (sh1) RNAi knockdown of LBR on the transcriptome and immunostained morphology of the human myeloid leukemia cell line (HL-60/S4). This examination was on sh1 cells induced to granulocytic form with Retinoic Acid (RA) versus sh1 cells maintained undifferentiated (0). By comparison to control cells (i.e., not sh1), we obtained gene lists that were differentially expressed only in the LBR knockdown cell line (i.e., “only-sh1-down” and “only-sh1-up”), in RA versus 0 cells. These curated gene lists were examined by Gene Ontology (GO) analysis. Aside from chromatin related GO terms, the most surprising finding was a significant downregulation of Golgi related genes only in the sh1 cells. Possible relationships between the “Cis-Golgi-Network” and LBR are discussed. Another surprise was a significant upregulation of “Ribosome” protein transcripts only in the sh1 cells. In parallel to these findings, an immunostaining comparison of nucleoli in S4 and sh1 cells demonstrated that the number and location of nucleoli in a single nucleus differs, depending upon the presence of LBR. Speculations on the influence of LBR levels upon the liquid-liquid phase separation model of nucleolar condensation are presented.
A Spike Trimer Dimer-Inducing Nanobody with Anti-Sarbecovirus Activity
Authors: Swart Iris C. , Debski-Antoniak Oliver J. , Zegar Aneta , de Bouter Thijs , Chatziandreou Marianthi , van den Berg Max , Drulyte Ieva , Pyrć Krzysztof , de Haan Cornelis A.M. , Hurdiss Daniel L. , Bosch Berend-Jan , Oliveira Sabrina
Published: June 2024

The continued emergence and zoonotic threat posed by coronaviruses highlight the urgent need for effective antiviral strategies with broad reactivity to counter new emerging strains. Nanobodies (or single-domain antibodies) are promising alternatives to traditional monoclonal antibodies, due to their small size, cost-effectiveness and ease of bioengineering. Here, we describe 7F, a llama-derived nanobody, targeting the spike receptor binding domain of sarbecoviruses and SARS-like coronaviruses. 7F demonstrates potent neutralization against SARS-CoV-2 and cross-neutralizing activity against SARS-CoV and SARS-like CoV WIV16 pseudoviruses. Structural analysis reveals 7F’s ability to induce the formation of spike trimer dimers by engaging with two SARS-CoV-2 spike RBDs, targeting the highly conserved class IV region. Bivalent 7F constructs substantially enhance neutralization potency and breadth, up to more recent SARS-CoV-2 variants of concern. Furthermore, we demonstrate the therapeutic potential of 7F against SARS-CoV-2 in the fully differentiated 3D tissue cultures mirroring the epithelium of the human airway ex vivo. The broad sarbecovirus activity and distinctive structural features of 7F underscore its potential as promising antiviral against emerging and evolving sarbecoviruses.
The JNK and Hippo pathways control epithelial integrity and prevent tumour initiation by regulating an overlapping transcriptome
Authors: Mitchell Katrina A. , Vissers Joseph H. A. , Pojer Jonathan M. , Brooks Elliot , Hilmi Abdul Jabbar Saiful , Papenfuss Anthony T. , Schröder Jan , Harvey Kieran F.
Published: June 2024

Epithelial organs maintain their integrity and prevent tumour initiation by actively removing defective cells, such as those that have lost apicobasal polarity. Here, we identify how transcription factors of two key signalling pathways – Jun-N-terminal kinase (JNK) and Hippo – regulate epithelial integrity by controlling transcription of an overlapping set of target genes. Targeted DamID experiments reveal that in proliferating cells of theDrosophila melanogastereye, the AP-1 transcription factor Jun, and the Hippo pathway transcription regulators Yorkie and Scalloped bind to a common suite of target genes that regulate organ growth. In defective neoplastic cells, AP-1 transcription factors repress transcription of growth genes together with the CtBP co-repressor. If gene repression by AP-1/CtBP fails, neoplastic tumour growth ensues, driven by Yorkie/Scalloped. Thus, AP-1/CtBP eliminates defective cells and prevents tumour initiation by acting in parallel to Yorkie/Scalloped to repress expression of a shared transcriptome. These findings shed new light on the maintenance of epithelial integrity and tumour suppression.
Early-Life Group Size Does Not Influence Japanese Quails’ Learning in a Response Inhibition Task
Authors: Willcox Kathryn , Vernouillet Alizée , Lens Luc , Verbruggen Frederick
Published: June 2024

In complex social environments, animals benefit from suppressing inappropriate responses (known as Response Inhibition - RI) to avoid conflicts and maintain group cohesion. Recent research suggests that an individual’s early-life social environment can shape their RI. However, these findings have mostly been correlational, and results vary across species. Furthermore, the role of learning is often overlooked when measuring RI, despite its potential importance to understanding group differences. We investigated the effect of early-life group size, a key determinant of social complexity, on RI in Japanese quails (Coturnix japonica), whilst taking the role of learning into account. Quails (n = 120) were raised in either small groups of five or large groups of 15 individuals. RI was assessed using the cylinder task. Up to 10 trials were administered to assess whether the birds’ responses changed with increasing experience of the task. Among the quails that completed 10 trials, we found that those raised in large groups consistently spent less time pecking the cylinder than those raised in small groups. The quails’ responses were also influenced by their body condition, food motivation, and sex. Importantly, the quails learned to inhibit their responses - successful trials increased, and time spent pecking the cylinder decreased, across 10 trials. However, learning rates did not differ between the treatment groups. These findings suggest that early-life social group size promotes the development of RI in quails, but not their learning during the cylinder task.
Time-resolved mitochondrial-focused screening identifies regulatory components of oxidative metabolism
Authors: Zamora-Dorta Marcos , Laine-Menéndez Sara , Abia David , González-García Pilar , López Luis C. , Fernández-Montes Díaz Paula , Calvo Enrique , Vázquez Jesús , Enríquez José Antonio , Balsa Eduardo
Published: June 2024

Defects in mitochondrial oxidative metabolism contribute to various genetic inherited disorders, termed mitochondrial diseases, with limited treatment options. Given the lack of functional annotation for numerous mitochondrial proteins, there is a necessity for an extensive gene inventory related to mitochondrial function, with special interest in Oxidative Phosphorylation (OXPHOS). To address this gap, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings at various time points to uncover novel regulators of mitochondrial function. Our study resulted in a gene catalog essential for mitochondrial oxidative metabolism, and constructed a dynamic timeline mapping a broad network of mitochondrial pathways, with a particular focus on the OXPHOS complexes. Computational analysis pinpointed RTN4IP1 and ECHS1 as key genes strongly associated with OXPHOS and whose mutations are associated with mitochondrial diseases in humans. RTN4IP1 was found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Deletion of ECHS1 leads to reduced catabolism of branched-chain amino acids (BCAAs), which impairs the activity of lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.
Immunoactive signatures of circulating tRNA- and rRNA-derived RNAs in chronic obstructive pulmonary disease
Authors: Shigematsu Megumi , Kawamura Takuya , Deshpande Deepak A. , Kirino Yohei
Published: June 2024

Chronic obstructive pulmonary disease (COPD) is the most prevalent lung disease, and macrophages play a central role in the inflammatory response in COPD. We here report a comprehensive characterization of circulating short non-coding RNAs (sncRNAs) in plasma from patients with COPD. While circulating sncRNAs are increasingly recognized for their regulatory roles and biomarker potential in various diseases, the conventional RNA-seq method cannot fully capture these circulating sncRNAs due to their heterogeneous terminal structures. By pre-treating the plasma RNAs with T4 polynucleotide kinase, which converts all RNAs to those with RNA-seq susceptible ends (5′-phosphate and 3′-hydroxyl), we comprehensively sequenced a wide variety of non-microRNA sncRNAs, such as 5′-tRNA halves containing a 2′,3′-cyclic phosphate. We discovered a remarkable accumulation of the 5′-half derived from tRNAValCACin plasma from COPD patients, whereas the 5′-tRNAGlyGCChalf is predominant in healthy donors. Further, the 5′-tRNAValCAChalf activates human macrophages via Toll-like receptor 7 and induces cytokine production. Additionally, we identified circulating rRNA-derived fragments that were upregulated in COPD patients and demonstrated their ability to induce cytokine production in macrophages. Our findings provide evidence of circulating, immune-active sncRNAs in patients with COPD, suggesting that they serve as inflammatory mediators in the pathogenesis of COPD.
Rapid degradation of Histone Deacetylase 1 (HDAC1) reveals essential roles in both gene repression and active transcription
Authors: English David M , Lee Samuel N , Sabat Khadija A , Baker India M , Pham Trong Khoa , Collins Mark O , Cowley Shaun M
Published: June 2024

Histone Deacetylase 1 (HDAC1) removes acetyl groups from lysine residues on the core histones, a critical step in the regulation of chromatin accessibility. Despite histone deacetylation being an apparently repressive activity, suppression of HDACs causes both up- and down-regulation of gene expression. Here we exploited the degradation tag (dTAG) system to rapidly degrade HDAC1 in embryonic stem cells (ESCs) lacking its paralog, HDAC2. Unlike HDAC inhibitors that lack isoform specificity, the dTAG system allowed specific degradation and removal of HDAC1 in <1 hour (100x faster than genetic knockouts). This rapid degradation caused increased histone acetylation in as little as 2 hours, with H2BK5 and H2BK11 being the most sensitive. The majority of differentially expressed genes following 2 hours of HDAC1 degradation were upregulated (275 genes up vs 15 down) with increased proportions of downregulated genes observed at 6 (1,153 up vs 443 down) and 24 hours (1,146 up vs 967 down) respectively. Upregulated genes showed increased H2BK5ac and H3K27ac around their transcriptional start site (TSS). In contrast, decreased acetylation of super-enhancers (SEs) was linked to the most strongly downregulated genes. These findings suggest a paradoxical role for HDAC1 in the maintenance of histone acetylation levels at critical enhancer regions required for the pluripotency-associated gene network.
PBP4 is required for serum-induced cell wall thickening and antibiotic tolerance inStaphylococcus aureus
Authors: Ledger Elizabeth V. K. , Massey Ruth C.
Published: June 2024

The bacterial pathogenStaphylococcus aureusresponds to the host environment by synthesising a thick peptidoglycan cell wall which protects the bacterium from membrane-targeting antimicrobials and the immune response. However, the proteins required for this response were previously unknown. Here, we demonstrate by three independent approaches that the penicillin binding protein PBP4 is crucial for serum-induced cell wall thickening. Firstly, mutants lacking various non-essential cell wall synthesis enzymes were tested, revealing that a mutant lackingpbp4was unable to generate a thick cell wall in serum. This resulted in reduced serum-induced tolerance of thepbp4mutant towards the last resort antibiotic daptomycin relative to wildtype cells. Secondly, we found that serum-induced cell wall thickening occurred in each of a panel of 134 clinical bacteraemia isolates, except for one strain with a naturally-occurring mutation that confers a S140R substitution in the active site of PBP4. Finally, inhibition of PBP4 with cefoxitin prevented serum-induced cell wall thickening and the resulting antibiotic tolerance in the USA300 strain and in clinical MRSA isolates. Together, this provides a rationale for combining daptomycin with cefoxitin, a PBP4 inhibitor, to potentially improve treatment outcomes for patients with invasive MRSA infections.
Spine loss in depression impairs dendritic signal integration in human cortical microcircuit models
Authors: Yao Heng Kang , Mazza Frank , Prevot Thomas , Sibille Etienne , Hay Etay
Published: June 2024

Major depressive disorder (depression) is associated with altered dendritic structure and function in excitatory cortical pyramidal neurons, due to decreased inhibition from somatostatin interneurons and loss of spines and associated synapses, as indicated in postmortem human studies. Dendrites play an important role in signal processing as they receive the majority of synaptic inputs and exhibit nonlinear properties including backpropagating action potentials and dendritic Na+spikes that enhance the computational power of the neuron. However, it is currently unclear how depression-related dendritic changes impact the integration of signals. Here, we expanded our previous data-driven detailed computational models of human cortical microcircuits in health and depression to include active dendritic properties that enable backpropagating action potentials as measured in human neurons, and spine loss in depression in terms of synapse loss and altered intrinsic property. We show that spine loss dampens signal response and thus results in a larger impairment of cortical function such as signal detection than due to reduced somatostatin interneuron inhibition alone. We further show that the altered intrinsic properties due to spine loss abolish nonlinear dendritic integration of signals and impair recurrent microcircuit activity. Our study thus mechanistically links cellular changes in depression to impaired dendritic processing in human cortical microcircuits.
Structural architecture of TolQ-TolR inner membrane protein complex from opportunistic pathogenAcinetobacter baumannii
Authors: Karimullina Elina , Guo Yirui , Khan Hanif M. , Emde Tabitha , Quade Bradley , Leo Rosa Di , Otwinowski Zbyszek , Tieleman Peter D. , Borek Dominika , Savchenko Alexei
Published: June 2024

Gram-negative bacteria harness the proton motive force (PMF) within their inner membrane (IM) to uphold the integrity of their cell envelope, an indispensable aspect for both division and survival. The IM TolQ-TolR complex is the essential part of the Tol-Pal system, serving as a conduit for PMF energy transfer to the outer membrane. Here we present cryo-EM reconstructions ofAcinetobacter baumanniiTolQ in apo and TolR- bound forms at atomic resolution. The apo TolQ configuration manifests as a symmetric pentameric pore, featuring a trans-membrane funnel leading towards a cytoplasmic chamber. In contrast, the TolQ-TolR complex assumes a proton non-permeable stance, characterized by the TolQ pentamer’s flexure to accommodate the TolR dimer, where two protomers undergo a translation-based relationship. Our structure-guided analysis and simulations support the rotor-stator mechanism of action, wherein the rotation of the TolQ pentamer harmonizes with the TolR protomers’ interplay. These findings broaden our mechanistic comprehension of molecular stator units empowering critical functions within the Gram-negative bacterial cell envelope.

Teaser

Apo TolQ and TolQ-TolR structures depict structural rearrangements required for cell envelope organization in bacterial cell division.
Unraveling the effects of polyhydroxyalkanoates accumulation inPseudomonas extremaustralisgrowth and survival under different pH conditions
Authors: Brito María Gabriela , López Nancy I. , Raiger Iustman Laura J.
Published: June 2024

Polyhydroxyalkanoates (PHAs) are intracellular polymers that enhance bacterial fitness against various environmental stressors.Pseudomonas extremaustralis14-3b is an Antarctic bacterium capable of accumulating, short-chain-length PHAs (sclPHAs), composed of C3–C5 monomers, as well as medium-chain-length PHAs (mclPHAs) containing ≥C6 monomers. Since pH changes are pivotal in bacterial physiology, influencing microbial growth and metabolic processes, we propose that accumulated PHA increasesP. extremaustralisfitness to cope with pH changes. To test this, we analyzed the production of sclPHA and mclPHA at different pH levels and its effect on bacterial survival against pH stress.P. extremaustraliswas able to grow and accumulate PHA when the culture media pH ranged from 6.0 to 9.5, showing a marked loss of viability outside this range. Additionally, based on the analysis of different PHA-deficient mutants, we found that when exposed to both acidic and alkaline conditions, sclPHA and mclPHA conferred different protection against pH stress, with sclPHA making the main contribution. These results highlight the importance of PHA in supporting survival in pH-stressful environments.
Optimizing protein production in the One-Pot Pure system: insights into reaction composition and expression efficiency
Authors: Zhang Yan , Deveikis Matas , Qiu Yanping , Björn Lovisa , Martinez Zachary A. , Chou Tsui-Fen , Freemont Paul S. , Murray Richard M.
Published: June 2024

The One-Pot PURE (Protein synthesisUsingRecombinantElements) system simplifies the preparation of traditional PURE systems by co-culturing and purifying 36 essential proteins for gene expression in a single step, thereby improving accessibility and affordability for widespread laboratory adoption and customization. However, replicating this protocol to match the productivity of traditional PURE systems can take considerable time and effort due to uncharacterized variability in the system’s biochemical composition. In this work, we observed unstable PURE protein expression inE. colistrains M15/pREP4 and BL21(DE3) and addressed this using glucose-mediated catabolite repression to minimize burdensome background expression. We also identified differences in optimal protein induction timing between these two strains, leading to growth incompatibility in co-culture, and observed proteolysis of PURE proteins expressed in M15/pREP4. We showed that consolidating all expression vectors into a protease-deficient BL21(DE3) strain could minimize proteolysis. This single-strain system also led to more uniform cell growth at the time of protein induction, improving the stoichiometry of critical translation initiation factors in the PURE reaction for efficient protein production. In addition to optimizing One-Pot PURE protein composition, we found that variations in commercial energy solution formulations could compensate for suboptimal PURE protein stoichiometry. Moreover, our study revealed significant differences in the expression capacity of commercially availableE. colitRNAs, suggesting the potential of optimizing tRNA codons to improve protein translation. Taken together, this work highlights the complex biochemical interplay influencing protein expression capacity in the One-Pot PURE system and presents strategies to improve its robustness and productivity.
Targeting SEZ6L2 in Colon Cancer: Efficacy of Bexarotene and Implications for Survival
Authors: Zheng Huajun , Zheng Jianying , Shen Yan
Published: June 2024

Background

Bexarotene, also recognized as Targretin, is categorized as a retinoid, a type of cancer drug. Nevertheless, the precise mechanisms of Bexarotene in relation to colon cancer remain unclear. In colon cancer, SEZ6L2 was suggested as one of the biomarkers and targets. This study presents a comprehensive exploration of the role of SEZ6L2 in colon cancer.

Methods

We utilized both TCGA data and a cohort of Chinese patients. In a meticulous analysis of 478 colon cancer cases, SEZ6L2 expression levels were examined in relation to clinical characteristics, staging parameters, and treatment outcomes. Additionally, we investigated the pharmacological impact of Bexarotene on SEZ6L2, demonstrating a significant downregulation of SEZ6L2 at both mRNA and protein levels in colon cancer patients following Bexarotene treatment.

Results

SEZ6L2 consistently overexpresses in colon cancer, serving as a potential universal biomarker with prognostic significance, validated in a diverse Chinese cohort. In vitro, SEZ6L2 promotes cell viability without affecting migration. Bexarotene treatment inhibits SEZ6L2 expression, correlating with reduced viability both in vitro and in vivo. SEZ6L2 overexpression accelerates declining survival rates in an in vivo context. Bexarotene’s efficacy is context-dependent, effective in parental cells but not with SEZ6L2 overexpression. Computational predictions suggest a direct SEZ6L2-Bexarotene interaction, warranting further experimental exploration.

Conclusion

The study provides valuable insights into SEZ6L2 as a prognostic biomarker in colon cancer, revealing its intricate relationship with clinical parameters, treatment outcomes, and Bexarotene effects. Context-dependent therapeutic responses emphasize the nuanced understanding required for SEZ6L2’s role in colon cancer, paving the way for targeted therapeutic strategies.
Chemically induced cell plasticity enables the generation of high-fidelity embryo model
Authors: Li Huanhuan , Huang Jiahui , Guan Wei , Wu Jinyi , Luo Haiping , Chang Litao , Zhao Haiyong , Chen Chuanxin , Gao Yake , Zhang Jian , Silva José C. R.
Published: June 2024

Embryo models open exciting opportunities for improving our understanding of development and advancing medicine. However, current models depend on intricate procedures and the integration of separately generated cell types. Here, we aimed to establish a chemical-only strategy to induce cellular plasticity and generate embryo founder-like cells. Within 60 hours, chemical-induced pluripotent stem cells activated early lineage specifiers,Cdx2andGata6, while maintainingOct4/ Pou5f1expression. Following a second 36-hour chemical treatment, founder-like cells developed into all blastocyst fates and self-assembled into embryo-like structures. These progressed into high-fidelity late-streak gastrulation stages within 4.5 days, displaying primitive streak formation via epithelial-to-mesenchymal transition, along with germ-layer tissues, amnion, and ectoplacental cone. Fate trajectories and molecular signatures from founder-like cells to chemically-induced embryo model (ci-MO) were defined, revealing remarkable similarity up to Embryonic day (E) 7.5 embryo. Summarily, ci-MO offers a straightforward, rapid, small-molecule-only, and high-fidelity approach to study embryonic development and cell fate specification.

Highlights

Generation of a direct, efficient, and sophisticated chemically induced embryo model (ci-MO)

Two-pulse chemical induction reprograms ESCs into founder-like cells capable of developing all embryo fates

Gastrulating ci-MOs display high morphological and molecular accuracy

ci-MOs reconstruct embryo developmental trajectories
Molecular details and phospho-regulation of the CENP-T-Mis12 complex interaction during mitosis in DT40 cells
Authors: Takenoshita Yusuke , Hara Masatoshi , Nakagawa Reiko , Ariyoshi Mariko , Fukagawa Tatsuo
Published: June 2024

To establish bi-polar attachments of microtubules to sister chromatids, an inner kinetochore subcomplex, the constitutive centromere-associated network (CCAN), is assembled on centromeric chromatin and recruits the microtubule-binding subcomplex called the KMN network. Although it is important to characterize the interaction between CCAN and KMN, it is difficult to evaluate the significance of each interaction in cells, since CCAN proteins CENP-C and CENP-T independently bind to the Mis12 complex (Mis12C) of KMN. Here, we demonstrate molecular details of the CENP-T-Mis12C interaction using chicken DT40 cells lacking CENP-C-Mis12C interaction. Based on AlphaFold2 predictions, we identified two binding surfaces for the CENP-T-Mis12C interaction, demonstrating that each surface is critical for Mis12C recruitment and cell viability. This interaction via two interaction surfaces is cooperatively regulated by dual phosphorylation of Dsn1 (a Mis12C component) and CENP-T, ensuring robust CENP-T-Mis12C interaction and proper mitotic progression. These findings deepen our understanding of kinetochores assembly in cells.
Developing a model of digital transformation of university libraries based on meta-synthesis
Authors: Khoeini Soheila , Noruzi Alireza , Naghshineh Nader , Sheikhshoaei Fatemeh
Published: June 2024

Purpose

The purpose of this study was to develop a model for the digital transformation of university libraries based on meta-synthesis.

Design/methodology/approach

The approach of this research was qualitative and used the Sandelowski and Barroso’s (2007) seven-step meta-synthesis method to systematically review the literature. The statistical population of the research includes all the scientific publications related to the foundations and dimensions of the digital transformation of university libraries, counting the scientific publications retrieved from six scientific databases in the period from 2004 to 2022, and was based on the critical appraisal skills programme and a screening process.

Findings

Based on the retrieved publications, 32 documents were selected for further review and analysis. First, a separate code was considered for all the factors extracted from the selected documents, and then, considering the concept of each of the codes, they were categorized into a similar concept. In this way, the research concepts were determined. Based on the analysis done with the help of the content analysis method, there are a total of seven main categories and 24 concepts, including digital culture (including: digital attitude, user-oriented, agility, participation and cooperation, creativity and innovation and learning digital skills of employees), digital librarian (containing: individual competence, knowledge competence, communication competence and skill competence), digital manager (comprising: individual competence, knowledge competence, skill competence), digital services and resources (including, optimally reorganizing library resources, providing digital services to users and providing digital services to the mother organization), digital technologies (containing: digital infrastructure, technological readiness and using digital technologies), support and cooperation of upstream institutions and the mother organization (dealing with: providing human resources, providing technological resources and equipment and making macro policies) and work process and development of digital strategies (comprising: digitalization of processes and development of library digital strategies).

Originality/value

Digital transformation is a complex and multi-faceted process, yet it is an indispensable endeavour for university libraries, and managers and librarians cannot be expected to be familiar with these concepts without training or study and then be able to move in the right direction towards the digital transformation of libraries. To the best of the authors’ knowledge, this is the first study to develop a model for the digital transformation of university libraries. The results of this research indicate the effective factors and requirements needed for the digital transformation of university libraries and address the importance of understanding the concepts for managers and librarians.
How does financial inclusion act as a catalyst for reducing financial crime among women?
Authors: Akram Tooba , Muhammad Naveed , RamaKrishnan Suresh
Published: June 2024

Purpose

This study aims to review financial inclusion as a catalyst to reduce financial scams and frauds faced by women in the five largest US states by population and proposed measures encouraging women’s financial safety.

Design/methodology/approach

Recognizing the unique socioeconomic landscape, the study seeks responses through a survey questionnaire from 4,113 women respondents analyzed by using a basic mixed-methods approach, including quantitative surveys analyzed through SPSS and qualitative short interviews thematically analyzed by using Nvivo.

Findings

The review results show that 94% of women believe that financial inclusion can protect them from scams and fraud. Also, it has been observed that financial crimes disproportionately affect women, often stemming from a desire to conceal such activities from close family members and partners. Older women, housewives and those from financially depressed areas need more financial inclusion plans to curb financial fraud.

Social implications

The proposed measures may have positive social and economic implications on the females residing in the financially depressed areas.

Originality/value

The study represents the authors’ original contribution, examining the role of financial inclusion in preventing women from engaging in financial crimes.
e–WOM and app stores in Iran: how online reviews influence purchase intention of paid mobile apps
Authors: Asadi Damavandi Azade , Ha Louisa
Published: June 2024

Purpose

This study aims to examine the relative importance of the impact of central and peripheral route processing of online reviews (ORs) on the acceptance of paid mobile apps among consumers in a fully Islamic market. The authors used the elaboration likelihood model (ELM) and technology acceptance model (TAM) to explain how ORs influence users’ perception and purchase intention of paid mobile apps.

Design/methodology/approach

An online survey of 384 Iranian paid mobile app users was conducted to compare the role of overall product ranking, argument quality and information quantity on the perceived usefulness (PU) and perceived ease of use (PEU) of mobile apps and purchase intentions of paid mobile apps.

Findings

Results show that only overall product ranking and argument quality influence perceived PEU and PU of paid mobile apps. The quantity of reviews on the app store does not affect perception of the app. The path model supports the mediating role of PU and PEU on information processing and attitude toward the app and purchase intention.

Practical implications

To Islamic markets such as Iran, this study shows that paid mobile app marketers need to monitor closely the reviews in the app stores and make prompt response to negative reviews even if there are only a few reviews because users did not pay attention to the quantity of reviews. The overall ranking and argument quality strongly affect perception and purchase intention of paid apps.

Originality/value

To the best of the authors’ knowledge, this is the first study that combines ELM and TAM in determining the relative importance of central and peripheral processing of information in online product reviews, specifically for paid mobile apps in app stores in a large Islamic market.
Switching intention of conventional bank customers to Sharia bank based on push-pull-mooring theory
Authors: Monoarfa Hilda , Al Adawiyah Rumaisah Azizah , Prananta Widya , Sadat Andi Mohammad , Vakhroh Disya Allifah
Published: June 2024

Purpose

This study aims to see the variables of customer satisfaction level, attractiveness of alternatives, subjective norms and level of religiosity of conventional bank customers in West Java and their effect on switching intentions.

Design/methodology/approach

A causality description technique with a quantitative approach is used in this research. The analytical technique used is partial least square-structural equation modeling with a sample of 320 respondents from conventional bank customers in West Java.

Findings

The results revealed that the level of customer satisfaction and subjective norms were in the medium category, whereas the level of alternative attractiveness, religiosity and switching intentions was in high level. The level of customer satisfaction harms switching intentions, whereas the level of alternative attractiveness and religiosity variables have a positive effect on switching intentions. In contrast, the subjective norm variable does not affect switching intentions. Therefore, customer satisfaction, the attractiveness of alternatives and religiosity are essential points to cause someone to have the intention to switch.

Practical implications

For stakeholders, especially the government or the Islamic banking industry, to improve the climate of the Islamic finance industry in Indonesia, in particular, to increase knowledge and insight from the public regarding the intention to switch conventional bank customers to Islamic banks.

Originality/value

The use of the religiosity variable as an independent variable on switching intentions is still rarely done. Hence, the authors combine this variable with customer satisfaction, alternative attractiveness and subjective norms. The update in this study also places conventional bank customers included in the millennial generation and generation Z categories who live in the province of West Java as research subjects.
Paid Leave Mandates and Care for Older Parents
Authors: ARORA KANIKA , WOLF DOUGLAS A.
Published: June 2024

Policy Points

We examined the effect of the Paid Family Leave policy (PFL) and Paid Sick Leave policy (PSL) on care provision to older parents.

We found that PSL adoption led to an increase in care provision, an effect mainly attributable to respondents in states/periods when PSL and PFL were concurrently offered. Some of the strongest effects were found among women and unpartnered adult children.

PFL adoption by itself was not associated with care provision to parents except when PFL also offered job protection.

Paid leave policies have heterogeneous effects on eldercare and their design and implementation should be carefully considered.

Context

Family caregivers play a critical role in the American long‐term care system. However, care responsibilities are known to potentially conflict with paid work, as about half of family caregivers are employed. The federal Family and Medical Leave Act passed by the US Congress in 1993 provides a nonuniversal, unpaid work benefit. In response, several states and localities have adopted the Paid Family Leave policy (PFL) and Paid Sick Leave policy (PSL) over the last two decades. Our objective is to examine the effect of these policies on the probability of personal care provision to older parents.

Methods

This study used longitudinal data from the Health and Retirement Study (1998‐2020). Difference‐in‐differences regression models were estimated to examine associations between state‐ and local‐level PFL and PSL mandates and personal care provision to older parents. We analyzed heterogeneous effects by the type of paid leave exposure (provision of job protection with PFL and availability of both PSL and PFL [with or without job protection] concurrently). We also examined results for different population subgroups.

Findings

PSL implementation was associated with a four‐ to five‐percentage point increase in the probability of personal care provision. These effects were mainly attributable to respondents in states/periods when PSL and PFL were concurrently offered. The strongest effects were found among adult children who were employed at baseline, women, younger, unpartnered, and college educated. PFL implementation by itself was not associated with care provision to parents except when the policy also offered job protection.

Conclusions

Paid leave policies have heterogeneous impacts on personal care provision, potentially owing to differences in program features, variation in caregiving needs, and respondent characteristics. Overall, the results indicate that offering paid sick leave and paid family leave, when combined with job protection, could support potential family caregivers.
The financial development and renewable energy consumption nexus in Africa: Does the quality of governance matter?
Authors: Alinsato Alastaire S. , Dossou Toyo Amègnonna Marcel , Dossou Pascal K. , N. Kambaye Emmanuelle , Asongu Simplice A.
Published: June 2024

The impact of financial development (FD) on renewable energy consumption has been extensively examined in recent years. Nevertheless, studies on the moderation of quality of governance in the financial development and renewable energy consumption nexus are sparse. By filling the gap in the literature relating to energy economicsc, this study investigates the moderating effect of the quality of governance on the relationship between financial development and consumption of renewable energy for a panel of 33 African countries over the period between 2000 and 2020. The fully modified ordinary least squares (FMOLS) estimation technique is used to account for cointegration and cross‐sectional dependence. The results unveil that the impact of governance quality and financial development on renewable energy consumption is negative and statistically significant. Moreover, the results reveal that the FD‐governance quality interactions are significant and negative. Governance quality thresholds at which the negative incidence of financial development on renewable energy consumption is completely nullified are provided.
Current therapeutic approach of chronic kidney disease‐mineral and bone disorder
Authors: Zaimi Maria , Grapsa Eirini
Published: June 2024

Chronic kidney disease (CKD) has emerged as one of the leading noncommunicable diseases affecting >10% of the population worldwide. Bone and mineral disorders are a common complication among patients with CKD resulting in a poor life quality, high fracture risk, increased morbidity and cardiovascular mortality. According to Kidney Disease: Improving Global Outcomes, renal osteodystrophy refers to changes in bone morphology found in bone biopsy, whereas CKD‐mineral and bone disorder (CKD‐MBD) defines a complex of disturbances including biochemical and hormonal alterations, disorders of bone and mineral metabolism and extraskeletal calcification. As a result, the management of CKD‐MBD should focus on the aforementioned parameters, including the treatment of hyperphosphatemia, hypocalcemia, abnormal PTH and vitamin D levels. Regarding the bone fragility fractures, osteoporosis and renal osteodystrophy, which constitute the bone component of CKD‐MBD, anti‐osteoporotic agents constitute the mainstay of treatment. However, a thorough elucidation of the CKD‐MBD pathogenesis is crucial for the ideal personalized treatment approach. In this paper, we review the pathology and management of CKD‐MBD based on the current literature with special attention to recent advances.