bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral hemodynamics response to dual-task paradigms in older adults: A systematic review and meta-analysis
Authors: Lapanan Kulvara , Kantha Phunsuk , Nantachai Gallayaporn , Hemrungrojn Solaphat , Maes Michael
Published: November 2022

Background

Functional near-infrared spectroscopy (fNIRS) is a method to measure cerebral hemodynamics response. Changes in the prefrontal cortex during dual-tasking help to identify the risk of falling, particularly in older adults.

Aims

To systematically review and meta-analyze the effects of dual-task paradigms on cerebral hemodynamics in older adults.

Methods

The search was conducted in PubMed, Scopus, and Web of Science. A total of 22 studies comprising 1,841 older adults were included in the meta-analysis.

Results

Inhibitory control and working memory tasks significantly increased HbO2in the PFC by 0.54 (p< 0.01, 95%CI = 0.36 – 0.72) and 0.13 (p< 0.01, 95%CI = 0.08 – 0.18) μmol/L, respectively. Overall, HbO2was significantly increased during dual-task paradigms by 0.36 μmol/L (P< 0.01, 95%CI = 0.27 – 0.45). However, dual-task paradigms did not change HbR in the PFC (P= 0.14, 95%CI = -0.05 – 0.01).

Conclusion

Cognitive tasks related to inhibitory control required greater cognitive demands, indicating higher PFC activation during dual-task walking in older adults. This finding emphasizes the significance of assessing hemodynamic responses under dual-task paradigms to detect the risk of falling in older adults at an early stage.
Clinical Profiles of children born with Orofacial Clefts: Results from Fourteen East African Countries
Authors: Belachew Fitsum Kifle , Gerbu Desta Galcha , Weldesenbet Ermiyas Belay , Abay Eleleta Surafel , Maswime Salome , Eshete Mekonen
Published: November 2022

Background

More than 100,000 cleft lip and palate patients have benefited from reconstructive surgeries in Africa because of surgical support from non-governmental organizations such as Smile Train. The Smile Train Express is the largest cleft-centered patient registry with over a million records of clinical records, globally. In this study, we reviewed data from the east African patient registry to analyze and understand the clinical profiles of cleft lip and palate patients operated at Smile Train partner hospitals in East Africa.

Method

A retrospective database review was conducted in all East African cleft lip and palate surgeries documented in the Smile Train database from November 2001 to November 2019.

Results

86,683 patient records from 14 East African countries were included in this study. The mean age was 9.1 years, the mean weight was 20.2kg and 19kg for males and females, respectively, and 61.8% of the surgeries were performed on male patients. Left cleft lip only (n=22,548, 28.4 %) and right cleft lip only (n=17862, 22.5%) were the most common types of clefts, with bilateral cleft lip only (n= 5712, 7.2%) being the least frequent. Complete right cleft lip with complete right alveolus was the most frequent cleft combination observed (n = 16,385) and Cleft lip to cleft lip and palate to cleft palate ratio (CL:CLP: CP) was 6.7:3.3:1. Unilateral primary lip-nose repairs were the most common surgeries (69%). General anesthesia was used for 74.6 % (52847) of the procedures.

Conclusion

Most children with cleft lip and/or palate were underweight, possibly due to malnutrition or related to socioeconomic status. There were more male patients compared to females, which could be related to gender disparities. Access to surgical care for children born with congenital defects needs to be improved, and inequities need to be addressed via more evidence-based collaborative intervention strategies.

Highlights

- More than 80,000 patient records from fourteen East African countries were analyzed in this study to describe orofacial clefts.

- Orofacial clefts were found most commonly in males, accounting for over 62% of all cases.

- To improve cleft care in East Africa, there is a greater need for evidence-based implementation of programs, research collaboration, and data-centric advocacy efforts.
Incidence, predictors and cognitive dysfunction in post-traumatic epilepsy following a traumatic brain injury: A study protocol
Authors: Ngadimon Irma Wati , Shaikh Mohd. Farooq , Mohan Devi , Khoo Ching Soong , Cheong Wing Loong , Aledo-Serrano Angel
Published: November 2022

Approximately 69 million people worldwide are annually affected by traumatic brain injury (TBI). In Malaysia, the traumatic injury was the leading cause of hospital admission and death, accounting for one in three emergency visits. Among the most recognised complication of TBI is post-traumatic epilepsy (PTE), which is an essential contributor to morbidity and mortality. However, there is a lack of local epidemiological data on PTE in Malaysia. This study aims to describe the incidence and predictors of PTE among TBI patients admitted to a tertiary healthcare centre in Kuala Lumpur, Malaysia. We hypothesised that increases in age, race, and severity of brain injury are among the main potential predictors of PTE. It will also provide evidence that patients with epilepsy following TBI are associated with significant impairment in cognitive performance than TBI patients without epilepsy. An analysis of a two years retrospective cohort will be employed, of which adults with a history of admission for TBI in 2019 and 2020 will be contacted, and the development of epilepsy will be ascertained using a validated tool and confirmed by our neurologists during visits. The patients will then be grouped into two, with PTE and without PTE, and assessed their cognitive performance by clinical psychologists. Given that the management of TBI and PTE patients involves a multidisciplinary team, the findings might be significant to many healthcare providers in determining policy and strategise a better treatment.
A bi-functional PARP-HDAC inhibitor with activity in Ewing sarcoma
Authors: Ramos Louise , Truong Sarah , Zhai Beibei , Joshi Jay , Ghaidi Fariba , Lizardo Michael M. , Shyp Taras , Adomat Hans , Le Bihan Stephane , Collins Colin , Bacha Jeffrey , Brown Dennis , Langlands John , Shen Wang , Lallous Nada , Sorensen Poul H. , Daugaard Mads
Published: November 2022

HDAC inhibition has been shown to induce pharmacological BRCAness in cancer cells with proficient DNA repair activity. This provides a rationale for exploring combination treatments with HDAC and PARP inhibition in cancer types that are insensitive to single-agent PARP inhibitors. Here, we report the concept and characterization of a novel bifunctional PARP inhibitor (kt-3283) with dual activity towards PARP1/2 and HDAC enzymes in Ewing sarcoma cells. Compared to the FDA-approved PARP (olaparib) and HDAC (vorinostat) inhibitors, kt-3283 displayed enhanced cytotoxicity in Ewing sarcoma models. The kt-3283-induced cytotoxicity was associated with a strong S and G2/M cell cycle arrest in the nanomolar concentration range and elevated DNA damage as assessed by γH2AX tracking and comet assays. In three-dimensional spheroid models of Ewing sarcoma, kt-3283 showed efficacy in lower concentrations than olaparib and vorinostat and kt-3283 inhibited colonization of Ewing sarcoma cells in anex vivolung metastasis model. In summary, our data demonstrates the preclinical justification for studying the benefit of dual PARP and HDAC inhibition in the treatment of Ewing sarcoma in a clinical trial and provides proof-of-concept for a bi-functional single-molecule therapeutic strategy.
Pan-cancer analyses of the associations between 109 pre-existing conditions and cancer treatment patterns across 19 adult cancers
Authors: Chang Wai Hoong , Lai Alvina G.
Published: November 2022

Comorbidities present considerable challenges to cancer treatment and care. However, little is known about the effect of comorbidity on cancer treatment decisions across a wide range of cancer types and treatment modalities. Harnessing a cohort of 280,543 patients spanning 19 site-specific cancers, we explored pan-cancer frequencies of 109 comorbidities. Multinomial regression revealed that patients with comorbidity exhibited lower odds of receiving chemotherapy and multimodality treatment. End-stage renal disease was significantly associated with a decreased odds of receiving chemotherapy and surgery. Patients with prostate cancer who have comorbid non-acute cystitis, obstructive and reflux uropathy, urolithiasis, or hypertension were less likely to receive chemotherapy. Among patients with breast cancer, dementia, left bundle branch block, peripheral arterial disease, epilepsy, Barrett’s oesophagus, ischaemic stroke, unstable angina and asthma were associated with lower odds of receiving multimodal chemotherapy, radiotherapy and surgery. Comorbidity is also consistently associated with the lower odds of receiving chemotherapy when comparing across 10 drug classes. Patients with comorbid dementia, intracerebral haemorrhage, subarachnoid haemorrhage, oesophageal varices, liver fibrosis sclerosis and cirrhosis and secondary pulmonary hypertension were less likely to receive antimetabolites. Comorbidity can influence the effectiveness and tolerability of cancer treatment and ultimately, prognosis. Multi-specialty collaborative care is essential for the management of comorbidity during cancer treatment, including prophylactic measures to manage toxicities.
Single-spore germination analyses reveal that calcium released duringClostridioides difficilegermination functions in a feed-forward loop
Authors: Ribis John W. , Melo Luana , Shrestha Shailab , Giacalone David , Rodriguez Enrique E. , Shen Aimee , Rohlfing Amy
Published: November 2022

Clostridioides difficileinfections begin when its metabolically dormant spores germinate in response to sensing bile acid germinants alongside amino acid and divalent cation co-germinants in the small intestine. While bile acid germinants are essential forC. difficilespore germination, it is currently unclear whether both co-germinant signals are required. One model proposes that divalent cations, particularly Ca2+, are essential for inducing germination, while another proposes that either co-germinant class can induce germination. The former model is based on the finding that spores defective in releasing large stores of internal Ca2+in the form of calcium dipicolinic acid (CaDPA) cannot germinate when germination is induced with bile acid germinant and amino acid co-germinant alone. However, since the reduced optical density of CaDPA-less spores makes it difficult to accurately measure their germination, we developed a novel automated, time-lapse microscopy-based germination assay to analyze CaDPA mutant germination at the single-spore level. Using this assay, we found that CaDPA mutant spores germinate in the presence of amino acid co-germinant and bile acid germinant. Higher levels of amino acid co-germinants are nevertheless required to induce CaDPA mutant spores to germinate relative to WT spores because CaDPA released by WT spores during germination can function in a feedforward loop to potentiate the germination of other spores within the population. Collectively, these data indicate that Ca2+is not essential for inducingC. difficilespore germination because amino acid and Ca2+co-germinant signals are sensed by parallel signaling pathways.

Importance

Clostridioides difficilespore germination is essential for this major nosocomial pathogen to initiate infection.C. difficilespores germinate in response to sensing bile acid germinant signals alongside co-germinant signals. There are two classes of co-germinant signals: Ca2+and amino acids. Prior work suggested that Ca2+is essential forC. difficilespore germination based on bulk population analyses of germinating CaDPA mutant spores. Since these assays rely on optical density to measure spore germination and the optical density of CaDPA mutant spores is reduced relative to WT spores, this bulk assay is limited in its capacity to analyze germination. To overcome this limitation, we developed an automated image analysis pipeline to monitorC. difficilespore germination using time-lapse microscopy. With this analysis pipeline, we demonstrate that, although Ca2+is dispensable for inducingC. difficilespore germination, CaDPA can function in a feedforward loop to potentiate the germination of neighboring spores.
IL-11 disrupts alveolar epithelial progenitor function
Authors: Kortekaas Rosa K. , Geillinger-Kästle Kerstin E. , Borghuis Theo , Belharch Kaoutar , Webster Megan , Timens Wim , Burgess Janette K. , Gosens Reinoud
Published: November 2022

IL-11 is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF), since IL-11 induces myofibroblast differentiation and stimulates their excessive collagen deposition in the lung. The alveolar architecture is disrupted in IPF, yet the effect of IL-11 on dysregulated alveolar repair associated with IPF remains to be elucidated.

We hypothesized that epithelial-fibroblast communication associated with lung repair is disrupted by IL-11. Thus, we studied whether IL-11 affects the repair responses of alveolar lung epithelium using mouse lung organoids and precision cut lung slices (PCLS). Additionally, we assessed the anatomical distribution of IL-11 and IL-11 receptor in human control and IPF lungs using immunohistochemistry.

IL-11 protein was observed in human control lungs in airway epithelium, macrophages and in IPF lungs, in areas of AT2 cell hyperplasia. IL-11R staining was predominantly present in smooth muscle and macrophages. In mouse organoid co-cultures of epithelial cells with lung fibroblasts, IL-11 decreased organoid number and reduced the fraction of pro-SPC expressing organoids, indicating dysfunctional regeneration initiated by epithelial progenitors. In mouse PCLS alveolar marker gene expression declined, whereas airway markers were increased. The response of primary human fibroblasts to IL-11 on gene expression level was minimal, though bulk RNA-sequencing revealed IL-11 modulated a number of processes which may play a role in IPF, including unfolded protein response, glycolysis and Notch signaling.

In conclusion, IL-11 disrupts alveolar epithelial regeneration by inhibiting progenitor activation and suppressing the formation of mature alveolar epithelial cells. The contribution of dysregulated fibroblast – epithelial communication to this process appears to be limited.
A mitochondrial SCF-FBXL4 ubiquitin E3 ligase complex restrains excessive mitophagy to prevent mitochondrial disease
Authors: Cao Yu , Zheng Jing , Wan Huayun , Sun Yuqiu , Fu Song , Liu Shanshan , He Baiyu , Cai Gaihong , Cao Yang , Huang Huanwei , Li Qi , Ma Yan , Chen She , Wang Fengchao , Jiang Hui
Published: November 2022

Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here via a mitochondria-targeted screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation.Fbxl4−/−mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of eitherBnip3orNixrescues metabolic derangements and viability of theFbxl4−/−mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.
Silc1 long noncoding RNA is an immediate-early gene promoting efficient memory formation
Authors: Perry Rotem Ben-Tov , Tsoory Michael , Tolmasov Michael , Ulitsky Igor
Published: November 2022

Long noncoding RNAs (lncRNAs) are expressed in many brain circuits and neuronal types, but their significance to normal brain functions has remained largely unknown. Here, we study the functions in the central nervous system ofSilc1, a lncRNA we previously showed to be important for neuroregeneration in the peripheral nervous system. We found thatSilc1is rapidly and strongly induced upon stimulation in the hippocampus and is required for efficient spatial learning.Silc1production is important for the induction ofSox11(its cis-regulated target gene) throughout the CA1-CA3 regions and the proper expression of keySox11target genes. Consistent with its newly found role in neuronal plasticity, we find that during aging and in models of Alzheimer’s diseaseSilc1levels decline. Overall, we uncover a novel plasticity pathway, in whichSilc1acts as an immediate-early gene to activateSox11to induce a neuronal growth-associated transcriptional program important for memory formation.
A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein
Authors: Thijssen Vito , Hurdiss Daniel L. , Debski-Antoniak Oliver J. , Spence Matthew A. , Franck Charlotte , Norman Alexander , Aggarwal Anupriya , Mokiem Nadia J. , van Dongen David A. A. , Vermeir Stein W. , Liu Minglong , Li Wentao , Chatziandreou Marianthi , Donselaar Tim , Du Wenjuan , Drulyte Ieva , Bosch Berend-Jan , Snijder Joost , Turville Stuart , Payne Richard J. , Jackson Colin J. , van Kuppeveld Frank J. M. , Jongkees Seino A. K.
Published: November 2022

The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 Wuhan strain infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor binding domain, N-terminal domain and S2 region, distal to the ACE2 receptor-interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially other drug-like molecules can target.

Significance statement

This study reports on the discovery of a macrocyclic peptide that is able to inhibit SARS-CoV-2 infection by exploiting a new vulnerable site in the spike glycoprotein. This region is highly conserved across SARS-CoV-2 variants and the subgenus sarbecovirus. Due to the inaccessability and mutational contraint of this site, it is anticipated to be resistant to the development of resistance through antibody selective pressure. In addition to the discovery of a new molecule for development of potential new peptide or biomolecule therapeutics, the discovery of this broadly active conserved site can also stimulate a new direction of drug development, which together may prevent future outbreaks of related viruses.
The circular RNA Ataxia-telangiectasia mutated (cATM) regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms
Authors: Fasolo F. , Winski G. , Li Z. , Wu Z. , Winter H. , Glukha N. , Roy J. , Hultgren R. , Pauli J. , Busch A. , Sachs N. , Knappich C. , Eckstein H.H. , Boon R.A. , Paloschi V. , Maegdefessel L.
Published: November 2022

An abdominal aortic aneurysm (AAA) is a pathological widening of the aortic wall characterized by loss of smooth muscle cells (SMCs), extracellular matrix degradation, and local inflammation. This condition is often asymptomatic until rupture occurs, leading to high morbidity and mortality rates. Diagnosis is often accidental, and for now, the only available treatment option remains surgical intervention. Circular RNAs (circRNAs) are RNA loops that originated from backsplicing, which have received increasing attention as a novel class of functional non-coding RNAs contributing to cardiovascular physiology and disease. Their high structural stability, combined with a remarkable enrichment in body fluids, make circRNAs promising disease biomarkers. We aimed to investigate the contribution of circRNAs to AAA pathogenesis and their potential application as biomarkers for AAA diagnosis. Combined circRNA array and quantitative real-time PCR analysis revealed the presence of differentially expressed circular transcripts stemming from AAA-relevant geneloci. Among these, the circRNA to the Ataxia-telangiectasia mutated gene (cATM) was upregulated in human AAA tissue specimens, in AAA patient-derived SMCs, and serum samples collected from aneurysm patients. In control primary aortic SMCs, cATMincreased upon angiotensin II stimulation, while its silencing triggered apoptosis. Furthermore, doxorubicin could induce cATM expression, supporting a link with acute stress response in SMCs. Constitutively higher cATMexpressing AAA patient-derived SMCs were less vulnerable to oxidative stress-induced cell death and survival pathways enriched when compared to control SMCs. Taken together, this data supports the role ofcATMin adapting SMCs to oxidative stress in the vascular AAA micromilieu. This molecular signature provides an additional parameter to be included in procedures for AAA screening in combination with already established practices.
Defining transcription factor nucleosome binding with Pioneer-seq
Authors: Tsompana Maria , Wilson Patrick D. , Murugaiyan Vijaya , Handelmann Christopher R. , Buck Michael J.
Published: November 2022

Gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. To comprehensively examine TF nucleosome binding, we developed Pioneer-Seq. In Pioneer-seq a library of nucleosomes containing thousands of DNA sequences with TF binding sites in all possible nucleosome orientations is bound to a TF and the protein-nucleosome complex is isolated and quantified. To demonstrate Pioneer-seq we examined nucleosome binding by OCT4, SOX2, KLF4, and c-MYC. Our results demonstrate that KLF4 and SOX2 can bind close to the nucleosome dyad with nucleosome sequence being the major factor regulating TF binding across all studied TFs.
Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfβ superfamily
Authors: Berková Linda , Fazilaty Hassan , Yang Qiutan , Kubovčiak Jan , Stastna Monika , Hrckulak Dusan , Vojtechova Martina , Brügger Michael David , Hausmann George , Liberali Prisca , Korinek Vladimir , Basler Konrad , Valenta Tomas
Published: November 2022

The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes in the villi. The differentiation of enterocytes is orchestrated by sub-epithelial mesenchymal cells producing distinct ligands along the villus axis, in particular Bmps and Tgfβ. Here we show that individual Bmp ligands and Tgfβ drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed mainly from the center to the upper part of the villus, and it activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus-tip mesenchymal cells, and it influences the adhesive properties of villus-tip epithelial cells and the expression of immunomodulators. Hence, Bmp2 promotes the terminal enterocytic differentiation at the villus-tip. Additionally, Tgfβ induces epithelial gene expression programs similar to that triggered by Bmp2. The inhibition of Bmp receptor type Iin vivoand using intestinal organoids lacking Smad4 revealed that Bmp2-driven villus-tip program is activated by a canonical Smad-dependent mechanism. Finally, we established an organoid cultivation system that enriches for villus-tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Altogether our data suggest that not only Bmp gradient, but also the activity of individual Bmp drives specific enterocytic programs.
Dynamic Reassociation of the Nuclear Lamina with Newly Replicated DNA
Authors: Lovejoy Callie M. , Nagarajan Prabakaran , Parthun Mark R.
Published: November 2022

The physical association of specific regions of chromatin with components of the nuclear lamina provides the framework for the 3-dimensionl architecture of the genome. The regulation of these interactions plays a critical role in the maintenance of gene expression patterns and cell identity. The breakdown and reassembly of the nuclear membrane as cells transit mitosis plays a central role in the regulation of the interactions between the genome and the nuclear lamina. However, other nuclear processes, such as transcription, have emerged as regulators of the association of DNA with the nuclear lamina. To determine whether DNA replication also has the potential to regulate DNA-nuclear lamina interactions, we adapted proximity ligation-based chromatin assembly assays to analyze the dynamics of nuclear lamina association with newly replicated DNA. We observe that lamin A/C and lamin B, as well as inner nuclear membrane proteins LBR and emerin, are found in proximity to newly replicated DNA. While core histones rapidly reassociate with DNA following passage of the replication fork, the complete reassociation of nuclear lamina components with newly replicated DNA occurs over a period of approximately 30 minutes. We propose models to describe the disassembly and reassembly of nascent chromatin with the nuclear lamina.
Tautomer-specific deacylation and Ω-loop flexibility explain carbapenem-hydrolyzing, broad-spectrum activity of the KPC-2 β-lactamase
Authors: Tooke Catherine L. , Hinchliffe Philip , Beer Michael , Zinovjev Kirill , Colenso Charlotte K. , Schofield Christopher J. , Mulholland Adrian J. , Spencer James
Published: November 2022

KPC-2 (Klebsiella pneumoniaecarbapenemase-2) is a globally disseminated serine-β-lactamase (SBL) responsible for extensive β-lactam antibiotic resistance in Gram-negative pathogens. SBLs inactivate β-lactams via a mechanism involving a hydrolytically labile covalent acyl-enzyme intermediate. Carbapenems, the most potent β-lactams, evade activity of many SBLs by forming long-lived inhibitory acyl-enzymes; however, carbapenemases such as KPC-2 efficiently catalyze deacylation of carbapenem-derived acyl-enzymes. We present high-resolution (1.25-1.4 Å) crystal structures of KPC-2 acyl-enzymes with representative penicillins (ampicillin), cephalosporins (cefalothin) and carbapenems (imipenem, meropenem and ertapenem), obtained utilizing an isosteric deacylation-deficient mutant (E166Q). Mobility of the Ω-loop (residues 165–170) negatively correlates with antibiotic turnover rates (kcat), highlighting the role of this region in positioning catalytic residues for efficient hydrolysis of different β-lactams. Carbapenem-derived acyl-enzyme structures reveal predominance of the Δ1-(2R) imine tautomer, except for the imipenem acyl-enzyme, which is present in dual occupancy in both Δ1-(2R) and (2S) configurations. Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations of deacylation of the KPC-2:meropenem acyl-enzyme, using an adaptive string method (ASM), show that the Δ1-(2R) isomer has a 7 kcal/mol higher barrier for the (rate-determining) formation of the tetrahedral deacylation intermediate than the Δ2 tautomer. The simulations identify tautomer-specific differences in hydrogen bonding networks involving the carbapenem C-3 carboxylate and the deacylating water, that, together with stabilization by protonated N-4 of accumulating negative charge during oxyanion formation, accelerate deacylation of the Δ2-enamine acyl-enzyme compared to the Δ1-imine. Taken together, our data show how the flexible Ω-loop helps confer broad spectrum activity upon KPC-2, while carbapenemase activity stems from efficient deacylation of the Δ2-enamine acyl-enzyme tautomer. Differentiation of the barriers associated with deacylation of these subtly different β-lactam isomers further identifies ASM as a sensitive method for calculation of reaction energetics that can accurately model turnover and, potentially, predict the impact of substrate modifications or point mutations upon activity.
Parallel Activation of Src and Hif1α Increases Localized Glycolytic ATP Generation for Re-assembly of Endothelial Adherens Junctions
Authors: Wang Li , Gajwani Priyanka , Chaturvedi Pallavi , Hong Zhigang , Ye Zijing , Schwarz Gregory J. , Pohl-Avila Nicole M. , Ray Anne-Marie , Krantz Sarah , Toth Peter T , Leckband Deborah E. , Karginov Andrei , Rehman Jalees
Published: November 2022

Endothelial adherens junctions (AJs) are critical for the regulation of vascular barrier integrity and undergo dis-assembly during inflammatory injury, thus causing vascular leakiness. AJ re-assembly is thus necessary for restoration of the endothelial barrier following the initial injury. Here we examine the metabolic underpinnings that drive restoration of vascular integrity. In response to inflammatory stimuli, the glycolysis regulatory enzyme PFKFB3 is activated, resulting in a rapid and sustained increase of intracellular glycolytic ATP, especially in the proximity of AJs at the plasma membrane. We engineered a novel chemo-genetic construct (RapT) which allowed for precise temporal control of PFKFB3 recruitment to the plasma membrane. Activation of RapT by rapamycin during the barrier restoration phase increased regional ATP and accelerated AJ re-assembly. Mechanistically, we observed that PFKFB3 is activated through two modes. Src-mediated post-translational phosphorylation rapidly increases PFKFB3 activity. Using another chemo-genetic approach to temporally control Src activity, we found that Src activates PFKFB3 by binding to and phosphorylating it at residues Y175, Y334, and Y363. Tyrosine-phospho-deficient mutants of PFKFB3 at these residues block the glycolytic activation upon inflammatory stimuli. In parallel, elevated reactive oxygen species generated during inflammatory stimulation create pockets of regional hypoxia and allow for increased Hif1α-mediated transcription of PFKFB3, leading to sustained glycolytic activation. Moreover, inhibition of PFKFB3 delays AJ reassembly and restoration of vascular integrity both in vitro and in vivo. In conclusion, we show that while inflammatory activation acutely compromises the endothelial barrier, inflammatory signaling also concomitantly generates a metabolic milieu in anticipation of the subsequent re-assembly of AJs and restoration of the vascular barrier.
High-throughput tagging of endogenous loci for rapid characterization of protein function
Authors: Kim Joonwon , Kratz Alexander F. , Chen Shiye , Sheng Jenny , Zhang Liudeng , Singh Brijesh Kumar , Chavez Alejandro
Published: November 2022

To facilitate the interrogation of protein function at scale, we have developed High-throughput Insertion of Tags Across the Genome (HITAG). HITAG enables users to rapidly produce libraries of cells, each with a different protein of interest C-terminally tagged is based on a modified strategy for performing Cas9-based targeted insertions, coupled with an improved approach for selecting properly tagged lines. Analysis of the resulting clones generated by HITAG reveals high tagging specificity with the majority of tagging events being indel free. Using HITAG, we fuse mCherry to a set of 167 stress granule-associated proteins and elucidate the features which drive a subset of proteins to strongly accumulate within these transient RNA-protein granules.
Traction force reconstruction assessment on real three-dimensional matrices and cellular morphologies
Authors: Apolinar-Fernández Alejandro , Barrasa-Fano Jorge , Cóndor Mar , Van Oosterwyck Hans , A. Sanz-Herrera José
Published: November 2022

Traction force microscopy (TFM) allows to estimate tractions on the surface of cells when they mechanically interact with hydrogel substrates that mimic the extracellular matrix (ECM). The field of mechanobiology has a strong interest in using TFM in 3D in vitro models. However, there are a number of challenges that hamper the accuracy of 3D TFM and that are often bypassed. In this study, the computational efficiency and accuracy of TFM, referred to traction reconstruction from synthetically generated (control) ground truth solutions, are assessed from four different perspectives: magnitude of cellular pulling force (and hence strain level achieved in the hydrogel), effect of the complexity of the cellular morphology, accuracy and computational efficiency of forward vs inverse traction recovery methods, and the effect of incorrectly selecting a constitutive model that describes the behavior of the ECM (i.e. linear/nonlinear). The main results showed: (i) traction reconstruction is more challenging for complex cell morphologies, (ii) there is no significant impact of the magnitude of cellular pulling force on the overall reconstruction accuracy, and (iii) modeling a nonlinear hydrogel with a linear constitutive model leads to non-negligible errors (up to 80% and 30% for forward and inverse methodologies, respectively) in traction reconstruction. This study expands the characterization of the accuracy and efficiency of 3D TFM, highlighting important factors to be considered in future 3D TFM in vitro applications.
Amino acid intake strategies define pluripotent cell states
Authors: Todorova Pavlina K. , Jackson Benjamin T. , Garg Vidur , Paras Katrina I. , Chen Yanyang , Baksh Sanjeethan C. , Yan Jielin , Hadjantonakis Anna-Katerina , Finley Lydia W. S.
Published: November 2022

Mammalian pre-implantation development is associated with striking metabolic robustness, as embryos can develop in a wide variety of nutrient conditions including even the complete absence of soluble amino acids. Here, we show that mouse embryonic stem cells (ESCs) capture the unique metabolic state of pre-implantation embryos and proliferate in the absence of several essential amino acids. Amino acid independence is enabled by constitutive uptake of exogenous protein through macropinocytosis alongside a robust lysosomal digestive system. Upon transition to more committed states, ESCs reduce digestion of extracellular protein and instead become reliant upon exogenous amino acids. Accordingly, amino acid withdrawal selects for ESCs that mimic the pre-implantation epiblast. More broadly, we find that all lineages of the pre-implantation blastocysts exhibit constitutive macropinocytotic protein uptake and digestion. Together, these results highlight exogenous protein uptake and digestion as an intrinsic feature of pre-implantation development and provide insight into the catabolic strategies that enable embryos to sustain viability prior to implantation.
Oscillatory brain networks in continuous speaking and listening
Authors: Abbasi Omid , Steingräber Nadine , Chalas Nikos , Kluger Daniel S. , Gross Joachim
Published: November 2022

Speech production and perception are fundamental processes of human cognition that both rely on an internal forward model that is still poorly understood. Here, we study this forward model by using Magnetoencephalography (MEG) to comprehensively map connectivity of regional brain activity within the brain and to the speech envelope during continuous speaking and listening. Our results reveal a partly shared neural substrate for both processes but also a dissociation in space, delay and frequency. Neural activity in motor and frontal areas is coupled to succeeding speech in delta band (1-3 Hz), whereas coupling in the theta range follows speech in temporal areas during speaking. Neural connectivity results showed a separation of bottom-up and top-down signalling in distinct frequency bands during speaking. Here, we show that frequency-specific connectivity channels for bottom-up and top-down signalling support continuous speaking and listening in a way that is consistent with the predictive coding framework.
Mapping the effect of healthy and unhealthy food and beverages marketing: two decades of bibliometric analysis
Authors: Sharma Yukti , Silal Prakrit
Published: November 2022

Purpose

With multiple theoretical traditions, diverse topical landscape and rapid regulatory advancements galvanising the ongoing discourse, the emergent marketing scholarship on healthy and unhealthy food and beverages (F&B) has become exhaustive, fragmented and almost non-navigable. Accordingly, this study aims to synthesise and trace two decades of research focused on healthy and unhealthy F&B marketing.

Design/methodology/approach

This study conducts a bibliometric analysis of papers published between 2000 and 2020. The data was retrieved from Web of Science (WoS) and Scopus, yielding 338 papers for final analysis. Using VOSviewer software and the Biblioshiny package, the authors performed a detailed bibliometric analysis comprising performance analysis and science mapping.

Findings

The study delineated the contribution, theoretical and thematic structure of healthy and unhealthy F&B marketing scholarship. The authors also mapped the evolution trajectory of the thematic structure, which helped us contemplate the research gaps.

Research limitations/implications

By delving deeper into the “who”, “where”, “how”, “what” and “when” of healthy and unhealthy F&B marketing, the study enhances the current understandings and future developments for both theorists and practitioners. However, the selection of literature is confined to peer-reviewed papers available in WoS and Scopus.

Practical implications

The findings delineate the existing scholarship which could guide F&B marketers and policymakers towards designing consumer-centric marketing/policy interventions.

Originality/value

To the best of the authors’ knowledge, this study is the first to perform a bibliometric analysis of healthy and unhealthy F&B marketing, likely to provide valuable guidelines for future scholars, policymakers and practitioners.
Gender managerial obstacles in private organizations: the UAE case
Authors: Mahdi Abaker Mohamed Osman Shereif , Patterson Helen Louise , Cho Boo Yun
Published: November 2022

Purpose

The purpose of this study is to report empirical research on gender managerial obstacles in UAE private organizations. It identifies the barriers that limit opportunities for gender equality promotion in managerial level positions.

Design/methodology/approach

Primary data were gathered from 384 female managers operating in UAE organizations using Survey Monkey and ANOVA for statistical analysis. Two variables (years of experience and industry) were used to compare the average means across the responses and the differences among the group.

Findings

The situation of gender equality in UAE management currently shows a positive trend. The females who participated in the survey have considerable work experience and jobs in a vital economic sector of the UAE industry. The earlier cultural stereotypes that worked against the interests of women in the UAE society are no longer relevant except for informal barriers and the level of cooperation among female leaders. We found differences among industry, service and transportation sectors in which gender managerial level in a private industry is dependent upon the number of years of experience for female managers.

Research limitations/implications

The limitation of the study is the online survey was affected by the COVID-19 pandemic during the lockdown period in the spring of 2020, which led to a low number of participants responding to the questionnaire. Additionally, the survey did not include a nationality question to distinguish Emiratis from non-Emirati.

Social implications

This study indicates a need to coordinate UAE female leaders' actions to protect their rights, develop formal and informal mechanisms of gender inequality realization in business and promote professional skills, orientation on social networks, and mentoring programs for female leaders. These initiatives improve the positions of female leaders.

Originality/value

The study of the UAE case adds to the existing literature on gender studies because the survey-based research in the UAE context contributes to the limited knowledge of Middle Eastern countries. The females’ employment and their representation in managerial levels remain lower compared to males. Differences exist among the industry, service and transportation sectors.
Applied personal profile ontology for personnel appraisals
Authors: Usip Patience Usoro , Udo Edward N. , Umoeka Ini J.
Published: November 2022

Purpose

The purpose of this paper is to apply the earlier enhanced personal profile ontology (e-PPO) developed by the authors as a case study for the appraisal of the lecturers in the department of computer science, University of Uyo, Uyo for the purposes of promotions. The developed e-PPO was a sample smart résumé for the selection of the best among three personnel using linguistic variables and formal rules representing the combination of the criteria and subcriteria was illustrated which was used to allocate competent personnel for software requirement engineering tasks. The need for the use of the smart resume for appraisal purposes was pointed out in the conference paper, calling for the applicant’s data to be inputted into the enhanced personal profile ontology (e-PPO) for personnel appraisa.

Design/methodology/approach

Appraisal is a regular review of employees’ performances and their overall contribution to the organization they are working for. The availability of a web application for personnel appraisal requires PPO which includes both static and dynamic features. Personal profile is often modified for several purposes calling for augmentation and annotation when needs arise. Resume is one resulting extract from personal profile and often contain slightly different information based on needs. The urgent preparation of resume may introduce bias and incorrect information for the sole aim of projecting the personnel as being qualified for the available job. Religious and gender biases may sometimes be observed during appointments of new personnel, which may not be the case during appraisals for promotions or reassignment of tasks because such biases become insignificant given the fact that job targets and the skills needed are already set and the appraisals passes through several phases that are not determined by a single individual. This work therefore applied the earlier developed e-PPO for appraisal of the academic staff of the department of computer science, university of Uyo, Uyo, Nigeria. A mixed approach of existing ontologies like Methontology and Neon have been followed in the creation of the e-PPO, which is a constraint-based semantic data model tested using Protégé inbuilt reasoner with its updated plugins. Upon application of e-PPO on personnel appraisals, promotion and selection of employee for specific assignments in any organization is possible using the smart resume.

Findings

The use of the smart resume reduces the numerous task that would have been taken up by the human resource team, thereby reducing the processing time for the appraisals. The appraisal task is done void of biases of any kind such as gender and religion.

Originality/value

This work is an extension of the original work done by the authors.
Critical success factors of implementing sustainable and responsible investment (SRI) Sukuk for economic recovery from COVID-19 pandemic
Authors: Marwan Syed , Ismail Suhaiza , Mohamed Haneef Mohamed Aslam , Engku Ali Engku Rabiah Adawiah
Published: November 2022

Purpose

There are three objectives of this paper. First, the study investigates the critical success factors critical success factors (CSFs) of implementing sustainable and responsible investment (SRI) Sukuk in Malaysia as perceived by stakeholders. Second, the study examines the differences between the developers and the investors in relation to the importance of the CSFs. Third, the study attempts to categorise the CSFs.

Design/methodology/approach

Using a questionnaire survey, 260 completed and useable responses were received representing a 42.54% response rate. In examining the importance of CSFs, the descriptive statistical tests of mean, standard deviation and mean score ranking were used. Independent t-tests were conducted to investigate the differences in the perceptions of the importance of CSFs between the developer and the investor groups. In categorising the CSFs, exploratory factor analysis (EFA) was undertaken.

Findings

Overall, the top five most important CSFs as perceived by respondents are as follows: (1) good governance framework, (2) fulfil ethical standards, (3) transparent procurement process, (4) well-defined scope and (5) viable feasibility study. On the other hand, the five factors that are ranked last are as follows: (1) defined stakeholder roles, (2) stable macro-economic conditions, (3) existing social programmes, (4) guarantor and (5) political will. The study also found that there is a significant statistical difference in how the developers and investors scored the CSFs. Moreover, there are three main categories of the CSFs that are effective feasibility study, financial and technical considerations and political willingness and agreeability.

Originality/value

The findings highlight the critical factors to consider when implementing SRI Sukuk. This can also serve as a reference and guideline for countries considering SRI Sukuk issuances for economic recovery stimulus post-coronavirus disease 2019 (COVID-19) pandemic.
Assessing non-linear effects of government size on inflation in India: recent evidence from smooth transition autoregression model
Authors: Tariq Asif , Ahmad Masroor , Amin Aadil
Published: November 2022

Purpose

Standard economic theory predicts that any increase in public spending is accompanied by a rise in inflation in an economy. This paper presents empirical proof that prices do not always rise with an increase in public expenditure but only up to a certain threshold level. The primary aim of this paper is to unearth the government size-inflation nexus in India for the period from 1971 to 2019.

Design/methodology/approach

The logistic STAR (smooth transition autoregression) model is employed to unravel the government size-inflation nexus for the Indian economy from a non-linear perspective.

Findings

The finding of our study confirm the non-linear relationship between the size of the government and inflation in India. The estimated threshold level for government size is precisely found to be 9.27%. The size of the government exerts a negative influence on inflation until it reaches the optimal or threshold level. Any further increase in the size of government beyond this threshold level would result in a rise in inflation.

Research limitations/implications

The findings have implications for the conduct of fiscal policy. Policymakers can increase government spending in a regime of small government size without having any inflationary impacts by generating revenues from taxes and other sources instead of relying much on the central bank. In the regime of a large-sized government, adhering strictly to the discipline in the conduct of fiscal and monetary policies would help curb inflation and enhance growth synchronously, hence alleviating any loss of welfare.

Originality/value

To the best of the authors’ knowledge, this study is an attempt to revisit the government size-inflation nexus in India from a non-linear perspective using the Smooth Transition Autoregression (STAR) model for the first time.