bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Particular SORL1 Micro-haplotype May Prevent Severe Liver Disease in a French Cohort of Alpha 1-Antitrypsin-deficient Children
Authors: Joly Philippe , Ruiz Mathias , Garin Roman , Karatas Esra , Lachaux Alain , Restier Lioara , Belmalih Abdelouahed , Renoux Céline , Lombard Christine , Dechomet Magali , Bouchecareilh Marion 
Published: March 2021

ABSTRACT
The presence of modifier genes is now well recognized in severe liver disease outcome associated with alpha-1-antitrypsin deficiency (A1ATD) but their identification remains to be fully elucidated. To address this goal, we performed a candidate gene study with the SORL1 gene, already identified as risk gene in early-onset Alzheimer Disease families. A particular SORL1 micro-haplotype constituted with 3 SNPs (wild-type form TTG) was genotyped on 86 ZZ A1ATD children issued from 66 families. Interestingly, the mutated forms of this micro-haplotype (CAT most of the time) were associated with lower occurrence of severe liver disease and in cellulo studies showed that SORL1 influences Z-A1ATD cellular toxicity and biogenesis. These data suggest that the mutated CAT form of SORL1 micro-haplotype may partly prevent from severe liver disease in A1ATD children. Overall, these findings support a replication study on an independent cohort and additional in cellulo studies to confirm these promising results.
Impaction fractures of the anterior tibial plafond
Authors: Chohan Moaz B.Y. , Del Balso Christopher , Ching Michael , Schemitsch Emil , Lawendy Abdel Rahman , Sanders David W. 
Published: March 2021

Abstract

Objectives:
To determine whether patients with AO/OTA 43-B anterior impaction tibial plafond fractures have worse clinical outcomes, and an increased risk of progression to ankle arthrodesis.

Design:
Retrospective cohort study.

Setting:
Level 1 academic trauma center.

Patients:
One hundred sixty-eight patients were included in the study, all of whom had tibial plafond fractures.

Intervention:
Study patients underwent external fixation and/or open reduction internal fixation (ORIF) as indicated by fracture/injury pattern.

Main outcome measurements:
Arthrodesis rate.

Results:
AO 43-B Anterior impaction tibial plafond fractures have an increased risk of progression to arthrodesis when compared to AO 43-B nonanterior impaction type fractures (19.4% vs 8%).

Conclusions:
AO 43-B anterior impaction tibial plafond fractures have a worse clinical outcome compared to AO 43-B nonanterior impaction fractures. These fractures also confer increased risk of progression to arthrodesis.

Conflicts of interest
The authors have no conflict of interests to declare.
Factors associating with surgical site infection following operative management of malleolar fractures at an urban level 1 trauma center
Authors: Rascoe Alexander S. , Kavanagh Michael D. , Audet Megan A. , Hu Emily , Vallier Heather A. 
Published: March 2021

Abstract

Objectives:
To identify comorbidities and injury characteristics associated with surgical site infection (SSI) following internal fixation of malleolar fractures in an urban level 1 trauma setting.

Design:
Retrospective.

Setting:
Level 1 trauma center.

Patients/Participants:
Seven-hundred seventy-six consecutive patients with operatively managed malleolar fractures from 2006 to 2016.

Intervention:
Open reduction internal fixation.

Main Outcome Measurements:
Superficial SSI (erythema and drainage treated with oral antibiotics and wound care) or deep SSI (treated with surgical debridement and antibiotics).

Results:
Fifty-six (7.2%) patients developed SSI, with 17 (30%) of these being deep infections. An a-priori power analysis of n = 325 (α=0.05, β=0.2) was tabulated for differences in univariate analysis. Univariate analysis identified categorical associations (P < .05) between SSI and diabetes mellitus, drug abuse, open fracture, and renal disease but not tobacco abuse, body mass index, or neuropathy. Multivariate logistic regression identified categorical associations between diabetes (OR = 2.2, 95% CI: 1.1–4.3), drug abuse (OR = 3.9, 95% CI: 1.2–12.7), open fracture (OR = 4.1, 95% CI: 1.3–12.8), and renal disease (OR = 2.7, 95% CI: 1.4–5.0) and any (superficial or deep) SSI. A separate multivariate logistic regression analysis found categorical associations between deep SSI requiring reoperation and diabetes (OR = 4.4, 95% CI: 1.6–12.2) and open fracture (OR = 4.1, 95% CI: 1.3–12.8). Furthermore, American society of anesthesiologists classification (ASA) Class 4 patients were (OR = 9.2, 95% CI: 2.0–41.79) more likely to experience an SSI than ASA Class 1 patients.

Conclusions:
Factors associated with SSI following malleolar fracture surgery in a single urban level 1 trauma center included diabetes, drug abuse, renal disease, and open fracture. The presence of diabetes or open type fractures were associated with deep SSI requiring reoperation.

Level of Evidence:
Level 3 prognostic: retrospective cohort study.
Neurobiology of SARS-CoV-2 interactions with the peripheral nervous system: implications for COVID-19 and pain
Authors: McFarland Amelia J. , Yousuf Muhammad S. , Shiers Stephanie , Price Theodore J. 
Published: March 2021

Abstract
SARS-CoV-2 is a novel coronavirus that infects cells through the angiotensin-converting enzyme 2 receptor, aided by proteases that prime the spike protein of the virus to enhance cellular entry. Neuropilin 1 and 2 (NRP1 and NRP2) act as additional viral entry factors. SARS-CoV-2 infection causes COVID-19 disease. There is now strong evidence for neurological impacts of COVID-19, with pain as an important symptom, both in the acute phase of the disease and at later stages that are colloquially referred to as “long COVID.” In this narrative review, we discuss how COVID-19 may interact with the peripheral nervous system to cause pain in the early and late stages of the disease. We begin with a review of the state of the science on how viruses cause pain through direct and indirect interactions with nociceptors. We then cover what we currently know about how the unique cytokine profiles of moderate and severe COVID-19 may drive plasticity in nociceptors to promote pain and worsen existing pain states. Finally, we review evidence for direct infection of nociceptors by SARS-CoV-2 and the implications of this potential neurotropism. The state of the science points to multiple potential mechanisms through which COVID-19 could induce changes in nociceptor excitability that would be expected to promote pain, induce neuropathies, and worsen existing pain states.
Integrative analyses identify potential key genes and pathways in Keshan disease using whole-exome sequencing
Authors: Huang Jichang , Zheng Chenqing , Luo Rong , Liu Mingjiang , Gu Qingquan , Li Jinshu , Wu Xiushan , Yang Zhenglin , Shen Xia , Li Xiaoping 
Published: March 2021

AbstractKeshan disease (KD), an endemic heart disease with multifocal necrosis and replacement fibrosis of the myocardium,is still a nightmare situation for human health. However, molecular mechanism in the pathogenesis of KD remains unclear. Herein, blood samples were collected from 68 KD patients and 100 controls, and we systematically analyzed mutation profiles using whole-exome sequencing (WES). Causative genes of dilated cardiomyopathy (DCM), gene-based burden analysis, disease and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. Of the 98 DCM-causative genes, 106 rare variants in 28 genes were detected in KD patients with minor allele frequency (MAF) < 0.001. Gene-based burden analysis, PPI network analysis, and automated Phenolyzer analysis were performed to prioritize 199 candidate genes, which combined with 98 DCM-causative genes, and reference genes from gene microarray or proteomics in KD. Then, 19 candidate pathogenic genes were selected, and 9 candidate genes were identified using PPI analysis, including HIF1A, GART, ALAD, VCL, DTNA, NEXN, INPPL1, NOS3, and JAK2. The 199 candidate genes were further analyzed using disease enrichment with CTD database and PPI analysis, and 21 candidate genes were identified. By combining with disease enrichment and PPI analysis, 7 Selenium (Se)-related genes were further identified, including ALAD, RBM10, GSN, GGT1, ADD1, PARP1, and NOS3. Based on the gene function and data validation, NEXN, TAF1C, FUT4, ALAD, ZNF608, and STX2 were the most likely pathogenic genes in KD. Notably, ALAD is the only candidate pathogenic gene identified by four different analyses, and its homozygous mutant mice could affect heart development and cause death.
A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection
Authors: Hassler Luise , Wysocki Jan , Gelarden Ian , Tomatsidou Anastasia , Gula Haley , Nicoleascu Vlad , Randall Glenn , Henkin Jack , Yeldandi Anjana , Batlle Daniel 
Published: March 2021

AbstractSevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2), which is membrane bound, as its initial cell contact receptor preceding viral entry. Here we report a human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) and bridged via a dimerization motif hinge-like 4-cysteine dodecapeptide, which we term ACE2 1-618-DDC-ABD. This protein is enzymatically active, has increased duration of action in vivo conferred by the ABD-tag, and displays 20-30-fold higher binding affinity to the SARS-CoV-2 receptor binding domain than its des-DDC monomeric form (ACE2 1-618-ABD) due to DDC-linked dimerization. ACE2 1-618-DDC-ABD was administered for 3 consecutive days to transgenic k18-hACE2 mice, a model that develops lethal SARS-CoV-2 infection, to evaluate the preclinical preventative/ therapeutic value for COVID-19. Mice treated with ACE2 1-618-DDC-ABD developed a mild to moderate disease for the first few days assessed by a clinical score and modest weight loss. The untreated control animals, by contrast, became severely ill and had to be sacrificed by day 6/7 and lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates. At 6 days, mortality was totally prevented in the treated group, lung histopathology was improved and viral titers markedly reduced. This demonstrates for the first time in vivo the preventative/ therapeutic potential of a novel soluble ACE2 protein in a preclinical animal model.
Cryo-EM structure of an elusive pre-transport intermediate of the multidrug ABC transporter BmrCD reveals modes of asymmetric drug binding
Authors: Thaker Tarjani M. , Mishra Smriti , Zhou Wenchang , Faraldo-Gomez Jose D. , Mchaourab Hassane S. , Tomasiak Thomas M. 
Published: March 2021

ABSTRACTVectorial substrate efflux by ATP binding cassette (ABC) transporters, which play a major role in multidrug resistance, entails the ATP-powered interconversion of the transporter between stable intermediates. Despite recent progress in structure elucidation of ABC transporters, a number of such intermediates have yet to be visualized and mechanistically interpreted. Here, we combine single particle cryo-EM, Double Electron Electron Resonance (DEER) spectroscopy with Molecular Dynamics simulations to profile and mechanistically frame the conformation of a hitherto unobserved intermediate in the context of BmrCD, a heterodimeric multidrug ABC exporter fromBacillus subtilis.In our cryo-EM structure, BmrCD adopts an inward-facing architecture bound to both ATP and the substrate Hoechst-33342 and is capped by an extracellular domain which undergoes ATP-dependent conformational changes. A striking feature of the structure is a symmetric arrangement of the nucleotide-binding domain (NBD) in the presence of ATP whereas binding of Hoechst at two distinct sites in an acidic pocket stabilizes an asymmetric arrangement of the transmembrane domain architecture (TMD). Mutation of residues coordinating Hoechst in the structure abrogates the cooperative stimulation of ATP hydrolysis. In conjunction with previous studies, our findings suggest a mechanistic role for symmetry mismatch between NBDs and TMDs in the conformational cycle of ABC transporters. Moreover, the resolved structures of bimodally-bound drugs are of notable importance for future rational design and optimization of molecules for targeted transport inhibition of ABC transporters.ONE SENTENCE SUMMARYCryo-EM and EPR analysis reveal cooperative substrate binding in BmrCD in an architecture primed for transport.
PD-1 dependent expansion of Amphregulin+FOXP3+cells is associated with oral immune dysfunction in HIV patients on therapy
Authors: Bhaskaran N , Schneider E , Faddoul F , Paes da Silva A , Asaad R , Talla A , Greenspan N , Levine AD , McDonald D , Karn J , Lederman MM , Pandiyan P 
Published: March 2021

AbstractResidual systemic inflammation and mucosal immune dysfunction persist in people living with HIV (PLWH) despite treatment with combined anti-retroviral therapy (cART), but the underlying immune mechanisms are poorly understood. Here we report an altered immune landscape involving upregulation of TLR- and inflammasome signaling, localized CD4+T cell hyperactivation, and counterintuitively, an enrichment of CD4+CD25+FOXP3+regulatory T cells (Tregs) in the oral mucosa of HIV+patients on therapy. Using human oral tonsil cultures, we found that HIV infection causes an increase in a unique population of FOXP3+cells expressing PD-1, IFN-γ, Amphiregulin (AREG), and IL-10. These cells persisted even in the presence of the anti-retroviral drug and underwent further expansion driven by TLR-2 ligands and IL-1β. IL-1β also promoted PD-1 upregulation in AKT1 dependent manner. PD-1 stabilized FOXP3 and AREG expression in these cells through a mechanism requiring the activation of Asparaginyl Endopeptidase (AEP). Importantly, these FOXP3+cells were incapable of suppressing CD4+T cellsin vitro. Concurrently, HIV+patients harbored higher levels of PD-1, IFN-γ, Amphiregulin (AREG), and IL-10 expressing FOXP3+cells, which strongly correlated with CD4+T cell hyperactivation, suggesting an absence of CD4+T cell regulation in the oral mucosa. Taken together, this study provides insights into a novel mechanism of FOXP3+cell dysregulation and reveals a critical link in the positive feedback loop of oral mucosal immune activation events in HIV+patients on therapy.One Sentence SummaryHIV-induced immune dysfunction in lymphoid and mucosal tissues
Increasing stimulus similarity drives nonmonotonic representational change in hippocampus
Authors: Wammes Jeffrey D. , Norman Kenneth A. , Turk-Browne Nicholas B. 
Published: March 2021

AbstractStudies of hippocampal learning have obtained seemingly contradictory results, with manipulations that increase coactivation of memories sometimes leading to differentiation of these memories, but sometimes not. These results could potentially be reconciled using the nonmonotonic plasticity hypothesis, which posits that representational change (memories moving apart or together) is a U-shaped function of the coactivation of these memories during learning. Testing this hypothesis requires manipulating coactivation over a wide enough range to reveal the full U-shape. To accomplish this, we used a novel neural network image synthesis procedure to create pairs of stimuli that varied parametrically in their similarity in high-level visual regions that provide input to the hippocampus. Sequences of these pairs were shown to human participants during high-resolution fMRI. As predicted, learning changed the representations of paired images in the dentate gyrus as a U-shaped function of image similarity, with neural differentiation occurring only for moderately similar images.
Evaluation of UV-A LED technology on the reduction of spiked aflatoxin B1and aflatoxin M1in whole milk: toxicity analysis using liver hepatocellular cells
Authors: Kurup Anjali H. , Patras Ankit , Pendyala Brahmaiah , Vergne Matthew J. , Bansode Rishipal R. 
Published: March 2021

AbstractThe effectiveness of a UV-A light emitting diode system (LED) to reduce the concentrations of aflatoxin B1, aflatoxin M1(AFB1, AFM1) in whole milk (WM) was investigated. Irradiation experiments were conducted using an LED system operating at 365 nm. Known concentrations of aflatoxins were spiked in WM and irradiated at quantified UV doses which was calculated based on the average volumetric intensity. LC-MS/MS product ion scans were used to identify and semi-quantify photodegraded products of AFB1and AFM1. It was observed that UV irradiation significantly reduced aflatoxins in WM, p<0.05. In comparison to control, the maximum UV-A exposure reduced AFB1and AFM1concentrations to 78.2 ± 2.36 % (at 836 mJ/cm2) and 65.7 ± 1.65% (at 857 mJ/cm2), respectively. In cell culture studies, our results demonstrated that the increase of UV-A dosage decreased the aflatoxins-induced cytotoxicity in HepG2 cells, and no significant aflatoxin-induced cytotoxicity was observed at highest given UV-A irradiation of 777 (AFB1), 838 (AFM1), and 746 (total AFs) mJ/cm2. Sensory quality of product, cytotoxicity, and mutagenicity of UV exposed aflatoxins in WM using animal models is warranted in the future.
How do biofilms feel their environment?
Authors: Asp Merrill , Ho Thanh Minh Tri , Gopinath Arvind , Patteson Alison 
Published: March 2021

AbstractThe ability of bacteria to colonize and grow on different surfaces is an essential process for biofilm development and depends on complex biomechanical interactions between the biofilm and the underlying substrate. Changes in the physical properties of the underlying substrate are known to alter biofilm expansion, but the mechanisms by which biofilms sense and respond to physical features of their environment are still poorly understood. Here, we report the use of synthetic polyacrylamide hydrogels with tunable stiffness and controllable pore size to assess physical effects of the substrate on biofilm development. Using time lapse microscopy to track the growth of expandingSerratia marcescenscolonies, we find that biofilm colony growth can increase with increasing substrate stiffness on purely elastic substrates, unlike what is found on traditional agar substrates. Using traction force microscopy, we find that biofilms exert transient stresses correlated over length scales much larger than a single bacterium. Our results are consistent with a model of biofilm development in which the interplay between osmotic pressure arising from the biofilm and the poroelastic response of the underlying substrate controls biofilm growth and morphology.
Postacquisition asset redeployment and marketing adaptation: a consumer perspective
Authors: Fong Cher-Min , Chang Hsing-Hua Stella 
Published: March 2021

PurposeThis research examines consumer assessments of brand value derived from the redeployment of brand-related assets following a crossborder acquisition (CBA). The current study synthesizes research on international marketing standardization/adaptation to the context of crossborder horizontal acquisitions as the market entry strategy to investigate consumer evaluations of the postacquisition choice of brand name and brand positioning.Design/methodology/approachA pretest and two studies were conducted in Taiwan to empirically examine effects from the theory-driven model of product legitimacy (PL) on an entity's postacquisition brand value, as well as any moderating effects of consumer localism.FindingsPostacquisition brands were evaluated more positively when positioned in a manner that was in accordance with perceived PL. Consumer localism as another contingency factor reflected consumers' favorable attitude toward marketing adaptation following CBAs.Originality/valueThis article is a pioneering work to draw on the consumer perspective to investigate asset redeployments between the acquirer and target following a crossborder horizontal acquisition. Specifically, this research introduces PL as a contingency factor to examine consumers' evaluation of brand value, which is derived from the redeployment of brand name and brand positioning in the context of a developed-country firm's acquisition of an advanced emerging-market firm for entry into the market.
Internal audit quality, punitive measures and accountability in Ugandan statutory corporations
Authors: Nalukenge Irene , Kaawaase Twaha Kigongo , Bananuka Juma , Ogwal Peter Francis 
Published: March 2021

PurposeThis study aims to (1) examine the contribution of internal audit quality, punitive measures to accountability in statutory corporations in developing countries such as Uganda and (2) test whether internal audit quality mediates the relationship between punitive measures and accountability in Uganda's statutory corporations.Design/methodology/approachThis study is cross-sectional and correlational. Data were collected through a questionnaire survey conducted for 82 statutory corporations. The study's unit of analysis was a statutory corporation. Chief Internal Auditors and Chief Finance Officers were the study's unit of inquiry. Data were analyzed through correlation coefficients and linear regression using Statistical Package for Social Sciences.FindingsThe results suggest that internal audit quality and punitive measures independently predict accountability. However, punitive measures do not predict accountability in the presence of internal audit quality. Results further indicate that internal audit quality mediates the relationship between punitive measures and accountability in Uganda's statutory corporations.Originality/valueThis study confirms internal audit quality (a preventive measure) as a significant predictor of accountability in statutory corporations relative to punitive measures. To achieve accountability, more emphasis thus needs to be put on preventive mechanisms than on punitive mechanisms. This study also enhances our understanding of the relationship between punitive measures, internal audit quality and accountability. In this study, we arrive at new evidence on the mediating role of internal audit quality in the relationship between punitive measures and accountability in Uganda's statutory corporations.
A Healthy Retirement Program for Thai government teachers: a quasi-experimental and comparison groups study
Authors: Insin Numporn , Tanasugarn Chanuantong , Benjakul Sarunya 
Published: March 2021

PurposeThe purpose of this study is to evaluate the Healthy Retirement Program's effectiveness toward skills improvement and evaluate changes in subjective health.Design/methodology/approachA quasi-experimental, pre and posttest of the comparison groups was conducted. Teachers who were going to retire within one year were recruited into the experimental (n = 47) and the comparison groups (n = 43). Questionnaires were administered at baseline, posttest and at the 6-months follow-up. An independent t-test and Mann–Whitney U test were applied to determine the differences in outcomes between groups.FindingsThe results revealed different effects regarding teachers' health status. In those who had no chronic disease, the experimental group had higher skills to understand health information at posttest and at follow-up (p = 0.036, 0.028). Skills to apply health information was also greater at follow-up (p = 0.042). Among those suffering from a chronic disease, skills to access and apply health information were significantly higher in the experimental group than that of the comparison at follow-up (p = 0.011, 0.046). Greater perceived health of the experimental group was also indicated (p = 0.032).Originality/valueWhile the health conditions of teachers at the preretirement period are inconsistent, healthy lifestyle management after retirement is a crucial skill for retirement adjustment. Supporting teachers to be health literate should be included in the retirement planning program which emphasizes preretiree's ability to understand and take control of their health.