bluuebunny/crossref_metadata_2025 huggingface dataset:
L-Cell Expression of Melanocortin-4-Receptor Is Marginal in Most of the Small Intestine in Mice and Humans and Direct Stimulation of Small Intestinal Melanocortin-4-Receptors in Mice and Rats Does Not Affect GLP-1 Secretion
Authors: Kuhre Rune E. , Modvig Ida M. , Jepsen Sara L. , Kizilkaya Hüsün S. , Bæch-Laursen Cecilie , Smith Christopher A. , Reimann Frank , Gribble Fiona M. , Rosenkilde Mette M. , Holst Jens J.
Published: August 2021

The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5–6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014—an often used MC4R antagonist, which we found to be a partial agonist—did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.
Precision Therapy for a Chinese Family With Maturity-Onset Diabetes of the Young
Authors: Li Juyi , Shu Meng , Wang Xiufang , Deng Aiping , Wen Chong , Wang Juanjuan , Jin Si , Zhang Hongmei
Published: August 2021

Objective

To determine the pathogenic gene and explore the clinical characteristics of maturity-onset diabetes of the young type 2 (MODY2) pedigree caused by a mutation in the glucokinase (GCK) gene.

Methods

Using whole-exome sequencing (WES), the pathogenic gene was detected in the proband—a 20-year-old young man who was accidentally found with hyperglycemia, no ketosis tendency, and a family history of diabetes. The family members of the proband were examined. In addition, relevant clinical data were obtained and genomic DNA from peripheral blood was obtained. Pathologic variants of the candidate were verified by Sanger sequencing technology, and cosegregation tests were conducted among other family members and non-related healthy controls. After adjusting the treatment plan based on the results of genetic testing, changes in biochemical parameters, such as blood glucose levels and HAblc levels were determined.

Results

In the GCK gene (NM_000162) in exon 9, a heterozygous missense mutation c.1160C > T (p.Ala387Val) was found in the proband, his father, uncle, and grandmother. Thus mutation, which was found to co-segregate with diabetes, was the first discovery of such a mutation in the Asian population. After stopping hypoglycemic drug treatment, good glycemic control was achieved with diet and exercise therapy.

Conclusion

GCK gene mutation c.1160C > T (p.Ala387Val) is the pathogenic gene in the GCK-MODY pedigree. Formulating an optimized and personalized treatment strategy can reduce unnecessary excessive medical treatment and adverse drug reactions, and maintain a good HbA1c compliance rate
A Dynamic Multi-Stage Planning Method for Integrated Energy Systems considering Development Stages
Authors: Fan Donglou , Dou Xun , Xu Yang , Wu Chen , Xue Guiyuan , Shao Yunfan
Published: August 2021

Integrated energy system (IES) planning is a long-term and rolling decision-making process. According to System Development Theory, the development-needs at different stages are different. Therefore, an IES dynamic multi-stage planning method considering different development stages is proposed. The first step of the method is putting forward a model based on the degree of system coupling, the reserve ratio, and the penetration rate of clean energy to divide dynamic development stages. Secondly, establishing a dynamic multi-stage planning model of the IES by combining the needs of different development stages through dynamic goals and constraints. Finally, the results given by the optimal configuration of critical IES equipment will be analysed in different scenarios. Following these steps, the result shows that the dynamic multi-stage planning method proposed is able to reduce the total planning cost of the system by 14% and reducing the clean energy penetration rate by 3%. Therefore, the proposed dynamic multi-stage planning scheme is effective and economical.
Simulated Experiment on Wind Erosion Resistance of Salix Residual in the Agro-Pastoral Ecotone
Authors: Li Qiang , Kang Furen , Zhang Zheng , Ma Chunyan , Nan Weige
Published: August 2021

Plant residual is of great importance in retarding soil wind erosion in the agro-pastoral ecotone. However, few studies have determined the effects of sand plant residual on wind erosion resistance. Based on field surveys, the influences of Salix residual biomass of 200, 400, 600, and 800 g m−2, soil incorporated with a residual thickness of 0.5, 1.0, and 2.0 cm, and typical proportion of residual branches and leaves (2:1, 1:1, and 1:2) on wind erosion resistance were investigated using a simulated wind tunnel. The results showed the following: 1) The soil loss amount ranged from 1.56 to 40.8 kg m−2 as Salix residual biomass decreased from 800 to 0 g m−2, with a critical residual biomass value of 400 g m−2. 2) As the thickness of soil-incorporated residual increased, the soil loss amount reduced rapidly, especially for 0–9 cm above the surface accounting for 84.6% of the total. 3) Salix branch residual is more important in resisting soil wind erosion as compared with its leaves. This kind of study may provide theoretical explanations for the optimal reconstruction of sandy vegetation in the northern wind-sand regions.
Zebrafish Models for Human Skeletal Disorders
Authors: Marí-Beffa Manuel , Mesa-Román Ana B. , Duran Ivan
Published: August 2021

In 2019, the Nosology Committee of the International Skeletal Dysplasia Society provided an updated version of the Nosology and Classification of Genetic Skeletal Disorders. This is a reference list of recognized diseases in humans and their causal genes published to help clinician diagnosis and scientific research advances. Complementary to mammalian models, zebrafish has emerged as an interesting species to evaluate chemical treatments against these human skeletal disorders. Due to its versatility and the low cost of experiments, more than 80 models are currently available. In this article, we review the state-of-art of this “aquarium to bedside” approach describing the models according to the list provided by the Nosology Committee. With this, we intend to stimulate research in the appropriate direction to efficiently meet the actual needs of clinicians under the scope of the Nosology Committee.
Integrated Analysis of mRNA- and miRNA-Seq in the Ovary of Rare Minnow Gobiocypris rarus in Response to 17α-Methyltestosterone
Authors: Liu Shaozhen , Yang Qiong , Chen Yue , Liu Qing , Wang Weiwei , Song Jing , Zheng Yao , Liu Wenzhong
Published: August 2021

17α-Methyltestosterone (MT) is a synthetic androgen. The objective of this study was to explore the effects of exogenous MT on the growth and gonadal development of female rare minnow Gobiocypris rarus. Female G. rarus groups were exposed to 25–100 ng/L of MT for 7 days. After exposure for 7 days, the total weight and body length were significantly decreased in the 50-ng/L MT groups. The major oocytes in the ovaries of the control group were vitellogenic oocytes (Voc) and cortical alveolus stage oocytes (Coc). In the MT exposure groups, some fish had mature ovaries with a relatively lower proportion of mature oocytes, and the diameter of the perinucleolar oocytes (Poc) was decreased compared with those of the control group. Ovarian VTG, FSH, LH, 11-KT, E2, and T were significantly increased after exposure to 50 ng/L of MT for 7 days. Unigenes (73,449), 24 known mature microRNAs (miRNAs), and 897 novel miRNAs in the gonads of G. rarus were found using high-throughput sequencing. Six mature miRNAs (miR-19, miR-183, miR-203, miR-204, miR-205, and miR-96) as well as six differentially expressed genes (fabp3, mfap4, abca1, foxo3, tgfb1, and zfp36l1) that may be associated with ovarian development and innate immune response were assayed using qPCR. Furthermore, the miR-183 cluster and miR-203 were differentially expressed in MT-exposed ovaries of the different G. rarus groups. This study provides some information about the role of miRNA–mRNA pairs in the regulation of ovarian development and innate immune system, which will facilitate future studies of the miRNA–RNA-associated regulation of teleost reproduction.
Comprehensive Bioinformatics Analysis Identifies POLR2I as a Key Gene in the Pathogenesis of Hypertensive Nephropathy
Authors: You Shilong , Xu Jiaqi , Wu Boquan , Wu Shaojun , Zhang Ying , Sun Yingxian , Zhang Naijin
Published: August 2021

Hypertensive nephropathy (HN), mainly caused by chronic hypertension, is one of the major causes of end-stage renal disease. However, the pathogenesis of HN remains unclarified, and there is an urgent need for improved treatments. Gene expression profiles for HN and normal tissue were obtained from the Gene Expression Omnibus database. A total of 229 differentially co-expressed genes were identified by weighted gene co-expression network analysis and differential gene expression analysis. These genes were used to construct protein–protein interaction networks to search for hub genes. Following validation in an independent external dataset and in a clinical database, POLR2I, one of the hub genes, was identified as a key gene related to the pathogenesis of HN. The expression level of POLR2I is upregulated in HN, and the up-regulation of POLR2I is positively correlated with renal function in HN. Finally, we verified the protein levels of POLR2I in vivo to confirm the accuracy of our analysis. In conclusion, our study identified POLR2I as a key gene related to the pathogenesis of HN, providing new insights into the molecular mechanisms underlying HN.
Cost-Effective Mapping of Genetic Interactions in Mammalian Cells
Authors: Khan Arshad H. , Smith Desmond J.
Published: August 2021

Comprehensive maps of genetic interactions in mammalian cells are daunting to construct because of the large number of potential interactions, ~ 2 × 108 for protein coding genes. We previously used co-inheritance of distant genes from published radiation hybrid (RH) datasets to identify genetic interactions. However, it was necessary to combine six legacy datasets from four species to obtain adequate statistical power. Mapping resolution was also limited by the low density PCR genotyping. Here, we employ shallow sequencing of nascent human RH clones as an economical approach to constructing interaction maps. In this initial study, 15 clones were analyzed, enabling construction of a network with 225 genes and 2,359 interactions (FDR < 0.05). Despite its small size, the network showed significant overlap with the previous RH network and with a protein-protein interaction network. Consumables were ≲$50 per clone, showing that affordable, high quality genetic interaction maps are feasible in mammalian cells.
Epigenetic Regulation of Vascular Smooth Muscle Cell Phenotype Switching in Atherosclerotic Artery Remodeling: A Mini-Review
Authors: Zurek Michelle , Aavik Einari , Mallick Rahul , Ylä-Herttuala Seppo
Published: August 2021

Atherosclerosis is a chronic inflammatory disease characterized by extensive remodeling of medium and large-sized arteries. Inward remodeling (=lumen shrinkage) of the vascular walls is the underlying cause for ischemia in target organs. Therefore, inward remodeling can be considered the predominant feature of atherosclerotic pathology. Outward remodeling (=lumen enlargement) is a physiological response compensating for lumen shrinkage caused by neointimal hyperplasia, but as a pathological response to changes in blood flow, outward remodeling leads to substantial arterial wall thinning. Thinned vascular walls are prone to rupture, and subsequent thrombus formation accounts for the majority of acute cardiovascular events. Pathological remodeling is driven by inflammatory cells which induce vascular smooth muscle cells to switch from quiescent to a proliferative and migratory phenotype. After decades of intensive research, the molecular mechanisms of arterial remodeling are starting to unfold. In this mini-review, we summarize the current knowledge of the epigenetic and transcriptional regulation of vascular smooth muscle cell phenotype switching from the contractile to the synthetic phenotype involved in arterial remodeling and discuss potential therapeutic options.
Exploring the Relationship Between Social Ties and Resilience From Evolutionary Framework
Authors: Agashe Sayli , Kumar Sunil , Rai Rishabh
Published: August 2021

This conceptual paper examines the necessity and importance of social bonds and networks in building resilience to fight the COVID-19. Resilience is a quality that energizes an individual’s actions and acts as a buffer to stressful events. The current article is intended to explore the evolutionary programmed behavior of the human mind to make social ties and structure. Humans have a strong need to connect and relate with other individuals by developing cooperation and perspective-taking. The ability to make social connections, group living, and sharing resources had a selective advantage in coping with physical and psychological stress. Social bonds provide resilience to people’s approach while making adjustments and adapting to situations, thus presents fitness benefits at both group and individual levels. An attempt has also been made to address how social isolation as a strategy to contain the infection adversely influence body homeostasis. Finally, this article recommends health practitioners, clinicians, and researchers to encourage research on the impact of social isolation/social interaction on mental and physical health indicators.
Case Report: Disseminated Talaromyces marneffei Infection in a Patient With Chronic Mucocutaneous Candidiasis and a Novel STAT1 Gain-of-Function Mutation
Authors: Chen Kuang , Tan Junfeng , Qian Shenxian , Wu Shenghai , Chen Qiong
Published: August 2021

Chronic mucocutaneous candidiasis (CMC) is a disorder of recurrent or persistent chronic noninvasive symptomatic infections of the skin, nails and mucous membranes. This disorder is primarily caused by Candida albicans. Many factors, including primary immunodeficiencies, can make a host more susceptible to CMC. Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are the most common genetic etiologies of CMC. We describe a case of CMC with disseminated Talaromyces marneffei infection caused by a new pathogenic Y287N mutation at amino acid 287 in the coiled-coiled domain of STAT1, which was identified using whole-exome sequencing. Position 287 might be a hot spot for missense mutations because several amino acid substitutions were found there. Flow cytometry suggested that the Y287N mutation might reduce the expression of IL-17 of Th17 cells in peripheral blood mononuclear cells stimulated by phorbol myristate acetate and ionomycin. The STAT1 Y287N GOF mutation may be the direct cause of recurrent cutaneous and mucosal candidiasis, including the T. marneffei infection in this patient.
BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity
Authors: Eggenhuizen Peter J. , Ng Boaz H. , Chang Janet , Fell Ashleigh L. , Cheong Rachel M. Y. , Wong Wey Y. , Gan Poh-Yi , Holdsworth Stephen R. , Ooi Joshua D.
Published: August 2021

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.
Warm, Sweetened Milk at the Twilight of Immunity - Alzheimer’s Disease - Inflammaging, Insulin Resistance, M. paratuberculosis and Immunosenescence
Authors: Dow Coad Thomas
Published: August 2021

This article prosecutes a case against the zoonotic pathogen Mycobacterium avium ss. paratuberculosis (MAP) as a precipitant of Alzheimer’s disease (AD). Like the other major neurodegenerative diseases AD is, at its core, a proteinopathy. Aggregated extracellular amyloid protein plaques and intracellular tau protein tangles are the recognized protein pathologies of AD. Autophagy is the cellular housekeeping process that manages protein quality control and recycling, cellular metabolism, and pathogen elimination. Impaired autophagy and cerebral insulin resistance are invariant features of AD. With a backdrop of age-related low-grade inflammation (inflammaging) and heightened immune risk (immunosenescence), infection with MAP subverts glucose metabolism and further exhausts an already exhausted autophagic capacity. Increasingly, a variety of agents have been found to favorably impact AD; they are agents that promote autophagy and reduce insulin resistance. The potpourri of these therapeutic agents: mTOR inhibitors, SIRT1 activators and vaccines are seemingly random until one recognizes that all these agents also suppress intracellular mycobacterial infection. The zoonotic mycobacterial MAP causes a common fatal enteritis in ruminant animals. Humans are exposed to MAP from contaminated food products and from the environment. The enteritis in animals is called paratuberculosis or Johne’s disease; in humans, it is the putative cause of Crohn’s disease. Beyond Crohn’s, MAP is associated with an increasing number of inflammatory and autoimmune diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis, multiple sclerosis, and rheumatoid arthritis. Moreover, MAP has been associated with Parkinson’s disease. India is one county that has extensively studied the human bio-load of MAP; 30% of more than 28,000 tested individuals were found to harbor, or to have harbored, MAP. This article asserts an unfolding realization that MAP infection of humans 1) is widespread in its presence, 2) is wide-ranging in its zoonosis and 3) provides a plausible link connecting MAP to AD.
Overcoming Obstacles in the Development of Antigen-Specific Immunotherapies for Type 1 Diabetes
Authors: Thomas Ranjeny , Carballido José M. , Wesley Johnna D. , Ahmed Simi T.
Published: August 2021

Antigen-specific immunotherapy (ASI) holds great promise for type 1 diabetes (T1D). Preclinical success for this approach has been demonstrated in vivo, however, clinical translation is still pending. Reasons explaining the slow progress to approve ASI are complex and span all stages of research and development, in both academic and industry environments. The basic four hurdles comprise a lack of translatability of pre-clinical research to human trials; an absence of robust prognostic and predictive biomarkers for therapeutic outcome; a need for a clear regulatory path addressing ASI modalities; and the limited acceptance to develop therapies intervening at the pre-symptomatic stages of disease. The core theme to address these challenges is collaboration—early, transparent, and engaged interactions between academic labs, pharmaceutical research and clinical development teams, advocacy groups, and regulatory agencies to drive a fundamental shift in how we think and treat T1D.
Hydrogen Addition to Natural Gas in Cogeneration Engines: Optimization of Performances Through Numerical Modeling
Authors: Costa Michela , Piazzullo Daniele , Dolce Alessandro
Published: August 2021

A numerical study of the energy conversion process occurring in a lean-charge cogenerative engine, designed to be powered by natural gas, is here conducted to analyze its performances when fueled with mixtures of natural gas and several percentages of hydrogen. The suitability of these blends to ensure engine operations is proven through a zero–one-dimensional engine schematization, where an original combustion model is employed to account for the different laminar propagation speeds deriving from the hydrogen addition. Guidelines for engine recalibration are traced thanks to the achieved numerical results. Increasing hydrogen fractions in the blend speeds up the combustion propagation, achieving the highest brake power when a 20% of hydrogen fraction is considered. Further increase of this last would reduce the volumetric efficiency by virtue of the lower mixture density. The formation of the NOx pollutants also grows exponentially with the hydrogen fraction. Oppositely, the efficiency related to the exploitation of the exhaust gases’ enthalpy reduces with the hydrogen fraction as shorter combustion durations lead to lower temperatures at the exhaust. If the operative conditions are shifted towards leaner air-to-fuel ratios, the in-cylinder flame propagation speed decreases because of the lower amount of fuel trapped in the mixture, reducing the conversion efficiencies and the emitted nitrogen oxides at the exhaust. The link between brake power and spark timing is also highlighted: a maximum is reached at an ignition timing of 21° before top dead center for hydrogen fractions between 10 and 20%. However, the exhaust gases’ temperature also diminishes for retarded spark timings. Lastly, an optimization algorithm is implemented to individuate the optimal condition in which the engine is characterized by the highest power production with the minimum fuel consumption and related environmental impact. As a main result, hydrogen addition up to 15% in volume to natural gas in real cogeneration systems is proven as a viable route only if engine operations are shifted towards leaner air-to-fuel ratios, to avoid rapid pressure rise and excessive production of pollutant emissions.
Direct Oral Anticoagulants as Successful Treatment of Heparin-Induced Thrombocytopenia: A Parisian Retrospective Case Series
Authors: Carré Julie , Guérineau Hippolyte , Le Beller Christine , Mauge Laëtitia , Huynh Benoit , Nili Roya , Planquette Benjamin , Clauser Sylvain , Smadja David M. , Helley Dominique , Lillo-Le Louet Agnès , Gendron Nicolas , Calmette Leyla
Published: August 2021

Background: Heparin-induced thrombocytopenia (HIT) is a prothrombotic life-threatening disorder caused by an adverse reaction to heparin exposure. In this context, it is imperative to stop heparin immediately and to replace it by a non-heparin anticoagulant therapy. Despite their advantages, the use of direct oral anticoagulants (DOACs) is only emerging for HIT treatment, and their use remains rare.

Objective: To improve our knowledge on the emerging role of DOACs as treatment of HIT and give an overview of our local practices in this context.

Patients/Methods: This is a multi-centric retrospective case series of HIT patients referred to our Parisian pharmacovigilance network and treated with DOACs.

Results: We report the cases of seven patients from four healthcare centers, diagnosed with HIT (4T score ≥ 4, positive anti-PF4/heparin immunoassay and positive serotonin-release assay) and treated with DOACs. After a few days on substitutive parenteral treatment (n = 6) or directly at HIT diagnosis (n = 1), these patients were treated with either rivaroxaban (n = 6) or apixaban (n = 1) during acute HIT phase. Mean time to platelet count recovery after heparin discontinuation was 3.3 days (range 3–5). No patient experienced major or clinically relevant non-major bleeding or thrombosis that could be related to DOAC treatment during follow-up.

Conclusions: Our cases studies are consistent with recent guidelines credit to the potential and safe use of DOAC during acute HIT in clinically stable patients.
Ten-Year Changes in Bloodstream Infection With Acinetobacter Baumannii Complex in Intensive Care Units in Eastern China: A Retrospective Cohort Study
Authors: Meng Xiao , Fu Jintao , Zheng Yue , Qin Weidong , Yang Hongna , Cao Dongming , Lu Haining , Zhang Lu , Du Zhiguo , Pang Jiaojiao , Li Wei , Guo Haipeng , Du Juan , Li Chen , Wu Dawei , Wang Hao
Published: August 2021

Background: There is little evidence on the changing prevalence, microbiological profile, and outcome of nosocomial Acinetobacter baumannii complex (ABC)-caused bloodstream infection (ABCBSI) specified in intensive care units (ICUs) in long-term studies, especially in China.

Objective: We aimed to investigate changes in incidence, antibiotic resistance, therapy, and prognosis of ABCBSI in ICUs in eastern China during 2009–2018.

Methods: A multicenter retrospective cohort study was conducted, and microbiological and clinical data for patients with ABCBSI acquired in nine adult ICUs in eastern China from 2009 to 2018.

Results: A total of 202 cases were enrolled. For the years 2009–2010, 2011–2012, 2013–2014, 2015–2016, and 2017–2018, the incidence of ABCBSI increased significantly, as did the percentage of pan-drug-resistant isolates and resistant rates to most of antimicrobial agents; the percentage of drug-sensitive isolates decreased (all P < 0.05). The frequency of treatment with carbapenems and tigecycline increased, and that of cephalosporins decreased. Compared with those in the first years (2009–2012), ABCBSI patients in the lattermost years (2017–2018) were less often treated with appropriate empirical therapy, more often underwent pneumonia-related ABCBSI and mechanical ventilation support, and had higher 28-day mortality rates. Multivariate Cox regression indicated that increase in the degree of ABC antibiotics resistance, pneumonia-related ABCBSI, and septic shock were risk factors of 28-day mortality and associated with significant lower survival days.

Conclusions: The past decade has witnessed a marked increase in the incidence of ABCBSI and in antibiotic resistance, with increasing pneumonia-related infections and worrisome mortality in ICUs in China. Controlling increasing resistance and preventing nosocomial pneumonia may play important roles in combatting these infections.
Retrospective Analysis of the Clinical Efficacy of N-Acetylcysteine in the Treatment of Hepatitis B Virus Related Acute-on-Chronic Liver Failure
Authors: Wang Meng-Lan , Yin Xiu-Jun , Li Xue-Lian , Wang Fa-Da , Zhou Jing , Tao Ya-Chao , Wang Yong-Hong , Wu Dong-Bo , Chen En-Qiang
Published: August 2021

Objective: HBV-related acute-on-chronic liver failure (HBV-ACLF) has a high mortality due to severe intrahepatic cholestasis and coagulation dysfunction, thus new treatment measures are urgently needed to improve the therapeutic effect. This study aimed to observe the efficacy of N-acetylcysteine (NAC) in the treatment of HBV-ACLF.

Methods: The data of patients with HBV-ACLF admitted to West China Hospital from October 2019 to August 2020 were collected retrospectively, and they were divided into treatment group and control group according to whether they had received additional NAC treatment. The improvement of biochemistry, coagulation function and disease severity score after 14 days of hospitalization were analyzed between two groups.

Results: A total of 90 HBV-ACLF patients were included, including 42 patients in treatment group and 48 patients in control group. Compared with baseline, serum TBil, DBil, TBA, GGT and ALP in two groups both decreased significantly, while PTA increased significantly. Interesting, the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were all significantly than these in control group. Additionally, more patients in treatment group than control group changed from CTP grade C to grade B. Subgroup analysis of CTP grade C patients showed that the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were significantly than these in control group.

Conclusion: The NAC treatment may help to improve intrahepatic cholestasis and coagulation dysfunction of HBV-ACLF.
The Impact of SARS-CoV-2 (COVID-19) Pandemic on International Dermatology Conferences in 2020
Authors: Ha Eun Seo , Hong Ji Yeon , Lim Sophie Soyeon , Soyer H. Peter , Mun Je-Ho
Published: August 2021

To limit the spread of the SARS-CoV-2 (COVID-19) outbreak, humans have been significantly restricted in their ability to travel and interact with others worldwide. Consequently, dermatology conferences were forced to adapt to such changes. The aim of this study is to investigate the impact of COVID-19 on international dermatology conferences. We retrospectively investigated decisions made for international dermatology conferences scheduled for 2020. Thirty-three major conferences were analyzed. Their data were obtained from their respective websites (data was accessed 2 June 2021). Among 33 conferences analyzed, 13 (39.4%) were conducted as scheduled, nine (27.3%) were canceled, eight (24.3%) were postponed to 2021 or 2022, and three (9.1%) were delayed but conducted in 2020. The number of the cancellation (44.4%) and postponement (75%) was the largest in the second quarter of the year. During the fourth quarter, most conferences were held on schedule (70%) but were run virtually. Eight out of 13 virtual conferences shortened their duration (61.5%). Most (90.9%) conferences have decided on the schedule of their meetings for 2021 or 2022 while three (9.1%) remain undecided. Twelve (40%) are planned to run virtually, eight (26.7%) have opted for a hybrid form, five (16.7%) are planned to run in-person, four (13.3%) have not decided on the format, and one (3.3%) has been canceled. Virtual and hybrid conference formats have facilitated people to share knowledge despite the travel restrictions posed by the COVID-19 pandemic. Such formats are environmentally friendly, are able to attract a large audience, and save delegates time and costs involved in attending. Therefore, virtual platforms should continue to be integrated within conferences in the post-pandemic era.
Sex-Specific Social Behavior and Amygdala Proteomic Deficits in Foxp2+/− Mutant Mice
Authors: Herrero Maria Jesus , Wang Li , Hernandez-Pineda David , Banerjee Payal , Matos Heidi Y. , Goodrich Meredith , Panigrahi Aswini , Smith Nathan Anthony , Corbin Joshua G.
Published: August 2021

In humans, mutations in the transcription factor encoding gene, FOXP2, are associated with language and Autism Spectrum Disorders (ASD), the latter characterized by deficits in social interactions. However, little is known regarding the function of Foxp2 in male or female social behavior. Our previous studies in mice revealed high expression of Foxp2 within the medial subnucleus of the amygdala (MeA), a limbic brain region highly implicated in innate social behaviors such as mating, aggression, and parental care. Here, using a comprehensive panel of behavioral tests in male and female Foxp2+/– heterozygous mice, we investigated the role Foxp2 plays in MeA-linked innate social behaviors. We reveal significant deficits in olfactory processing, social interaction, mating, aggressive, and parental behaviors. Interestingly, some of these deficits are displayed in a sex-specific manner. To examine the consequences of Foxp2 loss of function specifically in the MeA, we conducted a proteomic analysis of microdissected MeA tissue. This analyses revealed putative sex differences expression of a host of proteins implicated in neuronal communication, connectivity, and dopamine signaling. Consistent with this, we discovered that MeA Foxp2-lineage cells were responsive to dopamine with differences between males and females. Thus, our findings reveal a central and sex-specific role for Foxp2 in social behavior and MeA function.
Two Photon Fluorescence Microscopy of the Unstained Human Cochlea Reveals Organ of Corti Cytoarchitecture
Authors: Iyer Janani S. , Seist Richard , Moon In Seok , Stankovic Konstantina M.
Published: August 2021

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide, and it typically originates from the cochlea. Methods to visualize intracochlear cells in living people are currently lacking, limiting not only diagnostics but also therapies for SNHL. Two-photon fluorescence microscopy (TPFM) is a high-resolution optical imaging technique. Here we demonstrate that TPFM enables visualization of sensory cells and auditory nerve fibers in an unstained, non-decalcified adult human cochlea.
New Insights Into the Roles of Microglial Regulation in Brain Plasticity-Dependent Stroke Recovery
Authors: Yu Fang , Huang Tingting , Ran Yuanyuan , Li Da , Ye Lin , Tian Guiqin , Xi Jianing , Liu Zongjian
Published: August 2021

Stroke remains the leading cause of long-term disability worldwide with significant long-term sequelae. However, there is no highly effective treatment to enhance post-stroke recovery despite extensive efforts in exploring rehabilitative therapies. Neurorehabilitation is recognized as the cornerstone of functional restoration therapy in stroke, where treatments are focused on neuroplastic regulation to reverse neural structural disruption and improve neurofunctional networks. Post-stroke neuroplasticity changes begin within hours of symptom onset and reaches a plateau by 3 to 4 weeks within the global brain in animal studies. It plays a determining role in spontaneous stroke recovery. Microglia are immediately activated following cerebral ischemia, which has been found both proximal to the primary ischemic injury and at the remote brain regions which have functional connections to the primary injury area. Microglia exhibit different activation profiles based on the microenvironment and adaptively switch their phenotypes in a spatiotemporal manner in response to brain injuries. Microglial activation coincides with neuroplasticity after stroke, which provides the fundamental base for the microglia-mediated inflammatory responses involved in the entire neural network rewiring and brain repair. Microglial activation exerts important effects on spontaneous recovery after stroke, including structural and functional reestablishment of neurovascular networks, neurogenesis, axonal remodeling, and blood vessel regeneration. In this review, we focus on the crosstalk between microglial activation and endogenous neuroplasticity, with a special focus on the plastic alterations in the whole brain network and their implications for structural and functional restoration after stroke. We then summarize recent advances in the impacts of microglial phenotype polarization on brain plasticity, trying to discuss the potential efficacy of microglia-based extrinsic restorative interventions in promoting post-stroke recovery.
Comparison of Carrier and de novo Pathogenic Variants in a Chinese DMD/BMD Cohort
Authors: Lin Jinfu , Li Huan , Liao Ziyu , Wang Liang , Zhang Cheng
Published: August 2021

Background: Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessively inherited neuromuscular disorders caused by deletions, duplications, or small mutations in the DMD gene. With advances in prenatal diagnosis decreasing the number of affected offspring from carrier mothers, the frequency of de novo variants could increase. Therefore, determining the differences between the carrier and de novo variants of the DMD gene, which are rarely explored, is important for trial planning and genetic diagnosis in the future.

Methods: A total of 440 patients, 349 of whom had DMD and 91 had BMD, diagnosed in our department between 2012 and 2019, along with their respective mothers, were included in this study. Multiplex ligation-dependent probe amplification was used to detected deletions and duplications in patients and their mothers. Small mutations were detected using next-generation sequencing in the patients, followed by Sanger sequencing in the mothers.

Results: Deletions, duplications, and small mutations were identified in 204, 46, and 99 of the 349 patients with DMD and in 50, 10, and 31 of the 91 patients with BMD, respectively. De novo deletions were more concentrated in hotspot regions than carrier deletions of DMD/BMD. No clear bias was observed in the variant distribution between carriers, de novo duplications, and small mutations in DMD/BMD. The carrier frequency of DMD (61.6%) was lower than that of BMD (69.2%), but the difference was not statistically significant. The carrier frequency of deletions of the DMD gene (51.2%) was significantly lower than those of duplications (75%) and small mutations (81.5%).

Conclusion: Compared to de novo deletions, deletions from carrier mothers had a wider distribution. Moreover, there was no significant difference between the carrier frequencies of DMD and BMD. Duplications and small mutations were more commonly inherited, while deletions were present de novo.
Exploratory Radiomic Analysis of Conventional vs. Quantitative Brain MRI: Toward Automatic Diagnosis of Early Multiple Sclerosis
Authors: Lavrova Elizaveta , Lommers Emilie , Woodruff Henry C. , Chatterjee Avishek , Maquet Pierre , Salmon Eric , Lambin Philippe , Phillips Christophe
Published: August 2021

Conventional magnetic resonance imaging (cMRI) is poorly sensitive to pathological changes related to multiple sclerosis (MS) in normal-appearing white matter (NAWM) and gray matter (GM), with the added difficulty of not being very reproducible. Quantitative MRI (qMRI), on the other hand, attempts to represent the physical properties of tissues, making it an ideal candidate for quantitative medical image analysis or radiomics. We therefore hypothesized that qMRI-based radiomic features have added diagnostic value in MS compared to cMRI. This study investigated the ability of cMRI (T1w) and qMRI features extracted from white matter (WM), NAWM, and GM to distinguish between MS patients (MSP) and healthy control subjects (HCS). We developed exploratory radiomic classification models on a dataset comprising 36 MSP and 36 HCS recruited in CHU Liege, Belgium, acquired with cMRI and qMRI. For each image type and region of interest, qMRI radiomic models for MS diagnosis were developed on a training subset and validated on a testing subset. Radiomic models based on cMRI were developed on the entire training dataset and externally validated on open-source datasets with 167 HCS and 10 MSP. Ranked by region of interest, the best diagnostic performance was achieved in the whole WM. Here the model based on magnetization transfer imaging (a type of qMRI) features yielded a median area under the receiver operating characteristic curve (AUC) of 1.00 in the testing sub-cohort. Ranked by image type, the best performance was achieved by the magnetization transfer models, with median AUCs of 0.79 (0.69–0.90, 90% CI) in NAWM and 0.81 (0.71–0.90) in GM. The external validation of the T1w models yielded an AUC of 0.78 (0.47–1.00) in the whole WM, demonstrating a large 95% CI and a low sensitivity of 0.30 (0.10–0.70). This exploratory study indicates that qMRI radiomics could provide efficient diagnostic information using NAWM and GM analysis in MSP. T1w radiomics could be useful for a fast and automated check of conventional MRI for WM abnormalities once acquisition and reconstruction heterogeneities have been overcome. Further prospective validation is needed, involving more data for better interpretation and generalization of the results.
Impact of Temporal Visual Flicker on Spatial Contrast Sensitivity in Myopia
Authors: Ye Jie , Sinha Pawan , Hou Fang , He Xianghang , Shen Meixiao , Lu Fan , Shao Yilei
Published: August 2021

Purpose

To investigate whether short-term exposure to high temporal frequency full-field flicker has an impact on spatial visual acuity in individuals with varying degrees of myopia.

Methods

Thirty subjects (evenly divided between control and experimental groups) underwent a 5-min exposure to full-field flicker. The flicker rate was lower than critical flicker frequency (CFF) for the experimental group (12.5 Hz) and significantly higher than CFF for the controls (60 Hz). Spatial contrast sensitivity function (CSF) was measured before and immediately after flicker exposure. We examined whether the post flicker CSF parameters were different from the pre-exposure CSF values in either of the subject groups. Additionally, we examined the relationship between the amount of CSF change from pre to post timepoints and the degree of subjects’ myopia. The CSF parameters included peak frequency, peak sensitivity, bandwidth, truncation, and area under log CSF (AULCSF).

Results

There was no significant difference of all five pre-exposure CSF parameters between the two groups at baseline (P = 0.333 ∼ 0.424). Experimental group subjects exhibited significant (P < 0.005) increases in peak sensitivity and AULCSF, when comparing post-exposure results to pre-exposure ones. Controls showed no such enhancements. Furthermore, the extent of these changes in the experimental group was correlated significantly with the participants’ refractive error (P = 0.005 and 0.018, respectively).

Conclusion

Our data suggest that exposure to perceivable high-frequency flicker (but, not to supra-CFF frequencies) enhances important aspects of spatial contrast sensitivity, and these enhancements are correlated to the degree of myopia. This finding has implications for potential interventions for cases of modest myopia.
The Role of Calmodulin vs. Synaptotagmin in Exocytosis
Authors: Xue Renhao , Meng Hao , Yin Jiaxiang , Xia Jingyao , Hu Zhitao , Liu Huisheng
Published: August 2021

Exocytosis is a Ca2+-regulated process that requires the participation of Ca2+ sensors. In the 1980s, two classes of Ca2+-binding proteins were proposed as putative Ca2+ sensors: EF-hand protein calmodulin, and the C2 domain protein synaptotagmin. In the next few decades, numerous studies determined that in the final stage of membrane fusion triggered by a micromolar boost in the level of Ca2+, the low affinity Ca2+-binding protein synaptotagmin, especially synaptotagmin 1 and 2, acts as the primary Ca2+ sensor, whereas calmodulin is unlikely to be functional due to its high Ca2+ affinity. However, in the meantime emerging evidence has revealed that calmodulin is involved in the earlier exocytotic steps prior to fusion, such as vesicle trafficking, docking and priming by acting as a high affinity Ca2+ sensor activated at submicromolar level of Ca2+. Calmodulin directly interacts with multiple regulatory proteins involved in the regulation of exocytosis, including VAMP, myosin V, Munc13, synapsin, GAP43 and Rab3, and switches on key kinases, such as type II Ca2+/calmodulin-dependent protein kinase, to phosphorylate a series of exocytosis regulators, including syntaxin, synapsin, RIM and Ca2+ channels. Moreover, calmodulin interacts with synaptotagmin through either direct binding or indirect phosphorylation. In summary, calmodulin and synaptotagmin are Ca2+ sensors that play complementary roles throughout the process of exocytosis. In this review, we discuss the complementary roles that calmodulin and synaptotagmin play as Ca2+ sensors during exocytosis.
Memorable Food: Fighting Age-Related Neurodegeneration by Precision Nutrition
Authors: Milošević Maja , Arsić Aleksandra , Cvetković Zorica , Vučić Vesna
Published: August 2021

Healthcare systems worldwide are seriously challenged by a rising prevalence of neurodegenerative diseases (NDDs), which mostly, but not exclusively, affect the ever-growing population of the elderly. The most known neurodegenerative diseases are Alzheimer's (AD) and Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, but some viral infections of the brain and traumatic brain injury may also cause NDD. Typical for NDD are the malfunctioning of neurons and their irreversible loss, which often progress irreversibly to dementia and ultimately to death. Numerous factors are involved in the pathogenesis of NDD: genetic variability, epigenetic changes, extent of oxidative/nitrosative stress, mitochondrial dysfunction, and DNA damage. The complex interplay of all the above-mentioned factors may be a fingerprint of neurodegeneration, with different diseases being affected to different extents by particular factors. There is a voluminous body of evidence showing the benefits of regular exercise to brain health and cognitive functions. Moreover, the importance of a healthy diet, balanced in macro- and micro-nutrients, in preventing neurodegeneration and slowing down a progression to full-blown disease is evident. Individuals affected by NDD almost inevitably have low-grade inflammation and anomalies in lipid metabolism. Metabolic and lipid profiles in NDD can be improved by the Mediterranean diet. Many studies have associated the Mediterranean diet with a decreased risk of dementia and AD, but a cause-and-effect relationship has not been deduced. Studies with caloric restriction showed neuroprotective effects in animal models, but the results in humans are inconsistent. The pathologies of NDD are complex and there is a great inter-individual (epi)genetic variance within any population. Furthermore, the gut microbiome, being deeply involved in nutrient uptake and lipid metabolism, also represents a pillar of the gut microbiome–brain axis and is linked with the pathogenesis of NDD. Numerous studies on the role of different micronutrients (omega-3 fatty acids, bioactive polyphenols from fruit and medicinal plants) in the prevention, prediction, and treatment of NDD have been conducted, but we are still far away from a personalized diet plan for individual NDD patients. For this to be realized, large-scale cohorts that would include the precise monitoring of food intake, mapping of genetic variants, epigenetic data, microbiome studies, and metabolome, lipidome, and transcriptome data are needed.