Search

The degradation of macromolecules and organelles by the process of autophagy is critical for cellular homeostasis and is often compromised during aging and disease. Beclin1 and Beclin2 are implicated in autophagy induction, and these homologs share a high degree of amino acid sequence similarity but have divergent N-terminal regions. Here, we investigated the functions of the Beclin homologs in regulating autophagy and mitophagy, a specialized form of autophagy that targets mitochondria. Both Beclin homologs contributed to autophagosome formation, but a mechanism of autophagosome formation independent of either Beclin homolog occurred in response to starvation or mitochondrial damage. Mitophagy was compromised only in Beclin1-deficient HeLa cells and mouse embryonic fibroblasts because of defective autophagosomal engulfment of mitochondria, and the function of Beclin1 in mitophagy required the phosphorylation of the conserved Ser15 residue by the kinase Ulk1. Mitochondria-ER–associated membranes (MAMs) are important sites of autophagosome formation during mitophagy, and Beclin1, but not Beclin2 or a Beclin1 mutant that could not be phosphorylated at Ser15, localized to MAMs during mitophagy. Our findings establish a regulatory role for Beclin1 in selective mitophagy by initiating autophagosome formation adjacent to mitochondria, a function facilitated by Ulk1-mediated phosphorylation of Ser15 in its distinct N-terminal region. A tale of two Beclin homologs: Cells reclaim nutrients from macromolecules and organelles through the process called autophagy, the dysregulation of which contributes to the pathogenesis of several diseases. Quiles et al. dissected the roles of the highly homologous Beclin1 and Beclin2 in the initiation of autophagosome formation, a key step in autophagy. Analysis of cells expressing only Beclin1 or Beclin2 revealed that both homologs were required for autophagy under basal conditions but were dispensable for stress-induced autophagy. Beclin1 specifically promoted mitophagy, the autophagic degradation of mitochondria, a function that required the phosphorylation of an evolutionarily conserved serine residue in Beclin1 that is not found in Beclin2. These results delineate the roles of Beclin1 and Beclin2 in autophagy under varying conditions.—WW [ABSTRACT FROM AUTHOR]

Respiratory mucosal surfaces are continuously exposed to not only innocuous non-self antigens but also pathogen-associated molecular patterns (PAMPs) originating from environmental or symbiotic microbes. According to either “self/ non-self” or “danger” models, this should systematically result in homeostasis breakdown and the development of immune responses directed to inhaled harmless antigens, such as T helper type (Th)2-mediated asthmatic reactions, which is fortunately not the case in most people. This discrepancy implies the existence, in the lung, of regulatory mechanisms that tightly control immune homeostasis. Although such mechanisms have been poorly investigated in comparison to the ones that trigger immune responses, a better understanding of them could be useful in the development of new therapeutic strategies against lung diseases (e.g., asthma). Here, we review current knowledge on innate immune cells that prevent the development of aberrant immune responses in the lung, thereby contributing to mucosal homeostasis. [ABSTRACT FROM AUTHOR]

Reductive metal deposition at the interface between two immiscible electrolyte solutions (ITIES), the oil/water interface, is an attractive methodology to produce metal nanostructures. However, the metals that can be deposited are limited to noble metals; otherwise, water molecules are reduced. Herein, a method to overcome this limitation by utilizing a novel water‐free ITIES between a hydrophilic ionic liquid and oil was introduced. As proof‐of‐concept experiments, the reductive deposition of zinc, a base metal with a standard redox potential more negative than that of water, was successfully realized at the ionic liquid/oil interface. The morphology of the zinc nanostructures was investigated, and the reaction mechanism was discussed, in which the electron transfer and ion transfer reactions across the interface simultaneously occurred to maintain the electroneutrality of the liquids. [ABSTRACT FROM AUTHOR]

Dendritic cells (DC) are powerful cells that play critical roles in anti-tumor immunity, and their use in cancer immunotherapy unlocks hidden capabilities as an effective therapeutic. In order to maximize the full potential of DC, we developed a DC vaccine named CellgramDC-WT1 (CDW). CDW was pulsed with WT1, an antigen commonly expressed in solid tumors, and induced with zoledronate to aid DC maturation. Although our previous study focused on using Rg3 as an inducer of DC maturation, problems with quality control and access led us to choose zoledronate as a better alternative. Furthermore, CDW secreted IL-12 and IFN-γ, which induced the differentiation of naïve T cells to active CD8+ T cells and elicited cytotoxic T lymphocyte (CTL) response against cancer cells with WT1 antigens. By confirming the identity and function of CDW, we believe CDW is an improved DC vaccine and holds promising potential in the field of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (Knee OA) is an irreversible condition that causes bone deformity and degeneration of the articular cartilage that comprises the joints, resulting in chronic pain and movement disorders. The administration of cultured adipose-derived stem cells (ADSCs) into the knee joint cavity improves the clinical symptoms of Knee OA; however, the effect of synovial fluid (SF) filling the joint cavity on the injected ADSCs remains unclear. In this study, we investigated the effect of adding SF from Knee OA patients to cultured ADSCs prepared for therapeutic use in an environment that mimics the joint cavity. An increase in the viability of ADSCs was observed following the addition of SF. Gene expression profiling of SF-treated ADSCs using DNA microarrays revealed changes in several genes involved in cell survival. Of these genes, we focused on FOSL1, which is involved in the therapeutic effect of ADSCs and the survival and proliferation of cancer stem cells. We confirmed the upregulation of FOSL1 mRNA and protein expression using RT-PCR and western blot analysis, respectively. Next, we knocked down FOSL1 in ADSCs using siRNA and observed a decrease in cell viability, indicating the involvement of FOSL1 in the survival of ADSCs. Interestingly, in the knockdown cells, ADSC viability was also decreased by SF exposure. These results suggest that SF enhances cell viability by upregulating FOSL1 expression in ADSCs. For therapy using cultured ADSCs, the therapeutic effect of ADSCs may be further enhanced if an environment more conducive to the upregulation of FOSL1 expression in ADSCs can be established. [ABSTRACT FROM AUTHOR]

Asthma and obesity are considered as highly prevalent diseases with a great impact on public health. Obesity has been demonstrated to be an aggravating factor in the pathogenesis of asthma. Adipose tissue secretes proinflammatory cytokines and mediators, including leptin, which may promote the development and severity of asthma in obese patients. This study is a systematic review and a meta-analysis based on the relationship between leptin and asthma during obesity. MEDLINE, Cochrane, EMBASE and CINAHL databases were used. Data heterogeneity was analyzed using Cochran's Q and treatment effect with the DerSimonian and Laird method. Random effect analyses were carried out to test data sensitivity. Asymmetry was estimated using Begg's and Egger's tests. All studies showed significant differences in leptin levels. The effect of the measures (p < 0.001), data sensitivity (p < 0.05) and data asymmetry were statistically significant, as well as tBegg's test (p = 0.010) and Egge's test (p < 0.001). Despite the existing limiting factors, the results of this study support the relevant role of leptin in the pathophysiology of asthma in obese subjects. Nevertheless, further studies are needed to obtain better insight in the relationship between leptin and asthma in obesity. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation (AF) and premature ventricular complexes (PVC) are common arrhythmias. We aimed to investigate AF prevalence in patients with PVC and its impact on PVC ablation outcomes. Methods: Consecutive patients undergoing PVC ablation at a single institution between 2016 and 2019 were included and prospectively followed for 2 years. Patients with severe valvular heart disease, hyperthyroidism, malignancy, alcohol use disorder and advanced renal/hepatic diseases were excluded. Twelve‐lead electrocardiograms were used to diagnose AF and assess PVC morphology. All PVCs were targeted for ablation using 4‐mm irrigated‐tip catheters at standardized radiofrequency power guided by 3‐D mapping and intracardiac echocardiography. Patients were followed with remote monitoring, device interrogations and office visits every 6 months for 2 years. Detection of any PVCs in follow‐up was considered as recurrence. Results: A total of 394 patients underwent PVC ablation and 96 (24%) had concurrent AF. Patients with PVC and AF were significantly older (68.2 ± 10.8 vs. 58.3 ± 15.8 years, p <.001), had lower LV ejection fraction (43.3 ± 13.3% vs. 49.6 ± 12.4%, p <.001), higher CHA2DS2‐VASc (2.8 ± 1.3 vs. 2.0 ± 1.3, p <.001) than those without. PVCs with ≥2 morphologies were detected in 60.4% and 13.7% patients with vs without AF (p <.001). At 2‐year follow‐up, PVC recurrence rate was significantly higher in patients with vs without AF (17.7% vs. 9.4%, p =.02). Conclusion: AF was documented in 1/4 of patients undergoing PVC ablation and was associated with lower procedural success at long‐term follow‐up. This was likely attributed to older age, worse LV function and higher prevalence of multiple PVC morphologies in patients with concurrent AF. [ABSTRACT FROM AUTHOR]

1.3-thiazole is a unique heterocycle containing nitrogen and sulphur atoms. Thiazole chemistry has developed after the pioneering it of Hofmann and Hantzsch in 1887. Thiazole occupies an important place in medicinal chemistry. It is widely found in diverse pharmacologically active substances and in some naturally occurring compounds. In last decade, heterocyclic compounds containing thiazole moiety and their derivatives were found exhibiting nanoscale properties. In addition, they exhibit a wide spectrum of biological activities such as antioxidant, antitubercular, antiinflammatory, anti-HIV, antitumor, anticonvulsive, antifungal and antibacterial. Thiazole is an essential in many natural (vitamin B1—thiamine) and synthetic medicinally important compounds. This review focus on both the chemical and biological importance of thiazole as a nanoparticle and the different methods of synthesis of substituted thiazole with potential activities, which are now in developing phase. [ABSTRACT FROM AUTHOR]

Background: Pelvic lipomatosis (PL) is a rare condition that is characterized by excessive growth of fat in the pelvic cavity. Studies have yet to systematically review surgical treatments for PL. Objectives: To provide a reference for selecting reasonable surgical treatments for PL patients according to previous literature on the surgical treatment of PL. Design and methods: We conducted this systematic review in accordance with the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) of Individual Participant Data guidelines. Literature on PL published from 1968 to 2022 was retrieved from the PubMed and EMBASE databases. Data were collected and analyzed independently by two independent investigators. Results: A total of 42 studies, involving 231 patients with PL, were included in the analysis. The surgical treatments included transurethral resection (TUR) (48.5%), ureteral stent placement (11.7%), percutaneous nephrostomy (1.3%), ureterocutaneostomy (1.3%), ureteral reimplantation (10.4%), ileal conduit (13%), and allograft kidney transplantation (0.4%). After excluding patients with unclear prognoses, 42.9% of patients showed improvement in lower urinary tract symptoms (LUTS) after TUR. Ureteral stent placement provided relief of hydronephrosis in 62.5% of PL patients. Percutaneous nephrostomy resulted in stable renal function in 33.3% of PL patients, while ureterocutaneostomy led to remission of postoperative hydronephrosis in 33.3% of PL patients. After ureteral reimplantation, 70.8% of patients experienced relief of hydronephrosis or had stable renal function. Ileal conduit led to remission of hydronephrosis, alleviation of symptoms, or maintenance of stable renal function in 83.3% of PL patients. One patient with PL had stable renal function after allograft renal transplantation. Conclusion: The surgical treatments for PL include TUR, ureteral stent placement, urinary diversion, and allograft renal transplantation. However, the choice of surgical method should be determined after comprehensive consideration of the patient’s condition. [ABSTRACT FROM AUTHOR]

COVID-19 is characterized by the immune system's overreaction resulting in a 'cytokine storm', consisting in a massive release of cytokine into the bloodstream, leading to local and systemic inflammatory response. This clinical picture is further complicated in case of infection of patients with a peculiar immunological status, such as pregnancy. In this paper, we focused on Interferon-γ, which plays a pivotal immunomodulatory role in normal pregnancy and fetal development, as well as in defense against pathogens. In this study, we compared the levels of Interferon-γ and the Interferon autoantibodies of the peripheral and cord blood of pregnant women with confirmed mild COVID-19 and healthy pregnant women. The Interferon-γ was significantly lower both in the peripheral and cord blood of SARS-CoV-2-positive mothers, suggesting that infection can affect the fetal microenvironment even without severe maternal symptoms. In conclusion, further studies are needed to clarify whether lower levels of Interferon-γ due to SARS-CoV-2 infection affect the development or infection susceptibility of infants born to SARS-CoV-2-infected mothers. [ABSTRACT FROM AUTHOR]

Background: Sanfu herbal patch (SHP) is widely used in the prevention and treatment of bronchial asthma in China, but its efficacy and mechanism of action are not completely clear. This trial aims to determine the efficacy of SHP and the underlying mechanism. Methods/design: We will conduct a multi-centre parallel randomised controlled trial consisting of 72 participants with bronchial asthma recruited and randomly allocated at a ratio of 1:1 into two groups. The patients in one group will receive three courses of SHP treatment, and the patients in the other group will receive placebo treatment, with 24 weeks of follow-up evaluation for both groups. The primary outcome, i.e. forced expiratory volume in the first second (FEV1), which refers to the change in FEV1 from the beginning of the baseline to the end of 3 treatment sessions (TSs), will be assessed and compared via Student's t test or the Mann–Whitney U test. Other outcomes will include questionnaire surveys and laboratory indicators. Detailed and complete statistical analyses in a double-blinded fashion will be provided for evaluating this trial. Discussion: The data we obtain will be examined based on the above statistical analysis, which will help to reduce the risk of external reporting bias and data-driven results. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR1900024616. Registered on 19 July 2019. [ABSTRACT FROM AUTHOR]

Background: Anti-interferon-γ autoantibody (AIGA) positivity is an emerging immunodeficiency syndrome closely associated with intracellular infection in individuals without human immunodeficiency virus (HIV). However, the information on epidemiology, pathogen spectrum, and immunotherapy among these patients lack a systematic description of large data. Methods: This systematic literature review and multicenter retrospective study aimed to describe the pathogen spectrum and review treatment strategies among patients with AIGA positivity. Results: We included 810 HIV-negative patients with AIGA positivity infected with one or more intracellular pathogens. Excluding four teenagers, all the patients were adults. The most common pathogen was nontuberculous mycobacteria (NTM) (676/810, 83.5%). A total of 765 NTM isolates were identified in 676 patients with NTM, including 342 (44.7%) rapid-grower mycobacteria, 273 (35.7%) slow-grower mycobacteria, and 150 (19.6%) unidentified NTM subtype. Even with long-term and intensive antimicrobial treatments, 42.6% of patients with AIGA positivity had recurrence and/or persistent infection. Sixty-seven patients underwent immunoregulatory or immunosuppressive therapy, and most (60) achieved remission. The most common treatment strategy was rituximab (27/67, 40.3%) and cyclophosphamide (22/67, 32.8%), followed by cyclophosphamide combined with glucocorticoids (8/67, 11.9%). Conclusions: Intracellular pathogen was the most common infection in patients with AIGA positivity. The predominant infection phenotypes were NTM, varicellazoster virus, Talaromyces marneffei, and Salmonella spp., with or without other opportunistic infections. AIGA immunotherapy, including rituximab or cyclophosphamide, has yielded good preliminary results in some cases. [ABSTRACT FROM AUTHOR]

Gemini surfactants are advantageous over conventional surfactants as they find applications as antimicrobial agents, corrosion inhibitors, enhanced oil recovery, capping agents for nanoparticle synthesis, drug delivery agents, etc. This article provides a detailed overview of synthetic procedures for various types of geminis and the fundamental physicochemical parameters of these systems. This includes a discussion on the cationic geminis based on various groups such as biphenyl, amide (with/without alkane tail), binol, quaternary ammonium (with/without hydroxyl group as a spacer), morpholinium, pyridinium, amide (with/without alkane tail), ester quaternary ammonium, and imidazolium (spacer with/without hydroxyl group and thioether/ester) types. Further, it is focused on anionic geminis with carboxylate, borate, and sulfonate head groups. Zwitterionic geminis such as betaine surfactants, cocogem surfactants based on dodecylisopropylol amine and dicarboxylic acid, diester type, sulphobetaine gemini based on S‐triazine, zwitterionic hetero gemini containing ammonium and carboxylate head groups, zwitterionic gemini containing quaternary ammonium and a sulfate group, gemini containing phosphodiester anion and quaternary ammonium salt are also reviewed. Lastly, synthesis of nonionic geminis from sunflower oil, amide‐based nonionic, sulfonamide nonionic, N,N'‐diethylaminedialkyldiamide nonionic gemini, sugar‐based gemini, and nonionic gemini with sulfonate spacer have been discussed. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, the syndrome is poorly understood and remains underdiagnosed, and female patients are diagnosed with a delay. The heterogenous nature of this complex disorder results from the combined occurrence of genetic, environmental, endocrine, and behavioral factors. Primary clinical manifestations of PCOS are derived from the excess of androgens (anovulation, polycystic ovary morphology, lack of or scanty, irregular menstrual periods, acne and hirsutism), whereas the secondary manifestations include multiple metabolic, cardiovascular, and psychological disorders. Dietary and lifestyle factors play important roles in the development and course of PCOS, which suggests strong epigenetic and environmental influences. Many studies have shown a strong association between PCOS and chronic, low-grade inflammation both in the ovarian tissue and throughout the body. In the vast majority of PCOS patients, elevated values of inflammatory markers or their gene markers have been reported. Development of the vicious cycle of the chronic inflammatory state in PCOS is additionally stimulated by hyperinsulinemia and obesity. Changes in DNA methylation, histone acetylation and noncoding RNA levels are presented in this review in the context of oxidative stress, reactive oxygen species, and inflammatory signaling in PCOS. Epigenetic modulation of androgenic activity in response to inflammatory signaling is also discussed. [ABSTRACT FROM AUTHOR]

This study was designed to (1) investigate the effects of acute exercise under intermittent hypoxia on muscle mRNA and protein levels, and (2) clarify the mechanisms by which exercise under intermittent hypoxia improves endurance capacity. Experiment‐1: Male mice were subjected to either acute endurance exercise, exercise under hypoxia (14% O2), exercise under intermittent hypoxia (Int, three cycles of room air [10 min] and 14% O2 [15 min]). At 3 h after exercise under intermittent hypoxia, sirtuin‐6 mRNA levels and nuclear prolyl hydroxylases‐2 protein levels were significantly upregulated in white gastrocnemius muscle in the Int group. Experiment‐2: Mice were assigned to sedentary control (Sed), normoxic exercise‐trained (ET), hypoxic exercise‐trained (HYP) or exercise‐trained under intermittent hypoxia (INT) groups. Exercise capacity was significantly greater in the INT group than in the ET and HYP group. Activity levels of citrate synthase were significantly greater in the INT group than in the HYP group in soleus (SOL) and red gastrocnemius muscles. In SOL, nuclear N‐terminal PGC1α levels were considerably increased by the INT training (95% confidence interval [CI]: 1.09–1.79). The INT significantly increased pyruvate dehydrogenase complex activity levels in left ventricle (LV). Monocarboxylate transporter‐4 protein levels were significantly increased after the INT training in LV. Capillary‐to‐fiber ratio values were significantly increased in SOL and were substantially increased in LV (CI: 1.10–1.22) after the INT training. These results suggest that exercise training under intermittent hypoxia represents a beneficial strategy for increasing endurance performance via improving metabolic properties and capillary profiles in several hind‐leg muscles and the heart. [ABSTRACT FROM AUTHOR]

Reports of eosinophilic pneumonia (EP) as a side effect of dupilumab administration are limited in previous studies. Herein, we report two cases in which EP developed subsequent to the administration of dupilumab for eosinophilic chronic rhinosinusitis (ECRS). Case 1: A 55-year-old woman presented with ECRS, eosinophilic otitis media, and bronchial asthma, and was treated with dupilumab for ECRS. Five weeks later, fever and dyspnea developed, and infiltration shadows were observed in her lungs. The peripheral blood eosinophil count (PBEC) was 3848/μL (26%), bronchoalveolar lavage fluid showed eosinophilic infiltration, and EP was subsequently diagnosed. Her condition improved following prednisolone treatment. Case 2: A 59-year-old man presented with fatigue and dyspnea after receiving dupilumab for ECRS. He had infiltrative shadows throughout his left lung field, and his PBEC was 4850/μL (26.5%). Prednisolone was initiated, and his condition improved. EP developed in both patients during the period of elevated PBEC after dupilumab administration, and dupilumab was suspected to be the causative agent in their EP. Hence, EP should be considered as a differential diagnosis when fever and dyspnea appear following dupilumab administration. [ABSTRACT FROM AUTHOR]

Purpose of Review: To summarize current guidance and best practices surrounding non-orthopedic medical concerns in baseball. Recent Findings: Discussion of COVID19-related practice changes pertaining to the prevention and screening of communicable respiratory illness, concussion protocol updates, the enhanced role of a multi-disciplinary team of mental health professionals. Summary: Prevention, appropriate screening, and early identification remain cornerstones of effective primary care both within the general population as well as for the baseball athlete. [ABSTRACT FROM AUTHOR]

Acute liver failure caused by drug overdose is a significant clinical problem in developed countries. Acetaminophen (APAP), a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. In addition to APAP-induced direct hepatotoxicity, the intracellular signaling mechanisms of APAP-induced liver injury (AILI) including metabolic activation, mitochondrial oxidant stress and proinflammatory response further affect progression and severity of AILI. Liver inflammation is a result of multiple interactions of cell death molecules, immune cell-derived cytokines and chemokines, as well as damaged cell-released signals which orchestrate hepatic immune cell infiltration. The immunoregulatory interplay of these inflammatory mediators and switching of immune responses during AILI lead to different fate of liver pathology. Thus, better understanding the complex interplay of immune cell subsets in experimental models and defining their functional involvement in disease progression are essential to identify novel therapeutic targets for the treatment of AILI. Here, this present review aims to systematically elaborate on the underlying immunological mechanisms of AILI, its relevance to immune cells and their effector molecules, and briefly discuss great therapeutic potential based on inflammatory mediators. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatmentmodality. [ABSTRACT FROM AUTHOR]

Carburization of cladding materials has long been a concern for the nuclear industry and has led to the restricted use of high-thermal conductivity fuels such as uranium carbides. With the rise of small modular reactors (SMRs) that frequently implement a graphite core-block, carburization of reactor components is once more in the foreground as a potential failure mechanism. To ensure commercial viability for SMRs, neutron-friendly cladding materials such as Zr-based alloys are required. In this work, the carburization kinetics of Zircaloy-4 (Zry-4), for the temperature range 1073–1673 K (covering typical operating temperatures and off-normal scenarios) are established. The following Arrhenius relationship for the parabolic constant describing ZrC growth is derived: Kp (in μm2/s) = 609.35 exp(−1.505 × 105/RT)). Overall, the ZrC growth is sluggish below 1473 K which is within the operational temperature range of SMRs. In all cases the ZrC that forms from solid state reaction is hypo-stoichiometric, as confirmed through XRD. The hardness and elastic modulus of carburized Zry-4 are also examined and it is shown that despite the formation of a ZrC layer, C ingress in the Zry-4 bulk does not impact the mechanical response after carburization at 1073 K and 1473 K for 96 h. [ABSTRACT FROM AUTHOR]

In the present work, 1-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl) thiazol-5-yl)ethanone was used as building block for synthesis of novel four series of 5-(1-(2-(thiazol-2-yl)hydrazono)ethyl) thiazole derivatives in a one-pot three-component reaction using both thermal heating and microwave irradiation for comparison. All the structures of the synthesized compounds were elucidated based on their elemental analyses and spectral measurements. The bioactivities of the synthesized compounds were evaluated their antitumor activities against MCF-7 tumor cells in comparison with vinblastine sulfate and cisplatin reference drugs using MTT assay and the results revealed promising activities of five compounds (4d, 8b, 12e, 4a, and 12d). [ABSTRACT FROM AUTHOR]

Krabbe disease (KD) is a rare autosomal recessive disorder caused by mutations in the galactocerebrosidase gene (GALC). Defective GALC causes aberrant metabolism of galactolipids present almost exclusively in myelin, with consequent demyelinization and neurodegeneration of the central and peripheral nervous system (NS). KD shares some similar features with other neuropathies and heterozygous carriers of GALC mutations are emerging with an increased risk in developing NS disorders. In this work, we set out to identify possible variations in the proteomic profile of KD-carrier brain to identify altered pathways that may imbalance its homeostasis and that may be associated with neurological disorders. The differential analysis performed on whole brains from 33-day-old twitcher (galc −/−), heterozygous (galc +/−), and wild-type mice highlighted the dysregulation of several multifunctional factors in both heterozygous and twitcher mice. Notably, the KD-carrier mouse, despite its normal phenotype, presents the deregulation of vimentin, receptor of activated protein C kinase 1 (RACK1), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP), transitional endoplasmic reticulum ATPase (VCP), and N-myc downstream regulated gene 1 protein (NDRG1) as well as changes in the ubiquitinated-protein pattern. Our findings suggest the carrier may be affected by dysfunctions classically associated with neurodegeneration: (i) alteration of (mechano) signaling and intracellular trafficking, (ii) a generalized affection of proteostasis and lipid metabolism, with possible defects in myelin composition and turnover, and (iii) mitochondrion and energy supply dysfunctions. [ABSTRACT FROM AUTHOR]

Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity. [ABSTRACT FROM AUTHOR]

Vitamin D is commonly known for its properties of airway remodeling inhibition. Due to this, we decided to analyze the action of calcitriol with anti-asthmatic drugs in airway remodeling. The HFL1 cell line was treated with calcitriol, beclomethasone 17-propionate, montelukast sodium, LTD4 and TGF-β in different combinations. Real-time PCR was used to analyzed the expression of ACTA2, CDH-1, Vimentin, ADAM33, MMP-9 and CysLTR1 on the mRNA level, whereas Western blot was used to analyze gene expression on the protein level. One-way analysis variants, the Kruskal-Wallis test, Student's t-test or Welch's t-test were used for statistical analysis. Concerning the results, pre-treatment with calcitriol increased the inhibitory effect of beclomethasone 17-propionate and montelukast sodium on the expression of ACTA2 (p = 0.0072), Vimentin (p = 0.0002) and CysLTR1 (p = 0.0204), and 1,25(OH)2D3 had an influence on the effects of beclomethasone 17-propionate and montelukast sodium and of CDH1 expression (p = 0.0076). On the protein level, pre-treatment with calcitriol with beclomethasone 17-propionate and montelukast sodium treatment decreased ACTA2 expression in comparison to the LT (LTD4 and TGF-β) control group (p = 0.0191). Hence, our study not only confirms that vitamin D may inhibit airway remodeling, but also shows that vitamin D has a synergistic effect with anti-asthmatic drugs. [ABSTRACT FROM AUTHOR]

Purpose: Recently, single-inhaler triple therapy (SITT) has demonstrated efficacy in patients with uncontrolled asthma who were symptomatic despite treatment with inhaled corticosteroids/long-acting β 2 agonists. However, the characteristics of patients who benefit from SITT remain unclear in the real-world. The aim of this study was to examine the predictors of responsiveness to SITT in patients with asthma. Patients and Methods: A total of 45 patients with asthma who had regularly visited our respiratory clinic and were started on SITT from March 2019 to March 2021 were retrospectively analyzed. Patients' demographic characteristics, residual respiratory symptoms, type 2 biomarkers, and lung function before SITT were assessed from the patients' medical records. Predictors of responsiveness to four-week SITT were evaluated in these patients. The definition of responders was based on the physician-assessed global evaluation of treatment effectiveness. Results: Thirty-four (75%) of 45 patients were identified as responders to SITT. Non-responders showed significantly lower forced vital capacity (FVC) (%predicted) values, and complained of dyspnea more frequently than responders before SITT (p = 0.01 and p = 0.02, respectively). There were no significant differences in demographic characteristics and type 2 biomarkers between responders and non-responders. Clinical predictors of poor response to SITT were residual dyspnea (OR = 0.14, p = 0.02), low FVC (%predicted) values (OR = 1.05, p = 0.01), and FVC (%predicted) < 80% (OR = 0.11, p = 0.02). Multivariate analysis showed that poor response to SITT was associated with residual dyspnea before SITT (OR = 0.14, p = 0.02). On the other hand, patients with residual dyspnea had significantly lower FEF25– 75 (%predicted) values than patients without residual dyspnea before SITT (p = 0.04). Conclusion: Residual dyspnea, reflecting small airways dysfunction, may predict poor responsiveness to short-term SITT in patients with asthma. [ABSTRACT FROM AUTHOR]

Prostacyclin is a metabolic product of the cyclooxygenase pathway that is constitutively expressed and can be induced during inflammatory conditions. While prostacyclin and its analogs have historically been considered effective vasodilators and used in treating pulmonary hypertension, prostacyclin has demonstrated potent anti-inflammatory effects in animal models of allergic airway inflammation. In vitro studies reveal that prostacyclin directly inhibits type 2 cytokine production from CD4+ Th2 cells and ILC2 and reduces the ability of dendritic cells to generate Th2 cytokine production from CD4+ T cells in an antigen-specific manner. Thus, there is strong evidence that prostacyclin may be an additional therapeutic target for treating allergic inflammation and asthma in human subjects. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is an immune-mediated inflammatory condition characterized by immune cell infiltration of the nasal mucosa, with symptoms of rhinorrhea, sneezing, nasal obstruction, and itchiness. Currently, common medication for AR is anti-inflammatory treatment including intranasal steroids, oral, or intranasal anti-histamines, and immunotherapy. These strategies are effective to the majority of patients with AR, but some patients under medication cannot achieve symptom relieve and suffer from bothersome side effects, indicating a demand for novel anti-inflammatory treatment as alternatives. Chemokines, a complex superfamily of small, secreted proteins, were initially recognized for their chemotactic effects on various immune cells. Chemokines constitute both physiological and inflammatory cell positioning systems and mediate cell localization to certain sites via interaction with their receptors, which are expressed on responding cells. Chemokines and their receptors participate in the sensitization, early phase response, and late phase response of AR by promoting inflammatory cell recruitment, differentiation, and allergic mediator release. In this review, we first systemically summarize chemokines and chemokine receptors that are important in AR pathophysiology and then discuss potential strategies targeting chemokines and their receptors for AR therapy. [ABSTRACT FROM AUTHOR]

The article discusses stress-induced asthma and offers key insights for its prevention and management. Topics covered include the various types of stress that are associated with asthma symptoms, the symptoms of stress-induced asthma and how stress can cause asthma symptoms, and the difference of asthma attack from panic attack.

Leukotriene B4 (LTB4) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB4 are primarily mediated through the high-affinity LTB4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB4-BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1–3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB4-BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE) provides a liquid tumor microenvironment model that includes cancer cells and immune cells. However, the characteristics of tumor antigen-specific CD8+ T cells have not been investigated in detail. Here, we analyzed MPE samples taken from a patient with pancreatic cancer who received a dendritic cell vaccine targeting Wilms' Tumor 1 (WT1) antigen over the disease course (two points at MPE1st and 2nd, two months after MPE1st). Epithelial cell adhesion molecule (EpCAM)+ cancer cells (PD-L1− or T cell immunoglobulin mucin-3, TIM-3−), both PD-1 or TIM-3 positive CD8+ T cells, and CD14+CD68+CD163+TIM-3+ macrophages increased from the MPE1st to MPE2nd. The ratio of WT1-specific cytotoxic lymphocytes (WT1-CTLs) to MPE CD8+ T cells and IFN-γ secretion of WT1-CTLs were reduced with disease progression. Coincidentally, the fraction of central memory T (TCM) of WT1-CTLs was decreased. On the other hand, CD8+ T cells in response to SMAD4P130L, which is homogeneously expressed in EpCAM+ cancer cells, were detected using in vitro expansion with the HLA-A*11:01 restrictive SVCVNLYH neoantigen. Furthermore, the CD8+ T cell response to SMAD4P130L was diminished following remarkably decreased numbers of CD8+ TCM in MPE samples. In conclusion, CD8+ T cells responding to WT1 or SMAD4P130L neoantigen expressed in EpCAM+ pancreatic cancer cells were detected in MPE. A tumor antigen-specific immune response would provide novel insight into the MPE microenvironment. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity, especially in genetic alteration and microenvironment. Conventional therapeutic strategies for pancreatic cancer usually suffer resistance, highlighting the necessity for personalized precise treatment. Cancer vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting, minimal nonspecific effects, broad therapeutic window, low toxicity, and induction of persistent immunological memory. Multiple conventional vaccines based on the cells, microorganisms, exosomes, proteins, peptides, or DNA against pancreatic cancer have been developed; however, their overall efficacy remains unsatisfactory. Compared with these vaccine modalities, messager RNA (mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment, and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic cancer. This review summarizes the current progress on pancreatic cancer vaccines, highlights the superiority of mRNA vaccines over other conventional vaccines, and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Obesity is linked to reproductive disorders. Novel neuropeptide phoenixin demonstrated many therapeutic actions. In this study, we aim to evaluate phoenixin's potential effect in obesity-induced infertility through modulating mitochondrial dynamics. Ninety adult female rats were divided to 4 groups: (I), fed with normal pellet diet; (II), given phoenixin; (III), fed with high-fat diet. Rats that developed obesity and infertility were divided to 2 groups: (III-A), received no further treatment; (III-B), given phoenixin. Our results showed that phoenixin treatment in obese infertile rats significantly decreased serum levels of insulin and testosterone and ovarian levels of dynamin-related protein1(Drp1),reactive oxygen species ROS, TNF-α, MDA, and caspase-3. Phoenixin treatment also significantly increased serum estrogen progesterone, LH, and FSH together with ovarian levels of GnRH receptor (GnRHR), mitofusin2(Mfn2), mitochondrial transmembrane potential (ΔΨm), and electron transport chain (ETC) complex-I significantly when compared with obese group. Ovarian histopathological changes were similarly improved by phoenixin. Our data demonstrate phoenixin's role in improving obesity-induced infertility. [ABSTRACT FROM AUTHOR]

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot–Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot–Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases. [ABSTRACT FROM AUTHOR]

Purpose: Few questionnaires evaluate daytime and nighttime symptoms separately, although these assessments could contribute to the improvement of disease control levels and prevention of future risks in asthma. The purpose of this retrospective study was to investigate whether daytime and nighttime visual analog scales (VAS) are useful in measuring the perception of symptoms, assessing disease control levels, and evaluating the treatment effects in asthma. Patients and Methods: Self-reporting asthma control tests (ACT) before and after treatment are standardized tests used to determine disease control levels. A multiple regression analysis was performed to determine the correlation between daytime and nighttime VAS and the characteristics of patients before treatment, as well as the changes in VAS and lung functions and fractional exhaled nitrogen oxide after treatment in 55 treatment-naïve symptomatic adult patients with asthma. Results: Both daytime (r = − 0.57, P < 0.0001) and nighttime (r = − 0.46, P < 0.0001) VAS correlated well with ACT scores, and there was a correlation between daytime and nighttime VAS (r = 0.33, P = 0.0148) before treatment. In addition, the changes in daytime (r = − 0.65, P < 0.0001) and nighttime (r = − 0.44, P < 0.0001) VAS were significantly associated with changes in the ACT scores. The multiple regression analysis (β [95% confidence interval]) revealed that improvements in the daytime (− 2.33 [− 4.55 to − 0.11], P = 0.0405) and nighttime (− 3.09 [− 6.25 to 0.07], P = 0.0505) VAS were associated with an increased forced vital capacity after treatment, although there was no correlation between the VAS and characteristics before treatment. Conclusion: Our study demonstrated that daytime and nighttime VAS were useful in assessing disease control levels and evaluating the treatment effects in asthma. [ABSTRACT FROM AUTHOR]

Purpose: Asthma guidelines recommend considering the patient preference to optimize medication choices. Patient preference for inhaler medication may affect asthma outcomes, but evidence regarding this is lacking. This study investigated the associations between patient preference for inhaler medications and asthma outcomes. Patients and Methods: A multicenter questionnaire survey was conducted among 351 adult patients with asthma treated with regular inhaled corticosteroids. Agreement between patients' preferences and current medication was evaluated using two questions: matched preference was defined as patients answering that the current inhaler medication was the most preferred treatment and they were satisfied with it. Mismatched preference was defined as when patients reported that the current inhaler medication was not the most preferred treatment and/or they were not satisfied with it. We investigated the factors associated with patient preference for asthma inhaler medications. Results: In total, 269 (76.6%) patients were classified into the matched preference group and 82 (23.4%) patients into the mismatched preference group. Multivariate analyses showed that matched preference was independently associated with higher asthma control test scores (P< 0.001), fewer exacerbations (P=0.009), less regular oral corticosteroid use (P=0.009), and better inhaler adherence (P=0.006) than the mismatched preference group. In subgroup analysis, younger age was associated with matched preference in patients using dry powder inhalers but not in those using pressurized metered dose inhalers. Conclusion: The use of preference-matched inhaler medication was associated with better asthma outcomes. Evaluation of patients' preference for inhaler medication might provide useful information for individualized treatment with asthma inhaler medications. [ABSTRACT FROM AUTHOR]

Acquiring English collocations poses a major challenge for second language (L2) learners. It has been well noted that even advanced L2 English learners have difficulty using basic verb + noun collocations. Among the factors that make it difficult to acquire L2 collocations, the influence of learners' first language (L1) has been repeatedly pointed out in the literature. As learners' L1 and target language (L2) use data can help us to examine L1 influence effectively, in this study, we used a bilingual essay corpus, in which the same individuals (n = 524) produced L1 and L2 essays on the same topic, to investigate the relationship between Japanese efl (English as a foreign language) learners' L1 and their English collocation use in written essays. We also referred to essays written by native speakers of English on the same topic as a reference corpus (n = 200). The proficiency level of 524 individuals in the learner corpus data was divided into three levels according to the Common European Framework of Reference (cefr): A2 (Waystage), B1 (Threshold) and B2 (Vantage). We focussed on the use of 'make + noun' collocations as the target structure in this study and extracted them from the two corpora. Results suggest that, although the differences between the learner levels were not found to be statistically significant, the learners underused make + noun collocations with less variation, compared with native speakers of English. The pedagogical implications of this finding are discussed in terms of materials and syllabus development for efl learners. [ABSTRACT FROM AUTHOR]

This study intended to explore the different types of phraseological units in IELTS academic writing task 2 and probe into the IELTS candidates' perceptions of phraseological competence. To this end, a corpus entailing 100 essays (26,423 words) written for IELTS writing task 2 was scrutinized, through which phraseological units were extracted and their types were identified based on Moon's (Phraseology: Theory, analysis, and application, 1998) typology. In addition, semi-structured interviews were conducted with nine IELTS candidates. The results indicated that simple formulae were the most commonly used phraseological units in IELTS writing task 2. The interview data, using inductive thematic and summative content analyses, also demonstrated that IELTS candidates have had varying perceptions of phraseological competence, wherein higher band score candidates appeared to have a deeper and more accurate understanding of the concept. As for the candidates' perceived phraseological competence, they were found to under- or overestimate their own competence at using phraseology. The findings of the study can be employed in making learner dictionaries based on the phraseologies used in IELTS. [ABSTRACT FROM AUTHOR]

Background: Anti-interferon-gamma autoantibody-associated immunodeficiency syndrome is a rare and underrecognized adult onset immunodeficiency syndrome associated with severe opportunistic infections such as disseminated nontuberculous mycobacterium. Few cases have documented a relationship with IgG4-related disease. Concomitant diagnoses of these diseases present a diagnostic and management challenge. Case presentation: A 61 year old man of Southeast Asian descent with pulmonary mycobacterium avium complex infection presented to our hospital system with a new skin rash and worsening lymphadenopathy. He was eventually diagnosed with IgG4-related disease through excisional nodal biopsy. He was managed with immunosuppressive treatment with prednisone, rituximab and cyclophosphamide. He later re-presented with disseminated mycobacterium avium complex infiltration of his joints, bones and prostate. Original titers of anti-interferon-gamma autoantibodies were falsely negative due to being on immunosuppressive therapy for his IgG4-related disease. However, anti-interferon-gamma autoantibody titers were re-sent after immunosuppression was held and returned strongly positive. Conclusions: This case reviews diagnostic criteria and discusses management strategies with existing challenges in treating a patient with concomitant adult onset immunodeficiency syndrome, IgG4-related disease and a disseminated mycobacterial avium complex infection. [ABSTRACT FROM AUTHOR]

In most cases, herbal supplements found in illegal centers and herbal medicine stores have harmful content that causes irreparable damage to people. As a representative of the green chemistry method, a rapid and efficient dispersive micro solid-phase extraction (D-mSPE) method was applied to extract dexamethasone adulterant from handmade supplements sold as power natural enhancing materials. The quantification of the analyte was performed by high performance liquid chromatography with an ultraviolet detector. Effective parameters on the extraction recovery, including the type and amount of adsorbent, the kind of elution solvent, and the time of extraction and elution, were systematically investigated. The limit of detection of the method was 0.05 μg mL–1. Furthermore, inter-day precisions calculated as relative standard deviations were better than 10%. Ten dietary supplements, including liquid, capsule, tablet forms, and powder, were analyzed using the developed method, and four of them were detected as adulterated with dexamethasone. The developed method purifies the complex plant-based samples and results in a clean analysis with separation instruments. [ABSTRACT FROM AUTHOR]

Allergic respiratory diseases (ARDs) are still a major burden on global public health. Sublingual immunotherapy (SLIT) is a mode of allergen immunotherapy (AIT) which involves administration of the allergen under the tongue, and benefits from tolerogenic properties of the oral mucosa. Studies revealed reduced levels of eosinophilia and eosinophil-dominated inflammation in airways of both animals and humans after SLIT. SLIT was also suggested to lower basophil responsiveness and innate lymphoid cell-2 function in blood samples collected from patients with ARD. Moreover, apart from shifting pathogenic type 2 (TH2) to a type 1 (TH1) and protective regulatory (Treg) polarization of helper T-cell immune response, antibody isotype switch from IgE to IgG1, IgG2, IgG4 and IgA was also reported in patients with ARD receiving SLIT. Today, the literature on SLIT-mediated activities is still scarce and more studies are required to further enlighten the mechanisms utilized by SLIT for the induction of tolerance. The aim of this review is to summarize the current knowledge about the immune-regulatory mechanisms induced by SLIT against ARDs. [ABSTRACT FROM AUTHOR]

Treatment adherence, asthma control, inhaler satisfaction, and quality of life of patients with asthma were investigated to examine whether there were any differences between conventional fixed combined therapy and maintenance and reliever therapy after inhaler education. Cross-sectional observational follow-up of 120 patients with asthma receiving third- and fourth-step treatment was completed at zero, three, and six months. Fifty-eight patients received long-acting beta-agonists or inhaler corticosteroids (ICS) as maintenance therapy and short-acting beta-agonists (SABA) as reliever therapy (CONV) with Diskus and Ellipta devices. Sixty-two patients received ICS/formoterol as maintenance and reliever therapy (MART) with metered-dose inhaler and Turbuhaler devices. The asthma control test (ACT), feeling of satisfaction with the inhaler (FSI-10) questionnaire, Morisky Green Levine (MGL) scale, and quality of life questionnaire (AQLQ) were evaluated at each visit. Significant improvement was observed in the ACT, AQLQ, FSI-10, MGL scales, and inhaler technique in both groups over time (p < 0.05). There was no difference in the MGL scale between the groups at all visits. Nonadherence was highest in the Diskus device group (55%) and lowest in the Ellipta device group at the first visit (25%). While 36% of the patients had low adherence at the first visit, this decreased to 12% by the last visit. A significant correlation was found between ACT and MGL at all visits (p < 0.001). Asthma control, adherence, inhaler satisfaction, and quality of life improved equally with regular follow-up and standard inhaler education in the CONV and MART groups. [ABSTRACT FROM AUTHOR]