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Perinatal tissues, mainly the placenta and umbilical cord, contain a variety of different somatic stem and progenitor cell types, including those of the hematopoietic system, multipotent mesenchymal stromal cells (MSCs), epithelial cells and amnion epithelial cells. Several of these perinatal derivatives (PnDs), as well as their secreted products, have been reported to exert immunomodulatory therapeutic and regenerative functions in a variety of pre-clinical disease models. Following experience with MSCs and their extracellular vesicle (EV) products, successful clinical translation of PnDs will require robust functional assays that are predictive for the relevant therapeutic potency. Using the examples of T cell and monocyte/macrophage assays, we here discuss several assay relevant parameters for assessing the immunomodulatory activities of PnDs. Furthermore, we highlight the need to correlate the in vitro assay results with preclinical or clinical outcomes in order to ensure valid predictions about the in vivo potency of therapeutic PnD cells/products in individual disease settings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Papait, Silini, Gazouli, Malvicini, Muraca, O’Driscoll, Pacienza, Toh, Yannarelli, Ponsaerts, Parolini, Eissner, Pozzobon, Lim and Giebel.)

This study indicates the presence of quercetin in subfraction F1 and the standardized value of F1 derived from research using ultra-performance liquid chromatography (UPLC) and AlCl 3 colorimetric assays, which further proved that both F1 and quercetin are potential growth inhibitors in MDA-MB-231 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the process, staining of F1-treated cells with annexin/propidium iodide (PI) reduced cell proliferation and induced only S and G2 phases of cell cycle arrest in the treated cells by flow cytometry. Quercetin reduced cell proliferation by inducing apoptosis and S phase arrest. The 5'-bromo-2'-deoxyuridine (BrdU) incorporation of DNA synthesis in MDA-MB-231 cells was also inhibited after F1 and quercetin treatments. F1 and quercetin induced CYP1A1 and CYP1B1 gene expression, but only F1 induced CYP2S1 gene expression in the treated cells. Both F1 and quercetin inhibited the proliferation of MDA-MB-231 cells in different ways, but F1 is likely a better potential anticancer agent derived from the green approach towards breast cancer treatment., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Kar Xin Leong et al.)

The emergence of bacterial infections in companion animals is a growing concern as humans can also be infected through the transmission of pathogenic bacteria. Because there have been few studies conducted on companion animals, the extent and significance of prevalence in veterinary practices remain unknown. This is the first nationwide surveillance report aimed at elucidating the prevalence pattern and associated infections of isolated bacteria from dogs in Korea. Bacterial isolates were collected from seven different laboratories participating in the Korean Veterinary Antimicrobial Resistance Monitoring System from 2018 to 2019. The samples were obtained from the diarrheal stool, skin/ear, urine, and respiratory samples of veterinary hospital-visited dogs. Isolation and identification of bacterial species was carried out using a bacterial culture approach and then confirmed with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF) and polymerase chain reaction (PCR). Out of 3135 isolates in dogs, 1085, 1761, 171, and 118 were extracted from diarrheal stool, skin/ear, urine, and respiratory samples, respectively. The overall prevalence of bacteria was higher among two age groups (1-5 and 6-10 years) with a 66.5 percent prevalence. This study showed that Escherichia coli was the most prevalent species among isolated bacterial species of diarrheal and urine origin, whereas Staphylococcus pseudintermedius was the most prevalent among skin and respiratory sample isolates. The data on the prevalence of bacteria for each dog specimen could provide basic information to estimate the extent of bacterial infection and antimicrobial resistance development and to guide veterinarians in therapeutic decisions in clinical practices throughout Korea.

Alcoholic liver disease (ALD), which includes fatty liver, cirrhosis, steatosis, fibrosis, and hepatocellular carcinoma, is a global health problem. The probiotic effects of lactic acid bacteria (LAB) are well-known; however, their protective effect against ALD remains unclear. Therefore, in this study, our objective was to assess the protective effects of LAB on ALD. To this end, mice were fed either a normal diet or an alcohol diet for 10 days (to induce ALD) accompanied by vehicle treatment (the NC and AC groups) or kimchi-derived LAB ( Lactiplantibacillus plantarum DSR J266 and Levilactobacillus brevis DSR J301, the AL group; or Lacticaseibacillus rhamnosus GG, the AG group). Our results showed that mice in the AC group showed significantly higher serum aspartate aminotransferase and alanine aminotransferase levels than those in the normal diet groups; however, their levels in the AL and AG groups were relatively lower. We also observed that the AL and AG groups showed relatively lower interleukin-6 levels than the AC group. Additionally, AC group showed the accumulation of several fat vesicles in the liver, while the AL and AG groups showed remarkably lower numbers of fat vesicles. The relative abundance of Enterococcus feacalis , which showed association with liver injury, significantly increased in the AC group compared with its levels in the normal diet groups. However, the AG group showed a decreased relative abundance in this regard, confirming that LAB exerted an improvement effect on gut microbial community. These findings suggested that via gut microbiota alteration, the ingestion of LAB can alleviate the ill effects of alcohol consumption, including inflammation, liver damage, gut dysbiosis, and abnormal intestinal nutrient metabolism., Competing Interests: JK, SA, JYK, and SR were employed by the LISCure Biosciences Inc. BR was employed by the Daesang Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Ahn, Kim, Whon, Lim, Ryu, Han, Choi, Roh and Lee.)

The immune functions of heat-killed Limosilactobacillus reuteri PSC102 (hLR) were investigated in cyclophosphamide (CP)-treated immunosuppressed mice. BALB/c mice were randomly divided into five groups: normal control group, CP group, CP treated with levamisole (positive control group), and CP treated with low- and high-dose hLR. After receiving the samples for 21 days, mice were sacrificed, and different parameters, such as immune organ index, immune blood cells, splenocyte proliferation, lymphocyte subpopulations, cytokines, and immunoglobulins, were analyzed. Results showed that the immune organ (thymus and spleen) indices of hLR treatment groups were significantly increased compared to the CP group ( p < 0.05). hLR administration prevented CP-induced reduction in the numbers of white blood cells, lymphocytes, midrange absolute, and granulocytes, providing supporting evidence for hematopoietic activities. Splenocyte proliferation and T-lymphocyte (CD4 + and CD8 + ) subpopulations were also significantly augmented in mice treated with hLR compared to the CP group ( p < 0.05). Moreover, Th1-type [interferon-γ, interleukin (IL)-2, and tumor necrosis factor-α] and Th2-type (IL-4 and IL-10) immune factors and immunoglobulin (IgG) showed significant increasing trends ( p < 0.05). Additionally, the other proinflammatory cytokines (IL-1β and IL-6) were also significantly elevated ( p < 0.05). Taken together, this investigation suggested that orally administered hLR could recover immunosuppression caused by CP and be considered a potential immunostimulatory agent for the treatment of immunosuppressive disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ali, Lee, Quah, Birhanu, Suk, Lim and Park.)

A high-fat diet (HFD) induces low-grade, chronic inflammation throughout the body including the hypothalamus, a key brain region involved in the control of satiety and energy expenditure in central nervous system (CNS). Kimchi is a traditional fermented Korean food, which is recognized as a healthy food. In this study, we evaluated its ability to suppress the obesity-induced inflammation in mice fed an HFD. Male C57BL/6 mice were fed an HFD or HFD with kimchi (pH 5.2 ∼ 5.8). Oral administration of kimchi significantly reduced the body weight, fat mass gain, and levels of pro-inflammatory cytokines in serum. Furthermore, kimchi diminished the HFD-induced activation of astrocyte and microglial cells (reactive gliosis, a hallmark of CNS injury and inflammation) in hypothalamus region. IgG accumulation assay showed that kimchi ingestion suppressed HFD-induced breakage of the blood brain barrier (BBB) via upregulating the expression of tight junction molecules in cerebrovascular endothelial cells. In addition, kimchi modulated gut microbiome profiles, which showed an increase in the abundance of Akkermansia muciniphila. Moreover, kimchi enhanced acetate level and BBB integrity in A. muciniphila-colonized gnotobiotic mice. These results suggest that kimchi may exert beneficial effects to prevent and ameliorate obesity and associated neuroinflammation by changing gut microbiota composition and short-chain fatty acids production., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Complements and neutrophils are two key players of the innate immune system that are widely implicated as drivers of severe COVID-19 pathogenesis, as evident by the direct correlation of respiratory failure and mortality with elevated levels of terminal complement complex C5b-9 and neutrophils. In this study, we identified a feed-forward loop between complements and neutrophils that could amplify and perpetuate the cytokine storm seen in severe SARS-CoV-2-infected patients. We observed for the first time that the terminal complement activation complex C5b-9 directly triggered neutrophil extracellular trap (NET) release and interleukin (IL)-17 production by neutrophils. This is also the first report that the production of NETs and IL-17 induced by C5b-9 assembly on neutrophils could be abrogated by mesenchymal stem cell (MSC) exosomes. Neutralizing anti-CD59 antibodies abolished this abrogation. Based on our findings, we hypothesize that MSC exosomes could alleviate the immune dysregulation in acute respiratory failure, such as that observed in severe COVID-19 patients, by inhibiting complement activation through exosomal CD59, thereby disrupting the feed-forward loop between complements and neutrophils to inhibit the amplification and perpetuation of inflammation during SARS-CoV-2 infection., Competing Interests: Declaration of Competing Interests SKL holds founding shares in Paracrine Therapeutics., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background/aim: Inhalation toxicity tests of glycolic acid, which is used in many household products, have been reported, but the pulmonary toxicity of glycolic-acid has not been confirmed. Here, the lung damage caused by glycolic acid was investigated in rats., Materials and Methods: An intratracheal instillation test was performed with glycolic acid in male rats. Bronchoalveolar lavage fluid (BALF) and histopathological analysis were conducted to identify the pulmonary toxicities., Results: Intratracheal instillation of glycolic acid caused weight loss in animals and increased the content of lactate dehydrogenase, total protein, polymorphonuclear neutrophils, and inflammatory cytokines in BALF. In addition, pulmonary edema, alveolar/interstitial inflammation, and necrosis and desquamation of bronchial/bronchiolar epithelia were confirmed via histopathological examination., Conclusion: Exposure to glycolic acid can be harmful and toxic to the lungs., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hypertension is highly prevalent and a major contributor to cardiovascular mortality and morbidity. In spite of the availability of efficacious, safe and affordable anti-hypertensive drugs, hypertension remains poorly controlled in the majority of hypertensive patients. Various reasons including non-adherence to the anti-hypertensive drugs, account for the poor control. Resistant hypertension is also one of the reasons for poor control of blood pressure (BP). The sympathetic nervous system (SNS) has long been recognized as one of the determinants in the pathophysiology of a raised BP. Overactivity of the SNS is a contributor to sustained arterial hypertension. Renal denervation (RDN) is increasingly recognized as a safe and effective adjunctive therapy to control BP with or without pharmacotherapy. Hence for patients who remain uncontrolled despite all efforts, renal denervation (RDN) is a novel treatment that can potentially improve BP control, hence reducing the major adverse cardiovascular events (MACE). More recent randomized, sham control trials of RDN have shown that RDN produces a sustained lowering of BP. To date, this lowering of BP through RDN is maintained for at least 3 years. Furthermore, this procedure has been found to be safe. Hence this consensus summarises the science behind RDN and the available clinical data to support the use of this therapy. It is hoped that this consensus will offer guidance on the importance of identifying patients who will benefit most from this therapy. A multidisciplinary team approach in the management of the patient undergoing RDN is recommended., (© 2022. The Author(s).)

To exploit insect-derived fungi, insects were collected from seven different regions in Korea, including Gyeongbuk, Goryeong, and several fungi were isolated from them. A fungal strain designated 21-64-D was isolated from riparian tiger beetle ( Cicindela transbaicalica ) and morphologically identified as a species belonging to the genus Oidiodendron . Phylogenetic analysis using the nucleotide sequences of internal transcribed spacer (ITS) regions and the partial sequence of the large subunit of the nuclear ribosomal RNA (LSU) gene revealed the distinct phylogenetic position of the isolate among recognized Oidiodendron species including its closest neighbors O. chlamydosporicum , O. citrinum , O. maius , and O. pilicola . The hyphal and conidial morphology of the strain, particularly club-shaped hyphae, clearly differentiated it from its close relatives. Results indicated that 21-64-D is a novel species in the genus Oidiodendron , for which the name Oidiodendron clavatum sp. nov. is proposed., Competing Interests: The authors declare no potential conflict of interest., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Korean Society of Mycology.)

Background: The objective of this study was to examine the therapeutic effects of human mesenchymal stromal/stem cell (MSC) exosomes in a rat model of growth plate injury., Methods: A growth plate defect was surgically created on the distal part of the right femur of 40 female Sprague-Dawley rats. A single intra-articular injection of 100 µg of MSC exosomes in 100 µL of phosphate-buffered saline solution (PBS), or an equivalent volume of PBS alone, was administered to the right knee immediately after surgery. At 4 and 8 weeks post-treatment, limb length was measured with micro-CT, and tissue repair was assessed with histological, immunohistochemical, and histomorphometric analyses., Results: A single injection of MSC exosomes significantly increased limb length from 3.29 ± 0.07 cm at 4 weeks to 3.37 ± 0.11 cm at 8 weeks (p = 0.047). However, no improvement in limb length was observed in the PBS control group. The limb-length discrepancy between the involved limb and the contralateral limb in the exosome-treated group was significantly less than the discrepancy in the PBS-treated group at both 4 weeks (2.52% ± 1.30% versus 4.11% ± 0.93%; p = 0.006) and 8 weeks (5.27% ± 2.11% versus 8.06% ± 2.56%; p = 0.016). Consistent with the reduced limb-length discrepancy, the exosome-treated defects displayed significantly more chondrocytes (p < 0.05) and a higher area percentage with deposition of sulphated glycosaminoglycan (p < 0.05) and collagen II (p < 0.05) than PBS-treated defects at 8 weeks. However, bone bridge formation was not inhibited in either group., Conclusions: A single intra-articular injection of MSC exosomes significantly enhanced physeal repair and reduced limb-length discrepancy but did not inhibit bone-bridge formation., Clinical Relevance: This proof-of-concept study demonstrates for the first time the potential use of MSC exosomes as a minimally invasive cell-free therapeutic to promote physeal repair and reduce limb-length discrepancy following growth plate injuries., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G937)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Background: Recently, the Asian Working Group for Sarcopenia (AWGS) 2019 consensus redefined the sarcopenia including possible sarcopenia, sarcopenia and severe sarcopenia and grip strength cutoff value by sex., Aims: This study aimed to assess the prevalence, physical characteristics, physical fitness, and fall risk in older adults living in local communities, with possible sarcopenia using the diagnostic criteria suggested by the AWGS 2WG., Methods: A total of 431 participants (123 men and 308 women) aged 65-97 years were enrolled in this study. Based on the diagnostic criteria of possible sarcopenia suggested by AWGS 2, study participants were divided into normal and possible sarcopenia (grip strength: < 28 kg and < 18 kg for men and women, respectively) groups. Independent t-tests and logistic regression analyses were conducted to compare the differences between the two groups., Results: The possible prevalence of sarcopenia was 23.7%. Possible sarcopenia was present in older adults with lower weight, body mass index (BMI), skeletal muscle mass, and fat-free mass (P < 0.05) than those in the normal group. Older men with possible sarcopenia had poorer upper and lower body strength, aerobic endurance, lower body flexibility, agility and dynamic balance, and a higher fall risk than those in the normal group (P < 0.05). Older women with possible sarcopenia had a 2.5-fold and 3.3-fold higher fall risk than women in the normal group in both an unadjusted model (P = 0.001) and in a model adjusted for age and BMI (P < 0.001). However, there were no significant differences in fall risk among older men., Conclusion: The diagnostic criteria suggested by AWGS 2 may be highly useful for screening for declining physical function., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Among the starting materials of thermoplastic polyurethanes (TPUs), it was confirmed that succinic acid-based polyester biopolyols having different molecular weights (M n = 1000, 2000, and 4000) affect the physicochemical properties of the final polymer significantly. Bio-TPUs synthesized through a solvent-free one-shot polymerization process were synthesized with a polyester polyol, 1,4 butanediol (BDO), and 4,4'-methylene diphenyl diisocyanate (MDI) in a molar ratio of 1:1:2. As a control group, one typical petroleum-based TPU was synthesized and characterized along with other bio-based TPUs. Representative petroleum-based and bio-based TPUs synthesized were manufactured as monofilaments with a diameter of about 0.2 mm through an extrusion process with different draw ratios (4, 5, and 6 times). The molecular weight and structural properties of the TPUs were characterized by GPC and FT-IR analysis and thermal characterization by DSC and TGA analysis. Petroleum-based TPU and bio-based TPU having the same molecular weight soft segment (SS) tended to have similar molecular weight and hard segment (HS) content. TPUs with high HS content had excellent thermal stability, enabling stable extrusion of TPUs. In addition, it was confirmed that the bio-based TPU fibers produced in this way had a tensile strength corresponding to the physical properties of petroleum-based TPU fibers and an excellent elastic recovery rate of almost 100 %. These results indicate the application potential of bio-TPU.

People with end stage renal disease and undergoing hemodialysis experience a high symptom burden that impairs quality of life. This study aimed to assess the prevalence, dynamicity and determinants of symptom burden among middle-aged and older adult hemodialysis patients. A descriptive cross-sectional study together with a longitudinal assessment was used. A total of 118 and 102 hemodialysis patients were assessed at baseline and at a 6-month follow-up. Validated questionnaires were used to assess the symptom burden, stress, illness perception and social support. Multiple linear regression analysis was used to determine the factors associated with symptom burden. The median number of symptoms experienced was 21 (Interquartile Range (IQR); 18−23) and 19 (IQR; 13−22) at baseline and 6 months, respectively. Having elevated stress (β = 0.65, p ≤ 0.005) and illness perception (β = 0.21, p = 0.02) were significantly predicted symptom burden at baseline (F (4, 112) = 55.29, p < 0.005, R2 = 0.664). Stress (β = 0.28, p = 0.003), illness perception (β = 0.2, p = 0.03), poor social support (β = −0.22, p = 0.01) and low body weight (β = −0.19, p = 0.03) were the determinants for symptom burden at 6 months (F (5, 93) = 4.85, p ≤ 0.005, R2 = 0.24). Elevated stress, illness perception level, poor social support and low post-dialysis body weight were found to be determinants for symptom burden. Attention should be given to psychosocial factors of hemodialysis patients while conducting assessment and delivering care to patients.

Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the TGF-β pathway have been reported as constituents in the cargo of extracellular vesicles (EVs). EVs are secreted vesicles delimited by a lipid bilayer and play critical functions in intercellular communication, including regulation of the tumor microenvironment and cancer development. Thus, this review aims at summarizing the impact of EVs on TGF-β signaling by focusing on mechanisms by which EV cargo can influence tumorigenesis, metastatic spread, immune evasion and response to anti-cancer treatment. Moreover, we emphasize the potential of TGF-β-related molecules present in circulating EVs as useful biomarkers of prognosis, diagnosis, and prediction of response to treatment in cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodrigues-Junior, Tsirigoti, Lim, Heldin and Moustakas.)

Crystalline materials with broken inversion symmetry can exhibit a spontaneous electric polarization, which originates from a microscopic electric dipole moment. Long-range polar or anti-polar order of such permanent dipoles gives rise to ferroelectricity or antiferroelectricity, respectively. However, the recently discovered antiferroelectrics of fluorite structure (HfO 2 and ZrO 2 ) are different: A non-polar phase transforms into a polar phase by spontaneous inversion symmetry breaking upon the application of an electric field. Here, we show that this structural transition in antiferroelectric ZrO 2 gives rise to a negative capacitance, which is promising for overcoming the fundamental limits of energy efficiency in electronics. Our findings provide insight into the thermodynamically forbidden region of the antiferroelectric transition in ZrO 2 and extend the concept of negative capacitance beyond ferroelectricity. This shows that negative capacitance is a more general phenomenon than previously thought and can be expected in a much broader range of materials exhibiting structural phase transitions., (© 2022. The Author(s).)

Bacterial infections are a significant cause of illness and death in different animals. However, these bacterial infections could be a source of human disease or illness if these pathogenic bacteria are present in companion animals. This study aimed to investigate the prevalence of pathogenic bacteria associated with different site infections in cats in the Republic of Korea. For this purpose, samples were collected from the skin/ear, urine, respiratory, and diarrheal stool origins of cats obtained between 2018 and 2019 from seven different laboratories and centers participating in the Korean Veterinary Antimicrobial Resistance Monitoring System. These samples were subjected to analysis for the identification and isolation of associated bacterial species using a bacterial culture approach. A total of 609 isolates were identified in four different cat samples. Among them, 267, 184, 57, and 101 were extracted from diarrheal stool, skin, urine, and respiratory samples, respectively. The findings of this study showed that Escherichia coli was the most prevalent species among isolated bacterial species of diarrheal stool and urine origin. Staphylococcus felis and Pasteurella multocida were most prevalent in the skin and respiratory tract, respectively. However, there was no significant difference in bacterial distribution among the different age groups in all samples. This is the first nationwide surveillance report that associates bacterial prevalence with their site of origin and helps in the prevention of bacterial infections in cats. Moreover, the pattern of bacterial prevalence could provide sufficient guidance for the selection of empirical antimicrobial therapy against infections in cats.

Creatinine clearance (CrCl) is more accurate than other methods when assessing renal allograft function, but it is inconvenient for patients. In clinical practice, renal allograft function is often estimated using estimated glomerular filtration rate (GFR) equations. This cross-sectional study compared agreement between CrCl and serum creatinine-based equations among renal transplant recipients (RTRs) attending a transplant clinic in a tertiary center. Six equations (Cockcroft-Gault, Walser's, Nankivell, abbreviated Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], and European Kidney Function Consortium[EKFC]) were included in the analysis. The bias, precision, and accuracy of each equation were determined. Correlation analysis was performed by determining the correlation coefficient and plotting Bland-Altmann plots. A total of 165 subjects were included in this study. Mean serum creatinine was 112.03 ± 38.67 µmol/L, and mean CrCl was 58.44 ± 21.24 mL/min/1.73 m 2 . Walser's equation showed strongest correlation, lowest bias, and highest accuracy of the proportion of estimated GFR falling within ±30% of CrCl, followed by the 4-variable MDRD equation. All 6 equations systematically underestimated GFR among RTRs. Walser's equation showed the best estimation of GFR, suggesting that it may be the formula of choice to estimate GFR among RTRs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Previous studies have reported the efficacy of human mesenchymal stem cell (MSC) exosomes for the repair of osteochondral defects in rats and rabbits. However, the safety and efficacy of MSC exosomes remain to be validated in a clinically relevant large animal model., Purpose: To validate the safety and efficacy of human MSC exosomes for osteochondral repair in a clinically relevant micropig model., Study Design: Controlled laboratory study., Methods: Bilateral osteochondral defects (6-mm diameter and 1-mm depth) were surgically created in the medial femoral condyles in knees of 12 micropigs. The pigs then received 2-mL intra-articular injections of MSC exosomes and hyaluronic acid (HA) (Exosome+HA) or HA alone after surgery and thereafter at 8 and 15 days. Osteochondral repair was assessed by magnetic resonance imaging (MRI) at 15 days and at 2 and 4 months after surgery as well as by macroscopic, histological, biomechanical, and micro-computed tomography (micro-CT) analyses at 4 months after surgery., Results: Exosome+HA-treated defects demonstrated significantly better MRI scores than HA-treated defects at 15 days and at 2 and 4 months. Additionally, Exosome+HA-treated defects demonstrated functional cartilage and subchondral bone repair, with significantly better macroscopic and histological scores and biomechanical properties (Young modulus and stiffness) than HA-treated defects at 4 months. Micro-CT further showed significantly higher bone volume and trabecular thickness in the subchondral bone of Exosome+HA-treated defects than that of HA-treated defects. Importantly, no adverse response or major systemic alteration was observed in any of the animals., Conclusion: This study shows that the combination of MSC exosomes and HA administered at a clinically acceptable frequency of 3 weekly intra-articular injections can promote functional cartilage and subchondral bone repair, with significantly improved morphological, histological, and biomechanical outcomes in a clinically relevant porcine model., Clinical Relevance: Our findings provide a robust scientific rationale to support a phase 1/2 clinical trial to test MSC exosomes in patients with osteochondral lesions.

Background: Immunosuppressive therapy is the backbone of kidney transplantation in preventing acute rejection. T-cell depletion after doses of thymoglobulin is dose-dependent, as are their side effects. At the same time, basiliximab and other maintenance immunosuppressive drugs act at different signals on T lymphocytes. Therefore, studying the pattern of lymphocyte subset depletion depending on the induction regime given at transplantation could be an added tool in managing post-transplant recipients., Methodology: This prospective observational study recruited kidney transplant recipients from August 2019 through April 2021 at the University of Malaya Medical Centre. Blood tests for lymphocyte subsets were taken at pre-transplant, 1 week, 1 month, 3 months, and 6 months post-transplantation. At transplantation, recipients received either basiliximab, low-dose thymoglobulin (cumulative dose: 1.5 mg/kg), or standard-dose thymoglobulin (cumulative dose: 5 mg/kg)., Results: A total of 39 patients were recruited: 38.5% received basiliximab (15 of 39), 15.4% received low-dose thymoglobulin (6 of 39), and 46.2% received standard-dose thymoglobulin (18 of 39). Absolute lymphocyte counts 1 week post-transplantation were 1.5 ± 0.84 × 10 9 /L for basiliximab, 0.7 ± 0.57 × 10 9 /L for low-dose thymoglobulin, and 0.1 ± 0.08 × 10 9 /L for standard-dose thymoglobulin (P < .001). The CD4+ and CD8+ counts were severely depleted in the standard-dose thymoglobulin group, with a statistically significant differenceup to 6 months post-transplantation. In the low-dose thymoglobulin group, the CD4+ and CD8+ counts were depleted at 1 week post-transplantation and recovered at 1 month post-transplantation. There was no difference in allograft function and incidence of allograft rejection across groups., Conclusions: The effects on lymphocyte counts, CD4+ and CD8+, vary depending on the type and dose of induction immunosuppression. This could be a guiding tool in managing immunosuppression post-transplantation depending on the patient's immunologic risk., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Proteinuria and metabolic acidosis adversely affect long term renal allograft outcome and are highly prevalent in reported studies. The role of dietary intake in influencing proteinuria and metabolic acidosis remained uncertain. This study aims to determine the prevalence rate of proteinuria and metabolic acidosis among kidney transplant recipients (KTRs) and to study their relationship with dietary intake., Methods: We performed a cross-sectional study on KTRs with functioning renal allograft and at least 3 months post transplant. Dietary protein, salt, and dietary acid load were estimated using 24-hour urine collection. Demographic characteristics, concomitant medications, medical history, and laboratory results were obtained from electronic medical records., Results: A total of 204 KTRs were recruited with median age of 48 years (interquartile range [IQR], 18 years); male to female ratio was 61:39. A total of 79.9% (n = 163) were living related kidney transplants. The median duration after transplant was 71 months (IQR, 131 months), and median eGFR was 65 mL/min/1.73 m 2 (IQR, 25 mL/min/1.73 m 2 ). The prevalence rates of proteinuria (defined as ≥ 0.5 g/d) and metabolic acidosis (defined as at least 2 readings of serum bicarbonate ≤ 22 mmol/L in the past 6 months) were 17.7 % and 6.2%, respectively. High dietary protein of > 1.2 g/kg ideal body weight (adjusted odds ratio, 3.13; 95% CI, 1.35-7.28; P = .008) was significantly associated with proteinuria. Dietary protein, salt, and acid load did not correlate with chronic metabolic acidosis., Conclusions: The prevalence rate of proteinuria is consistent with published literature, but metabolic acidosis rate is extremely low in our cohort. High protein intake (> 1.2 g/kg ideal body weight) is a risk factor of proteinuria and may have negative impact on KTR outcome., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Allograft rejection remains a significant challenge in managing post-transplant recipients despite the improvement in immunologic risk assessment and immunosuppressive therapy. Published literature including animal studies has demonstrated that the cells responsible for rejection are beyond the innate T and B cells, and other studies revealed evidence supporting natural killer (NK) cells' role in kidney allograft injury. This study aims to find the association between the peripheral blood lymphocyte subset counts, primarily NK cells, and the kidney allograft biopsy findings., Methods: This is a prospective cross-sectional study among a total of 100 kidney allograft biopsies in 61 kidney transplant recipients. The peripheral blood for the lymphocyte subset was sent just before the allograft biopsy. The patients' immunosuppression and other laboratory investigations were managed as per clinical practices by the attending nephrologist., Results: Overall, the mean age of our patients was 43.72 ± 10.68 years old, and 55.7% of recipients were male. Higher counts of T cells (CD4+; 658.8 ± 441.4 cells/µL; P = .043) and NK cells (CD3-CD16+CD56+; 188 [interquartile range = 133.0-363.0 cells/µL]; P = .002) were associated with higher risk of allograft rejection in the initial analysis. Patients with an allograft age <12 months had significantly higher total T cells, CD4+ T cells, and NK cells in the rejection groups. However, after assessing factors associated with rejection in the multivariate analysis, we only found that being ABO-incompatible and having >497 CD4+ cells/µL had a higher odds of allograft rejection., Conclusions: Higher CD4± counts were associated with a higher risk of allograft rejection. However, there was no significant increase in CD8±, CD19±, and NK cells count in our cohort with allograft rejection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Evaluation of donor renal function as glomerular filtration rate (GFR) is a crucial part of pretransplant workup. Most guidelines recommend measured GFR (mGFR) using exogenous markers with creatinine clearance (CrCl) as an alternative. However, exogenous markers are difficult to obtain and perform, and CrCl may overestimate GFR., Objective: We explore the use of CrCl and combined urea and creatinine clearance as an alternative for GFR assessment., Methods: A retrospective study involving 81 kidney donors from 2007 to 2020, with mGFR collected by chromium 51-labeled ethylenediaminetetraacetic acid ( 51 Cr-EDTA) and CrCl and combined urea and creatinine clearance. We analyzed the performance of CrCl and combined urea and creatinine clearance against 51 Cr-EDTA. Adequacy of urine volume was taken into consideration., Results: A total of 81 candidates with a mean age of 44.80 ± 10.77 years were enrolled. Mean mGFR from 51 Cr-EDTA was 123.66 ± 26.91 mL/min/1.73 m 2 , and combined urea and creatinine clearance and CrCl were 122.13 ± 47.07 and 133.40 ± 36.32 mL/min/1.73 m 2 , respectively. CrCl overestimated 51 Cr-EDTA. Though combined urea and creatinine clearance had minimal bias, it had a lower correlation coefficient (0.25 vs 0.43), lower precision (49.51 vs 38.10), and slightly lower accuracy within 30% of 51 Cr-EDTA (74.07% vs 76.54%)., Conclusions: Combined urea and creatinine clearance did not improve the performance of CrCl. Nevertheless, it can potentially be used as first-line GFR assessment, followed by mGFR in selected donors, to ascertain threshold of safe kidney donation. A stringent urine collection method is essential to ensure accurate measurement., (Copyright © 2021. Published by Elsevier Inc.)

The short- and long-term outcome of donations from living donors of kidneys (LKDs) remains controversial. Information regarding metabolic changes after donation in Malaysia remains limited despite Malaysia having the highest record prevalence of diabetes, obesity, and hypertension in Asia. There were 159 LKDs in our center from 2010 to 2020. We analyzed pre and post donation clinical data and laboratory results from 140 LKDs, retrospectively, from electronic medical records and looked for any metabolic changes. Among these 140 LKDs, 99 were women (70.7%), with a mean age of 47.23 ± 11.67 before donation. The median follow-up was 4 years (range, 2-6 years). Median body mass index increased from 24.35 kg/m 2 (range, 22.11-26.93) to 25.56 kg/m 2 (range, 22.78-28.57; Z=-3.934, P = .000) after donation. Prevalence of obesity increased from 24.18% to 30.77%. Only 2.8% of LKDs developed proteinuria postnephrectomy (P = .250). Serum creatinine increased from 60 mmol/L (range, 52-74) to 87 mmol/L (range, 74-108) 1 year after donation (P = .000), and the latest results decrease to 83 mmol/L (range, 73-101; P = .000). Systolic blood pressure increased from 127.83 ± 12.25 mm Hg to 131.30 ± 18.16 mm Hg, (t[97] = -2.012; P = .047); and prevalence of hypertension increased from 19.81% to 23.58% (P = .125), with 22.64% requiring treatment. We noted that 22.54% of the LKDs had dyslipidemia before donation, a number that increased to 50% after donation (P = .000). LKDs with hyperuricemia increased significantly from 7.92% to 34.65%, with uric acid level increasing from 311.94 ± 78.51umol/L to 381.87 ± 86.96 umol/L (t[94] = -10.805; P = .000). Fasting blood glucose and glycated hemoglobin level recorded no significant changes after donation. Post donation kidney function of LKDs compensated well and stable in short term. We noted statistically significant increment of weight, post donation body mass index, systolic blood pressure, uric acid, and lipids. We suggest prospective studies with longer follow-up and more subjects for clinical correlation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cell-based therapy using Mesenchymal Stromal Cell (MSC) has generally been efficacious in treating a myriad of diseases in animal models and clinical trials. The rationale for MSC therapy was predicated on the potential of MSC to differentiate and form new replacement cells in the diseased tissue. However, pre-clinical animal and clinical data were more consistent with a secretion- and not a differentiation-based rationale. Analysis of MSC secretion led to the identification of small extracellular vesicles (sEVs) as therapeutically active, secretory agents. MSC-sEVs are defined as bi-lipid membrane vesicles of 50-200 nm in diameter that are secreted by MSCs. They reportedly exert similar therapeutic efficacy as MSCs in many diseases including neurological diseases. MSC-sEVs being small and non-living are intrinsically safer than living MSCs. Manufacturing of MSC-sEVs may also be less complex. Nevertheless, realising the therapeutic potential of MSC-sEVs will require exacting scientific rigor and robustness, as well as compliance to regulatory oversight. This review summarises the scientific rationale for the transition of MSC therapy from a cell- to an EV-based therapy and discusses critical scientific issues in the development of MSC-sEVs therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Antimicrobial-resistant bacteria in food animals pose a major public health threat worldwide. In this study, we aimed to assess the antimicrobial resistance profiles and resistance trends of commensal Escherichia coli isolated from the feces of healthy cattle, pigs, and chickens in South Korea during 2010 and 2020. A total of 7237 E. coli isolates (2733 cattle, 2542 pig, and 1962 chicken isolates) were tested for susceptibility towards 12 antimicrobials. About 48%, 90%, and 97% of cattle, pig, and chicken isolates, respectively, were resistant to one or more antimicrobial agents. Cattle isolates presented low resistance (<15%) to most of the tested antimicrobials. In contrast, chicken and pig isolates demonstrated a relatively high (>45%) resistance rate to ampicillin, chloramphenicol, streptomycin, and tetracycline. We observed high ciprofloxacin and nalidixic acid resistance rates in chicken (76.1% and 88.6%, respectively), isolates in pig (12.7% and 26.7%, respectively) and cattle (2.7% and 8.2%, respectively) isolates. Notably, a very small proportion of isolates (<5%) from cattle, chickens, and pigs demonstrated resistance to amoxicillin/clavulanic acid, cefoxitin, and colistin. We identified ceftiofur resistance in a small proportion of chicken (8.8%), pig (3.7%), and cattle (0.7%) isolates. We noted an increasing but fluctuating trend of ampicillin, amoxicillin/clavulanic acid, ceftiofur, cefoxitin, chloramphenicol, ciprofloxacin, and streptomycin resistance in pig isolates. Similarly, the ampicillin, ceftiofur, and chloramphenicol resistance rates were increased but fluctuated through time in chicken isolates. Overall, 56% of the isolates showed multidrug-resistant (MDR). The proportion of MDR isolates was low in cattle (17.1%); however, this proportion was high in chickens (87.1%) and pigs (73.7%). Most of the resistance patterns included streptomycin and tetracycline in pigs and cattle, and ciprofloxacin and nalidixic acid in chickens. In conclusion, this study showed high resistance of commensal E. coli isolated from major food animals in Korea to commonly used antimicrobials including critically important antimicrobials. These bacteria could not only be a resistance reservoir but also could have potential to spread this resistance through gene transfer to pathogenic bacteria. Thus, the high prevalence of antimicrobial resistance in food animals highlights the urgent need for measures to restrict and ensure the prudent use of antimicrobials in Korea.

Background: Patients requiring hemodialysis (HD) often have several chronic comorbidities, which necessitate the use of several medications and hence put them at high risk of polypharmacy. Medication-related problems (MRPs) among HD patients are a serious issue as they can increase morbidity and nonadherence with medications. To overcome this issue, a unique pharmacy practice model including medication review (MR) and motivational interviewing (MI) is needed to improve medication adherence, by reducing MRPs and optimizing therapeutic outcomes. The present study aims to assess the effectiveness of MR and MI in improving medication adherence, quality of life (QOL) and clinical outcomes among end-stage renal disease (ESRD) patients who are on dialysis., Method and Design: This pre-post study will be conducted prospectively among patients with ESRD who have been on dialysis at the Hemodialysis Unit, Hospital Kuala Lumpur and the Hemodialysis Affiliated Centers of the University Malaya Medical Centre, from August 2020 till August 2021. Medication adherence will be assessed using the General Medication Adherence Scale (GMAS), whilst patients' HRQOL will be assessed using the Kidney Disease Quality of Life Short Form 36 (KDQOL-36). Clinical parameters such as blood glucose level, calcium, phosphate, hemoglobin and serum low-density lipoprotein (LDL) levels will be obtained from medical records. A total of 70 patients will be recruited., Discussion: We hypothesize that the implementation of pharmacy-based MR and MI may expect an increase in medication adherence scores and increase in HRQOL scores from baseline as well as achieving the clinical lab parameters within the desired range. This would indicate a need for a pharmacist to be involved in the multidisciplinary team to achieve a positive impact on medication adherence among hemodialysis patients., Trial Registration: Ethical approval has been obtained from the National Medical Research and Ethics Committee NMRR: 20-1135-54435 and Medical Research Ethics Committee, University Malaya Medical Centre MREC ID NO: 202127-9811., Competing Interests: The authors have declared that no competing interests exist.

The recent studies reported that DNA methylation markers show changes with age, and expected that the DNA methylation markers can be effectively used for estimation of age in forensic genetics. In this study, we applied droplet digital PCR (ddPCR) method to investigate the DNA methylation pattern in the CpG sites, and we constructed an age prediction model based on the ddPCR method. The ddPCR is capable of highly sensitive quantitation of nucleic acid and detection of sequence variations in gene by separating the sample into large number of partitions and clonally amplifying nucleic acids in each partition. We extracted DNA from saliva samples collected from several age groups. The DNA was bisulfite converted and subjected to ddPCR using specifically designed primers and probes. The methylation ratio of each sample was calculated and correlation between the methylation ratio and the chronological age was analyzed. In the results, methylated DNA ratio at the 4 CpG sites (cg14361627, cg14361627, cg08928145 and cg07547549) showed strong correlation with chronological age. Percent-methylation values at 4 CpG markers and chronological ages of the 76 individuals were analyzed by multiple regression analysis, and we constructed an age prediction model. We observed a strong correlation (Spearman's rho = 0.922) between predicted and chronological ages of 76 individuals with a MAD from chronological age of 3.3 years. Collectively, the result in this study showed the potential applicability of ddPCR to predict age from saliva., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sutures are used to facilitate wound healing and play an important role in ensuring the success of surgical interventions in healthcare facilities. Suture-associated surgical site infection (SSI) may develop when bacterial contaminants colonize the suture surface and establish biofilms that are highly resistant to antibiotic treatment. The outcome of SSI affects postoperative care, leading to high rates of morbidity and mortality, prolonged hospitalization, and increased financial burden. Antimicrobial sutures coated with antiseptics such as triclosan and chlorhexidine have been used to minimize the occurrence of SSI. However, as the efficacy of antiseptic-based sutures may be affected due to the emergence of resistant strains, new approaches for the development of alternative antimicrobial sutures are necessary. This review provides an update and outlook of various approaches in the design and development of antimicrobial sutures. Attaining a zero SSI rate will be possible with the advancement in suturing technology and implementation of good infection control practice in clinical settings.

As part of the glomerular filtration membrane, podocyte is terminally differentiated, structurally unique, and highly specialized in maintaining kidney function. Proteinuria caused by podocyte injury (foot process effacement) is the clinical symptom of various kidney diseases (CKD), including nephrotic syndrome. Podocyte autophagy has become a powerful therapeutic strategy target in ameliorating podocyte injury. Autophagy is known to be associated significantly with sirtuin-1, proteinuria, and podocyte injury. Various key findings in podocyte autophagy were reported in the past ten years, such as the role of endoplasmic reticulum (ER) stress in podocyte autophagy impairment, podocyte autophagy-related gene, essential roles of the signaling pathways: Mammalian Target of Rapamycin (mTOR)/ Phosphoinositide 3-kinase (PI3k)/ serine/threonine kinase 1 (Akt) in podocyte autophagy. These significant factors caused podocyte injury associated with autophagy impairment. Sirtuin-1 was reported to have a vital key role in mTOR signaling, 5'AMP-activated protein kinase (AMPK) regulation, autophagy activation, and various critical pathways associated with podocyte's function and health; it has potential value to podocyte injury pathogenesis investigation. From these findings, podocyte autophagy has become an attractive therapeutic strategy to ameliorate podocyte injury, and this review will provide an in-depth review on therapeutic targets he podocyte autophagy., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To determine the seroprevalence and transmission dynamics of dengue virus (DENV), age-stratified longitudinal serological surveys were conducted in Bangphae district, Ratchaburi province, Thailand, for 3 years between April 2012 and April 2015., Methodology: The surveys enrolled 2012 healthy children and adults between 1 and 55 years-of-age, and a longitudinal serosurvey of six repeated bleeds of the same cohort of individuals was conducted every 8 months for the first 2 years (M0, M8, M16) and every half a year (M24, M30, M36) for the rest of the study period. All samples were tested using in-house indirect sandwich dengue IgG ELISA to determine DENV antibody titer, and 640 paired samples which showed rising of DENV IgG titers in paired serum were further tested using in-house neutralization assay, Plaque Reduction Neutralization Test (PRNT50)., Principal Findings: When compared against the gold standard based on the results of PRNT50, sensitivity and specificity of indirect ELISA were found to be both about 85%. The overall DENV IgG positivity determined by ELISA was 74.3% in 2012 and increased to 79.4% by the final sample collection in 2015. In our study sample, more than 98% of subjects older than 25 years were found to be seropositive. Among 518 IgG negative subjects at enrollment, the seroconversion rates were measured in paired bleeds; the rates (between successive visits, approximately 6 months) ranged between 4.8% (between M16 and M24) and 14.7% (between M0 and M8). The dominant serotype of primary DENV infection cases based on seroconversion was identified from the PRNT results and it was DENV-2., Conclusions: Our study documented high levels of seroprevalence and rate of transmission. Given the importance of the serostatus and disease burden in consideration for dengue vaccine introduction, our data could be used in decision-making on implementation of various dengue control and preventive measures., Competing Interests: The authors have declared that no competing interests exist.

Background: Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for escaping from G1/S cell cycle arrest in HPV-infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site., Objective: To design a peptide inhibitor targeting HPV E7 through an in silico approach., Methods: In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was further investigated in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome, and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptides., Results: In the in silico approach, a 9-amino acids peptide sequence formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines, where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%) and a reduction of cells in the G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor., Conclusion: A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb can inhibit HPV E7 by causing a cell accumulation effect in G0/G1, and S phases of the cell cycle in the HPV transformed cell lines. These findings could contribute to HPV E7 peptide inhibitor in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: This study evaluated the effects of mesenchymal stem cell-extracellular vesicles (MSC-EVs) on chondrocyte proliferation in vitro and on cartilage repair in vivo following bone marrow stimulation (BMS) of focal chondral defects of the knee., Methods: Six adult Göttingen minipigs received 2 chondral defects in each knee. The pigs were randomized to treatment with either BMS combined with MSC-EVs or BMS combined with phosphate-buffered saline (PBS). Intraarticular injections MSC-EVs or PBS were performed immediately after closure of the surgical incisions, and at 2 and 4 weeks postoperatively. Repair was evaluated after 6 months with gross examination, histology, histomorphometry, immunohistochemistry, and micro-computed tomography (µCT) analysis of the trabecular bone beneath the defect., Results: Defects treated with MSC-EVs had more bone in the cartilage defect area than the PBS-treated defects (7.9% vs. 1.5%, P = 0.02). Less than 1% of the repair tissue in both groups was hyaline cartilage. International Cartilage and Joint Preservation Society II histological scoring showed that defects treated with MSC-EVs scored lower on "matrix staining" (20.8 vs. 50.0, P = 0.03), "cell morphology" (35.4 vs. 53.8, P = 0.04), and "overall assessment" (30.8 vs. 52.9, P = 0.03). Consistently, defects treated with MSC-EVs had lower collagen II and higher collagen I areal deposition. Defects treated with MSC-EVs had subchondral bone with significantly higher tissue mineral densities than PBS-treated defects (860 mg HA/cm 3 vs. 838 mg HA/cm 3 , P = 0.02)., Conclusion: Intraarticular injections of MSC-EVs in conjunction with BMS led to osseous ingrowth that impaired optimal cartilage repair, while enhancing subchondral bone healing.

Obesity and related metabolic diseases are major problems worldwide. Some probiotics are currently considered potential therapeutic strategies for obesity. We aimed to investigate the antiobesity efficacy of Latilactobacillus sakei WIKIM31 in obese mice induced by a high fat diet. The administration of a high-fat diet with L. sakei WIKIM31 reduced body weight gain, epididymal fat mass, triglyceride and total cholesterol levels in the blood, and remarkably decreased the expression of lipogenesis-related genes in the epididymal adipose tissue and liver. Interestingly, intake of L. sakei WIKIM31 improved gut barrier function by increasing the gene expression of tight junction proteins and suppressing the inflammatory responses. Additionally, L. sakei WIKIM31 enhanced the production of short-chain fatty acids, such as butyrate and propionate, in the intestinal tract. These results showed that L. sakei WIKIM31 can be used as a potential therapeutic probiotic for obesity.

Background: Erythropoietin stimulating agent (ESA) has been standard of care in treating renal anaemia for the past 20 years. Many patients have limited access to ESA in view of long-term costs leading to suboptimal ESA dosage. Biosimilar epoetin is a potential cost-effective alternative to originator for optimal renal anaemia management., Objective: To determine efficacy and safety of PDA10 in treating renal anaemia in haemodialysis patients, in comparison to the originator epoetin-α, Eprex®., Methods: A phase 3, multicentre, multi-national, double-blind, randomised, active-controlled and parallel group study conducted over 40 weeks in Malaysia and Korea. End stage kidney disease patients undergoing regular haemodialysis who were on erythropoietin treatment were recruited. The study has 3 phases, which included a 12-week titration phase, followed by 28-week double-blind treatment phase and 24-week open-label extension phase., Results: The PDA10 and Eprex® were shown to be therapeutically equivalent (p < 0.0001) with mean absolute change in haemoglobin from baseline of - 0.176 (± 0.91) g/dl and - 0.118 (± 1.114) g/dl, respectively. Weekly dose change was 10.01 IU/kg/week in PDA10 group and 10.30 IU/kg/week in Eprex® group, which has no significant difference. There were no significant differences in the safety profile between PDA10 and Eprex® groups., Conclusion: This study has confirmed the therapeutic equivalence between PDA10 and Eprex® in terms of efficacy, dosage requirement and safety profile in haemodialysis patients with renal anaemia., Trial Registration: The study was registered with the National Medical Research Register ( NMRR-13-400-16313 ). This study has been registered retrospectively with Clinical Research Information Service ( CRiS ), Republic of Korea on 25 March 2021., (© 2021. The Author(s).)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic kidney disorder that impairs renal functions progressively leading to kidney failure. The disease affects between 1:400 and 1:1000 ratio of the people worldwide. It is caused by the mutated PKD1 and PKD2 genes which encode for the defective polycystins. Polycystins mimic the receptor protein or protein channel and mediate aberrant cell signaling that causes cystic development in the renal parenchyma. The cystic development is driven by the increased cyclic AMP stimulating fluid secretion and infinite cell growth. In recent years, natural product-derived small molecules or drugs targeting specific signaling pathways have caught attention in the drug discovery discipline. The advantages of natural products over synthetic drugs enthusiast researchers to utilize the medicinal benefits in various diseases including ADPKD., Conclusion: Overall, this review discusses some of the previously studied and reported natural products and their mechanisms of action which may potentially be redirected into ADPKD., (© 2021. Japanese Society of Nephrology.)

There has been increased interest in using stem cells for regenerative medicine and cancer therapy in the past decade. Mesenchymal stem cells (MSCs) are among the most studied stem cells due to their unique characteristics, such as self-renewal and developmental potency to differentiate into numerous cell types. MSC use has fewer ethical challenges compared with other types of stem cells. Although a number of studies have reported the beneficial effects of MSC-based therapies in treating various diseases, their contribution to cancer therapy remains controversial. The behaviour of MSCs is determined by the interaction between intrinsic transcriptional genes and extrinsic environmental factors. Numerous studies continue to emerge, as there is no denying the potential of MSCs to treat a wide variety of human afflictions. Therefore, the present review article provided an overview of MSCs and their differences compared with embryonic stem cells, and described the molecular mechanisms involved in maintaining their stemness. In addition, the article examined the therapeutic application of stem cells in the field of cancer. The present article also discussed the current divergent roles of MSCs in cancer therapy and the future potential in this field., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Lim et al.)

Dialyzers have been commercially used for hemodialysis application since the 1950s, but progress in improving their efficiencies has never stopped over the decades. This article aims to provide an up-to-date review on the commercial developments and recent laboratory research of dialyzers for hemodialysis application and to discuss the technical aspects of dialyzer development, including hollow fiber membrane materials, dialyzer design, sterilization processes and flow simulation. The technical challenges of dialyzers are also highlighted in this review, which discusses the research areas that need to be prioritized to further improve the properties of dialyzers, such as flux, biocompatibility, flow distribution and urea clearance rate. We hope this review article can provide insights to researchers in developing/designing an ideal dialyzer that can bring the best hemodialysis treatment outcomes to kidney disease patients.

Background: Genome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson's disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ) gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry., Methods: A total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays., Results: The G allele of rs10513789 (OR = 0.83, p = 0.001) and A allele of rs12637471 (OR = 0.79, p = 0.007) in the MCCC1/LAMP3 locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the other MCCC1/LAMP3 rs12493050 variant or with the DGKQ (rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis., Conclusion: MCCC1/LAMP3 variants rs10513789 and rs12637471 protect against PD in the Malay population., (© 2021. Fondazione Società Italiana di Neurologia.)

Treatment of infectious diseases caused by carbapenem-resistant Pseudomonas aeruginosa is becoming a greater challenge. This study aimed to identify the imipenem resistance mechanism in P. aeruginosa isolated from a dog. Minimum Inhibitory Concentration (MIC) was determined by the broth microdilution method according to the Clinical and Laboratory Standards Institute recommendations. We performed polymerase chain reaction and whole-genome sequencing to detect carbapenem resistance genes. Genomic DNA of P. aeruginosa K19PSE24 was sequenced via the combined analysis of 20-kb PacBio SMRTbell and PacBio RS II. Peptide-Peptide Nucleic Acid conjugates (P-PNAs) targeting the translation initiation region of bla OXA-913 were synthesized. The isolate (K19PSE24) was resistant to imipenem and piperacillin/tazobactam yet was susceptible to most of the tested antimicrobials. Whole-genome sequencing revealed that the K19PSE24 genome comprised a single contig amounting to 6,815,777 base pairs, with 65 tRNA and 12 rRNA genes. K19PSE24 belonged to sequence type 313 and carried the genes aph(3)-IIb , fosA , catB7 , crpP , and bla OXA-913 (an allele deposited in GenBank but not described in the literature). K19PSE24 also carried genes encoding for virulence factors (exoenzyme T, exotoxin A, and elastase B) that are associated with adhesion, invasion, and tissue lysis. Nevertheless, we did not detect any of the previously reported carbapenem resistance genes. This is the first report of the bla OXA-913 gene in imipenem-resistant P. aeruginosa in the literature. Notably, no viable colonies were found after co-treatment with imipenem (2 µg/mL) and either of the P-PNAs (12.5 µM or 25 µM). The imipenem resistance in K19PSE24 was primarily due to bla OXA-913 gene carriage.

Sodium metal chloride batteries have become a substantial focus area in the research on prospective alternatives for battery energy storage systems (BESSs) since they are more stable than lithium ion batteries. This study demonstrates the effects of the cathode microstructure on the electrochemical properties of sodium metal chloride cells. The cathode powder is manufactured in the form of granules composed of a metal active material and NaCl, and the ionic conductivity is attained by filling the interiors of the granules with a second electrolyte (NaAlCl 4 ). Thus, the microstructure of the cathode powder had to be optimized to ensure that the second electrolyte effectively penetrated the cathode granules. The microstructure was modified by selecting the NaCl size and density of the cathode granules, and the resulting Na/(Ni,Fe)Cl 2 cell showed a high capacity of 224 mAh g -1 at the 100th cycle owing to microstructural improvements. These findings demonstrate that control of the cathode microstructure is essential when cathode powders are used to manufacture sodium metal chloride batteries.

Genetic mutations such as single nucleotide polymorphisms (SNP) are known as one of the most common forms which related to various genetic disorders and cancers. Among of the methods developed for efficient detection of such SNP, polymerase chain reaction (PCR) methods are widely used worldwide for its cost and viable advantages. However, the technique to discriminate small amounts of SNP mixed in abundant normal DNA is incomplete due to intrinsic technical problems of PCR such as amplification occurring even in 3'mismatched cases because of high enzyme activity of DNA polymerases. To overcome the issue, specifically designed PCR platform, STexS (SNP typing with excellent specificity) using double stranded oligonucleotides was implemented as a means to emphasize the amplification of SNP templates by decreasing unwanted amplification of 3'mismatched DNA copies. In this study, the results indicate several EGFR mutations were easily detected specifically utilizing the STexS platform. Further trials show the novel method works effectively to discriminate mutations in not only general allele specific (AS)-PCRs, but also amplification refractory mutation system (ARMS)-PCR. The STexS platform will give aid in PCRs targeting potential SNPs or genetically mutated biomarkers in human clinical samples., (© 2021. The Author(s).)

Lactobacillus amylovorus are known to exist in the intestinal flora of healthy cattle or pigs. The L. amylovorus strain 1394N20 was isolated from the feces of the Hanwoo calf ( Bos taurus coreanae ). The genome of strain 1394N20 consists of a single circular chromosome (2,176,326 bp) with overall guanine + cytosine content of 37.8 mol%. Moreover, 2,281 protein-coding sequences, 15 rRNAs, and 65 tRNAs genes were identified in the chromosome based on the results of annotation. The bacterium has a gene encoding endoglucanase, an enzyme that hydrolyzes the 1,4-β-D-glycosidic linkages in cellulose, hemicellulose, lichenin, and cereal β-D-glucans. Genomic sequencing of L. amylovorus strain 1394N20 reveals the immense potential of the strain as a probiotic with nutrient digestibility., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Copyright 2021 Korean Society of Animal Science and Technology.)

Due to its highly immunogenic nature and the great engineerability, filamentous phage has shown promising antitumor activities in preclinical studies. Previous designs of antitumor phage mainly focused on tumor targeting using a cancer-specific moiety displayed on the minor capsid protein, pIII. In this work, we developed a new therapeutic platform of filamentous phage, in which the major capsid protein pVIII was utilized for displaying an antitumor cytokine. We showcased that a 16.1-kD cytokine GM-CSF could be efficiently presented on the M13 phage particle using the 8 + 8 type display system through a highly tolerable pVIII variant P8(1a). We verified that the GM-CSF phage was a potent activator for STAT5 signaling in murine macrophage. The GM-CSF phage significantly reduced the tumor size by more than 50% as compared to the unmodified phage in a murine colorectal cancer model. Immunological profiling of the tumor-infiltrating leukocytes revealed that an increase of CD4+ lymphocytes in the GM-CSF phage treatment group. Furthermore, the combined therapy of the GM-CSF phage and radiation greatly improved the therapeutic potency with a 100% survival rate and a 25% complete remission rate. We observed that the IFN-γ expression was dramatically up-regulated by the combined therapy in multiple types of tumor-infiltrating immune cells. Overall, we created a novel vehicle for cytokine therapy using the pVIII filamentous phage display. This new platform can be multiplexed with other phage engineering approaches, such as displaying targeting ligands on pIII or encapsulating therapeutic genes inside phage capsids, to create multifunctional nanoparticles for cancer therapy.

Background: Due to frequent hospitalizations, complex dialysis procedures and immune compromising effects of end stage renal disease (ESRD), patients on dialysis are more prone to healthcare associated infections (HCAIs). Objective: To study the impact of HCAIs on survival and treatment outcomes among ESRD patients on renal replacement therapy (RRT). Methodology: A multicenter, retrospective study was conducted from June to December 2019 at two public hospitals of Malaysia. ESRD patients with minimum of 6 months on RRT were included, while pregnant patients and patients <18 years were excluded. Multinomial logistic regression was performed to identify risk factors associated with unsuccessful treatment outcomes. Kaplan Meier analysis was performed to study the survival. Results: A total of 670 records were examined, of which 400 patients were included as per the inclusion criteria. The mean survival time of patients without HCAIs [22.7 (95%CI:22.1-23.2)] was higher than the patients with HCAIs [19.9 (95%CI:18.8-20.9)]. Poor survival was seen in patients with >2 comorbidities, >60 years of age, low hemoglobin concentration and high C-reactive protein levels. The most frequent treatment outcome was cured [113 (64.9%)], followed by death [37 (21.3%)] and treatment failure [17 (9.8%)]. Advancing age, and low hemoglobin concentration were independent risk factors associated with death, while recurrent HCAIs, use of central venous catheters, and low serum sodium levels were risk factors for treatment failure. Conclusion: The high burden of HCAIs is a profound challenge faced by patients on RRT, which not only effects the treatment outcomes but also contributes substantially to the poor survival among these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abbasi, Aftab, Lai, Lim and Zainol Abidin.)

Adipose tissue senescence is implicated as a major player in obesity- and ageing-related disorders. There is a growing body of research studying relevant mechanisms in age-related diseases, as well as the use of adipose-derived stem cells in regenerative medicine. The cell banking of tissue by utilising cryopreservation would allow for much greater flexibility of use. Dimethyl sulfoxide (DMSO) is the most commonly used cryopreservative agent but is toxic to cells. Trehalose is a sugar synthesised by lower organisms to withstand extreme cold and drought that has been trialled as a cryopreservative agent. To examine the efficacy of trehalose in the cryopreservation of human adipose tissue, we conducted a systematic review of studies that used trehalose for the cryopreservation of human adipose tissues and adipose-derived stem cells. Thirteen articles, including fourteen studies, were included in the final review. All seven studies that examined DMSO and trehalose showed that they could be combined effectively to cryopreserve adipocytes. Although studies that compared nonpermeable trehalose with DMSO found trehalose to be inferior, studies that devised methods to deliver nonpermeable trehalose into the cell found it comparable to DMSO. Trehalose is only comparable to DMSO when methods are devised to introduce it into the cell. There is some evidence to support using trehalose instead of using no cryopreservative agent.