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Shu Jiao Zhang,1,2,&ast; Yi Fei Zhang,1,2,&ast; Xue Hui Bai,1,2 Meng Qi Zhou,1,2 Ze Yu Zhang,1,2 Shuai Xing Zhang,1,2 Zi Jing Cao,1,2 Lin Wang,1,2 Shao Wei Ding,1,2 Hui Juan Zheng,1,2 Yu Ning Liu,1– 3 Guo Yong Yu,1 Wei Jing Liu1– 3 1Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Key Laboratory of Chinese Internal Medicine of Ministry of Education, Beijing Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Renal Research Institution of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guo Yong Yu, Dongzhimen Hospital, Beijing University of Chinese Medicine, No. 5 Haiyuncang, Beijing, Dongcheng District, 100700, People’s Republic of China, Email 18901133535@163.com Wei Jing Liu, Renal Research Institution of Beijing University of Chinese Medicine, and Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, Tel/Fax +86-010-84013190, Email 1977@hotmail.comBackground: Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically.Methods: First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated.Results: Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P< 0.05), alongside mitigated podocyte injury (P< 0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1β, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway.Conclusion: Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside’s efficacy in DKD treatment, providing a foundation for further basic and clinical research.Keywords: DKD, acteoside, network pharmacology, experimental verification

Shiu-Ju Yang,1 Ting-Chun Wei,1 Chih-Hao Hsu,1 Sin-Ni Ho,1 Chi-Yun Lai,2 Shiu-Feng Huang,2,3 Yih-Yuan Chen,4 Shih-Jen Liu,1 Guann-Yi Yu,1 Horng-Yunn Dou1,5 1National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 2Pathology Core Laboratory, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 3National Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan; 4Department of Biochemical Science and Technology, National Chiayi University, Chia-Yi, 60070, Taiwan; 5Department of Biological Science & Technology, National Yang Ming Chiao Tung University, Hsinchu, TaiwanCorrespondence: Horng-Yunn DouNational Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County, 35053, TaiwanTel +886-37-206-166 ext 35529Fax +886-37-583-009Email hydou@nhri.edu.twBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus which caused a global respiratory disease pandemic beginning in December 2019. Understanding the pathogenesis of infection and the immune responses in a SARS-CoV-2-infected animal model is urgently needed for vaccine development.Methods: Syrian hamsters (Mesocricetus auratus) were intranasally inoculated with 105, 5× 105, and 106 TCID50 of SARS-CoV-2 per animal and studied for up to 14 days. Body weight, viral load and real-time PCR amplification of the SARS-CoV-2 N gene were measured. On days 3, 6 and 9, lung, blood, liver, pancreas, heart, kidney, and bone marrow were harvested and processed for pathology, viral load, and cytokine expression.Results: Body weight loss, increased viral load, immune cell infiltration, upregulated cytokine expression, viral RNA, SARS-CoV-2 nucleoprotein, and mucus were detected in the lungs, particularly on day 3 post-infection. Extremely high expression of the pro-inflammatory cytokines MIP-1 and RANTES was detected in lung tissue, as was high expression of IL-1β, IL-6, IL-12, and PD-L1. The glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GOT/GPT) ratio in blood was significantly increased at 6 days post-infection, and plasma amylase and lipase levels were also elevated in infected hamsters.Conclusion: Our results provide new information on immunological cytokines and biological parameters related to the pathogenesis and immune response profile in the Syrian hamster model of SARS-CoV-2 infection.Keywords: SARS-CoV-2, hamster, immune response, pathogenesis

Ming Lei,1 Guang-Yuan Yu,2 Yong-Gang Zhao,3 Ji-Ping Wang,1 Su-Yun Feng1 1Center of Hair Transplantation, Department of Burn and Plastic Surgery, The Fourth Medical Center of the General Hospital of PLA, Beijing, People’s Republic of China; 2Department of Dermatology, The Fourth Medical Center of the General Hospital of PLA, Beijing, People’s Republic of China; 3First Department of Surgery, Beijing Armed Police Corps Hospital, Beijing, People’s Republic of ChinaCorrespondence: Ji-Ping WangCenter of Hair Transplantation, Department of Burn and Plastic Surgery, The Fourth Medical Center of the General Hospital of PLA, No. 51 of Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of ChinaTel +86 10-66867304Email wangjp693587@163.comObjective: This study aims to establish the concept of invalid extraction rates in follicular unit extraction and evaluate its clinical value.Methods: The present study involved 30 patients with alopecia. Three young surgeons (nominated A, B, and C) each performed follicular unit extraction on a randomly selected portion of the donor site of each patient for ten minutes. The outcomes were separately recorded and calculated, and converted to an invalid extraction rate for each surgeon using the formula, “invalid extraction rate = 1 − successfully extracted follicular units/actually extracted units × 100%.”Results: The follicular unit invalid extraction efficiency of each surgeon gradually declined. The average efficiency level of surgeon B was evaluated as excellent, while the levels of surgeons A and C were evaluated as good.Conclusion: With experience, surgeons can speed up the process of follicular unit extraction and gradually increase performance quality through both extraction speed and success rate.Keywords: follicular unit extraction, operating level, evaluation

Abstract Oxidative stress plays an essential role in the progression of Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. Streptozotocin (STZ)-induced abnormal brain insulin signaling and oxidative stress play crucial roles in the progression of Alzheimer’s disease (AD)-like pathology. Peroxiredoxins (Prxs) are associated with protection from neuronal death induced by oxidative stress. However, the molecular mechanisms underlying Prxs on STZ-induced progression of AD in the hippocampal neurons are not yet fully understood. Here, we evaluated whether Peroxiredoxin 1 (Prx1) affects STZ-induced AD-like pathology and cellular toxicity. Prx1 expression was increased by STZ treatment in the hippocampus cell line, HT-22 cells. We evaluated whether Prx1 affects STZ-induced HT-22 cells using overexpression. Prx1 successfully protected the forms of STZ-induced AD-like pathology, such as neuronal apoptosis, synaptic loss, and tau phosphorylation. Moreover, Prx1 suppressed the STZ-induced increase of mitochondrial dysfunction and fragmentation by down-regulating Drp1 phosphorylation and mitochondrial location. Prx1 plays a role in an upstream signal pathway of Drp1 phosphorylation, cyclin-dependent kinase 5 (Cdk5) by inhibiting the STZ-induced conversion of p35 to p25. We found that STZ-induced of intracellular Ca2+ accumulation was an important modulator of AD-like pathology progression by regulating Ca2+-mediated Calpain activation, and Prx1 down-regulated STZ-induced intracellular Ca2+ accumulation and Ca2+-mediated Calpain activation. Finally, we identified that Prx1 antioxidant capacity affected Ca2+/Calpain/Cdk5-mediated AD-like pathology progress. Therefore, these findings demonstrated that Prx1 is a key factor in STZ-induced hippocampal neuronal death through inhibition of Ca2+/Calpain/Cdk5-mediated mitochondrial dysfunction by protecting against oxidative stress.

Cyprinids are popular species for aquaculture worldwide, with Asia being a significant contributor to their production. In Korea, common carp (Cyprinus carpio), koi carp (Cyprinus rubrofuscus), and goldfish (Carassius auratus) are cultivated domestically and imported for ornamental or human consumption purposes. Among the viruses that infect cyprinids, cyprinid herpesvirus-2 (CyHV-2), koi herpesvirus (KHV, also known as cyprinid herpesvirus-3), and carp edema virus (CEV) are of particular concern as they cause substantial economic losses to the aquaculture industry. In this study, we investigated these viruses in both of domestic and imported cyprinids. Our results revealed that CyHV-2 was only detected in imported goldfish from Thailand. To further investigate the genetic characteristics of them, the marker A region was analyzed. Despite belonging to the same cluster with isolates from China, France, Poland, and Israel, CyHV-2 detected in this study showed distinct differences in their repetitive sequence sizes. Furthermore, two different forms of KHV/CEV coinfection were identified from domestic koi carp, both of which exhibited typical symptoms. Phylogenetic analysis showed that one KHV isolate (ScKc-2105-K) was of the Asian type and closely related to isolates from Japan, Indonesia, Belgium, Taiwan, and China. Two CEV isolates (ScKc-2105-CE and GhKc-2207-CE) belonged to the IIa type and showed high similarity with isolates from the USA, France, and Korea. Notably, koi carp injected with cultured KHV (ScKc-2105-K) showed 78.0% cumulative mortality within 14 days post-injection (dpi). Our findings support the importance of regular surveillance of viral diseases in cyprinids.

Oral lichen planus (OLP) is a chronic inflammatory disease that is characterized by the infiltration of T cells into the oral mucosa, causing the apoptosis of basal keratinocytes. OLP is a multifactorial disease of unknown etiology and is not solely caused by the malfunction of a single key gene but rather by various intracellular and extracellular factors. Non-coding RNAs play a critical role in immunological homeostasis and inflammatory response and are found in all cell types and bodily fluids, and their expression is closely regulated to preserve normal physiologies. The dysregulation of non-coding RNAs may be highly implicated in the onset and progression of diverse inflammatory disorders, including OLP. This narrative review summarizes the role of non-coding RNAs in molecular and cellular changes in the oral epithelium during OLP pathogenesis.

Early detection of lung cancer is crucial for patient survival and treatment. Recent advancements in next-generation sequencing (NGS) analysis enable cell-free DNA (cfDNA) liquid biopsy to detect changes, like chromosomal rearrangements, somatic mutations, and copy number variations (CNVs), in cancer. Machine learning (ML) analysis using cancer markers is a highly promising tool for identifying patterns and anomalies in cancers, making the development of ML-based analysis methods essential. We collected blood samples from 92 lung cancer patients and 80 healthy individuals to analyze the distinction between them. The detection of lung cancer markers Cyfra21 and carcinoembryonic antigen (CEA) in blood revealed significant differences between patients and controls. We performed machine learning analysis to obtain AUC values via Adaptive Boosting (AdaBoost), Multi-Layer Perceptron (MLP), and Logistic Regression (LR) using cancer markers, cfDNA concentrations, and CNV screening. Furthermore, combining the analysis of all multi-omics data for ML showed higher AUC values compared with analyzing each element separately, suggesting the potential for a highly accurate diagnosis of cancer. Overall, our results from ML analysis using multi-omics data obtained from blood demonstrate a remarkable ability of the model to distinguish between lung cancer and healthy individuals, highlighting the potential for a diagnostic model against lung cancer.

Abstract Background Fibrolamellar hepatocellular carcinoma (FL-HCC) is a liver tumor that occurs almost exclusively in young adults without underlying liver disease. In spite of its distinct clinical characteristics and specific imaging findings, preoperative diagnosis is often difficult due to the extremely low incidence of the tumor. Although FL-HCC shows particular morphological features on H&E-stained tissue sections, differential diagnosis from ordinary HCC, especially the scirrhous variant of HCC, and intrahepatic cholangiocarcinoma needs additional immunohistochemical (IHC) analyses and/or molecular genetic testing. Case presentation A 21-year-old male patient was referred to our hospital for further evaluation of a large liver mass. Abdominal ultrasound examination, contrast-enhanced computed tomography, and magnetic resonance imaging revealed a well-defined hypervascular lobulated liver mass, 11 × 11 cm in diameter, with a central scar and calcification, in segments 5/8. Under the diagnosis of FL-HCC, we carried out extended anterior sectorectomy, including a part of segment 4. On microscopic examination, the tumor was composed of proliferating polygonal cells with abundant eosinophilic granular cytoplasm containing nuclei with vesicular chromatin and enlarged nucleoli, in an abundant stroma. Collagen fibers arranged in a parallel lamellar pattern were seen in the tumor stroma. These findings, together with the results of subsequent IHC analyses using HAS, CK7, and CD 67, we made the diagnosis of FL-HCC, which was further confirmed by detection of the DNAJB1-PRKACA fusion gene in the tumor cells by RT-PCR. Conclusion FL-HCC shows distinct imaging appearances. Although it also has characteristic morphological features, combined use of IHC and/or molecular genetic studies are necessary for the final diagnosis.

Abstract Background Percutaneous transhepatic gallbladder drainage (PTGBD) is indicated for patients with acute cholecystitis (AC) who are not indicated for urgent surgery, but external tubes reduce quality of life (QOL) while waiting for elective surgery. The objective of the present study was to investigate the feasibility of laparoscopic cholecystectomy after endoscopic trans-papillary gallbladder stenting (ETGBS) comparing with after PTGBD. Methods Intraoperative and postoperative outcomes of patients with ETGBS and PTGBD were retrospectively compared. Results Eighteen ETGBS and ten PTGBD patients were compared. Differences in the duration of ETGBS and PTGBD [median 209 min (range 107–357) and median 161 min (range 130–273), respectively, P = 0.10], median blood loss [ETGBS 2 (range 2–180 ml) and PTGBD 24 (range 2–100 ml), P = 0.89], switch to laparotomy (ETGBS 11% and PTGBD 20%, P = 0.52), and median postoperative hospital stay [ETGBS 8 (range 4–24 days) and ETGBS 8 (range 4–16 days), P = 0.99]. Thickening of the cystic duct that occurred in 60% of the ETGBS patients and none of the PTGBD patients (P = 0.005) interfered with closure of the duct by clipping. No obstruction occurred in ETGBS patients. Conclusion ETGBS did not make laparoscopic cholecystectomy less feasible than after PTGBD. This is a pilot study, and further investigations are needed to validate the results of the present study.

Abstract Background Pancreaticoduodenectomy after esophageal resection is technically difficult, because blood flow of the gastric conduit should be preserved. Celiac axis stenosis (CAS) is also a problem for pancreaticoduodenectomy, because arterial blood supply for the liver comes mainly through the collateral route from the superior mesenteric artery (SMA) via the gastroduodenal artery (GDA). Herein, we report the case of a patient with pancreatic head cancer who underwent a pancreaticoduodenectomy after esophagectomy with concomitant CAS. Case presentation A 76-year-old man with pancreatic head cancer was referred to our department. He had a history of esophagectomy with retrosternal gastric conduit reconstruction for esophageal cancer. Computed tomography showed severe CAS and a dilated collateral route between the SMA and the splenic artery (SPA). We prepared several surgical options depending on the intraoperative findings, and performed radical pancreaticoduodenectomy with concomitant resection of the distal gastric conduit. The right gastroepiploic artery (RGEA) of the remnant gastric conduit was fed from the left middle colic artery (MCA) with microvascular anastomosis. Despite CAS, when the GDA was dissected and clamped, good blood flow was confirmed, and the proper hepatic artery did not require reconstruction. The patient was discharged on postoperative day 90. Conclusions We successfully performed radical pancreaticoduodenectomy after esophagectomy with concomitant CAS, having prepared multiple surgical options depending upon the intraoperative findings.

The hemiparkinsonian nonhuman primate model induced by unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the carotid artery is used to study Parkinson’s disease. However, there have been no studies that the contralateral distribution of MPTP via the cerebral collateral circulation is provided by both the circle of Willis (CoW) and connections of the carotid artery. To investigate whether MPTP-induced unilaterally damaged regions were determined by asymmetrical cerebral blood flow, the differential asymmetric damage of striatal subregions, and examined structural asymmetries in a circle of Willis, and blood flow velocity of the common carotid artery were observed in three monkeys that were infused with MPTP through the left internal carotid artery. Lower flow velocity in the ipsilateral common carotid artery and a higher ratio of ipsilateral middle cerebral artery diameter to anterior cerebral artery diameter resulted in unilateral damage. Additionally, the unilateral damaged monkey observed the apomorphine-induced contralateral rotation behavior and the temporary increase of plasma RANTES. Contrastively, higher flow velocity in the ipsilateral common carotid artery was observed in the bilateral damaged monkey. It is suggested that asymmetry of blood flow velocity and structural asymmetry of the circle of Willis should be taken into consideration when establishing more efficient hemiparkinsonian nonhuman primate models.

Background: The pathophysiological symptom of Sasang typology is essential for getting clinical diagnosis and analyzing treatment effects. The clinical index for examining urination and defecation related symptoms were developed and validated with established clinical measures. Methods: Questionnaire items of six subscales of Sasang Urination and Defecation Inventory (SUDI) were developed based on previous systematic reviews, and its clinical validity was examined with clinical measures of Urogenital Distress Inventory-6 (UDI-6), Overactive Bladder Symptom Score (OBSS), and ROME 3 criteria for Irritable Bowel Syndrome (ROME3-IBS) and Functional Constipation (ROME3-FC) using 48 healthy participants. The internal consistency of six subscales of SUDI were examined with Cronbach alpha. The Pearson correlation was used to examine correlation between SUDI and Western clinical measures, and the ANOVA was adopted to investigate differences among Sasang type groups in clinical measures. Results: The SUDI-UCHR (problematic characteristics of urine) and SUDI-ANMD (defecation anomaly discomfort) were found to represent unique concept of traditional Korean medicine, however SUDI-IRRB (irritability of bowel movement) and SUDI-FCON (functional constipation) were similar with functional gastrointestinal disease of western medicine. SUDI-URET (ability to retain urine), SUDI-UDIS (urinary discomfort) and SUDI-ANMD of So-Yang type (7.95 ± 2.16, 14.33 ± 2.01, and 13.10 ± 2.57) are significantly different from those of So-Eum type (9.94 ± 2.54, 12.18 ± 2.96, and 10.59 ± 3.47, respectively). Conclusion: The pathophysiological symptoms of urination and defecation in Sasang typology were systematically scrutinized, and summarized into six subscales of SUDI in this study. The SUDI would be useful for analyzing clinical symptoms of Sasang typology along with integrative collaboration of traditional Korean and Western medicine. Keywords: Sasang typology, Pathophysiological symptom, Sasang Urination and Defection Inventory, Excretory function

BackgroundTechnical proficiency of the operating surgeons is one of the most important factors in the safe performance of pancreaticoduodenectomy. The objective of the present study was to investigate whether surgical simulation of pancreatico-jejunostomy (PJ) using an inanimate biotissue model could improve the technical proficiency of hepato-biliary pancreatic (HBP) surgical fellows.MethodsThe biotissue drill consisted of sewing biotissues to simulate PJ. The drill was repeated a total of five times by each of the participant surgical fellows. The improvement of the surgical fellows' technical proficiency was evaluated by the supervisor surgeons using the Objective Structured Assessment of Technical Skills (OSATS) scale.ResultsEight HBP surgical fellows completed all the 5 drills. Both the OSATS 25 score and OSATS summary score, assessed by the two supervisor surgeons, improved steadily with repeated execution of the PJ drill. The average OSATS score, as assessed by both the supervisor surgeons, improved significantly from the first to the final drill, with a P value of 0.003 and 0.014 for the assessment by the two surgeons, respectively. On the other hand, no chronological alteration was observed in time of procedure (P = 0.788).ConclusionRepeated execution of a biotissue PJ drill improved the HBP surgical fellows' technical proficiency, as evaluated by OSATS. The present study lends support to the evidence that simulation training can contribute to shortening of the time required to negotiate the learning curve for the technique of PJ in the actual operating room.

Glioblastoma is an actively growing and aggressive brain tumor with a high propensity of recurrence. Although the surgical removal of tumor mass is the primary therapeutic option against glioblastoma, supportive pharmacotherapy is highly essential due to incredibly infiltrative characteristic of glioblastoma. Temozolomide, an FDA-approved alkylating agent, has been used as a first-line standard pharmacological approach, but several evident limitations were repeatedly reported. Despite additional therapeutic options suggested, there are no medications that successfully prevent a recurrence of glioblastoma and increase the five-year survival rate. In this study, we tested the possibility that finasteride has the potential to be developed as an anti-glioblastoma drug. Finasteride, an FDA-approved medication for the treatment of benign prostate hyperplasia and androgenic alopecia, is already known to pass through the blood–brain barrier and possess antiproliferative activity of prostate epithelial cells. We showed that finasteride inhibited the maintenance of glioma stem-like cells and repressed the proliferation of glioblastoma. Mechanistically, finasteride lowered intracellular ROS level by upregulating antioxidant genes, which contributed to inefficient β-catenin accumulation. Downregulated β-catenin resulted in the reduction in stemness and cell growth in glioblastoma.

Salivary adenoid cystic carcinoma (SACC) is one of the most common subtypes of salivary gland carcinomas and frequently metastasizes to distant organs. However, little is known about the molecular mechanisms that promote SACC metastasis. In this study, we report that transforming growth factor (TGF)-[beta]1 was highly expressed in the highly metastatic SACC-LM cell line as compared with its parental low-metastatic SACC-83 cell line. Exogenous addition of TGF-[beta]1 induced Smad2 phosphorylation and promoted the migration and invasion of SACC-83 cells. Consistently, the inhibition of endogenous TGF-[beta]1 signaling in SACC-LM cells by an inhibitor specific to the type I TGF-[beta]1 receptor (T[beta]RI) suppressed cell migration and invasion. Moreover, we found that TGF-[beta]1 expression was significantly increased in human primary SACC samples with metastasis. Taken together, our results suggest that TGF-[beta]1 may play a crucial role in SACC metastasis. [ABSTRACT FROM AUTHOR]

alpha(1)-Adrenoceptor has been discovered to exist in many human tissues and mediates important physiological functions. The purpose of this study was to detect the expression, distribution, and function of alpha(1)-adrenoceptor subtypes in human submandibular glands. alpha(1A)- and alpha(1B)-Adrenoceptor mRNAs were identified by reverse-transcription/polymerase chain-reaction (RT-PCR), and their proteins were detected by Western blotting. No expression of the alpha(1D)-adrenoceptor mRNA and protein was found. By in situ hybridization and immunohistochemistry, alpha(1A)- and alpha(1B)-adrenoceptor mRNAs and proteins were shown to be widespread in both ductal and acinar cells. By confocal microscopy, phenylephrine (stimulating both alpha(1A)- and alpha(1B)-adrenoceptors) or A61603 (alpha(1A)-selective agonist) induced an increase in intracellular calcium by 2.33 +/- 0.18-fold and 1.81 +/- 0.43-fold, respectively, while 5-methylurapidil (alpha(1A)-selective antagonist) partly blocked calcium mobility stimulated by phenylephrine. The results indicated that functional alpha(1A)- and alpha(1B)-adrenoceptors were expressed in human submandibular glands, and might contribute to the regulation of saliva synthesis and secretion. [ABSTRACT FROM AUTHOR]

Aging is characterized by a progressive decline or loss of physiological functions, leading to increased susceptibility to disease or death. Several aging hallmarks, including genomic instability, cellular senescence, and mitochondrial dysfunction, have been suggested, which often lead to the numerous aging disorders. The periodontium, a complex structure surrounding and supporting the teeth, is composed of the gingiva, periodontal ligament, cementum, and alveolar bone. Supportive and protective roles of the periodontium are very critical to sustain life, but the periodontium undergoes morphological and physiological changes with age. In this review, we summarize the current knowledge of molecular and cellular physiological changes in the periodontium, by focusing on soft tissues including gingiva and periodontal ligament.

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.

The relationship between the change of pulse transit time and the presence of clinical signs after stallate ganglion block (SGB) was investigated in patients with disorders mediated by the sympathetic nervous system. SGB is used for the treatment and diagnosis of these disorders; however, a successful objective marker does not exist. Therefore, identifying increased blood flow following SGB and determining whether pulse transit time could be used to verify the success of SBG would be a helpful resource.

We explored the use of a hybrid filler consisting of graphite nanoplatelets (GNPs) and single walled carbon nanotubes (SWCNTs) in a polyamide 6 (PA 6) matrix. The composites containing PA 6, powdered GNP, and SWCNT were melt-processed and the effect of filler content in the single filler and hybrid filler systems on the thermal conductivity of the composites was examined. The thermal diffusivities of the composites were measured by the standard laser flash method. Composites containing the hybrid filler system showed enhanced thermal conductivity with values as high as 8.8 W (m · K)−1, which is a 35-fold increase compared to the thermal conductivity of pure PA 6. Thermographic images of heat conduction and heat release behaviors were consistent with the thermal conductivity results, and showed rapid temperature jumps and drops, respectively, for the composites. A composite model based on the Lewis–Nielsen theory was developed to treat GNP and SWCNT as two separate types of fillers. Two approaches, the additive and multiplicative approaches, give rather good quantitative agreement between the predicted values of thermal conductivity and those measured experimentally.

BackgroundA dynamic preload index such as stroke volume variation (SVV) is not as reliable in spontaneous breathing (SB) patients as in mechanically ventilated patients. This study examined the hypothesis that spectral analysis of hemodynamic variables during paced breathing (PB) activity may be a feasible index of volume changes and fluid responsiveness, despite insufficient respiratory changes in the preload index during SB activity.MethodsBlood pressure and stroke volume (SV) were measured in 16 subjects undergoing PB (15 breaths/min), using a Finometer device and the Modelflow method. Respiratory systolic pressure variation (SPV) and SVV were measured and respiratory frequency (RF, 0.2-0.3 Hz) of power spectra of SPV (SPVRF) and SVV (SVVRF) were computed using fast Fourier transformation. Progressive hypovolemia was simulated with lower body negative pressure (LBNP). Volume challenges were produced by infusion of normal saline and subsequent release of LBNP to baseline. Fluid responsiveness, defined as a >20% increase in SV, was assessed by the area under the curve (AUC) of receiver operating characteristic curves.ResultsGraded hypovolemia caused a significant increase in SPVRF and a decrease in SVVRF. During volume expansion, SPVRF decreased and SVVRF rose significantly. Fluid responsiveness was better predicted with SVVRF (AUC 0.75) than with SPVRF, SPV, or SVV. SVVRF before volume challenge was significantly correlated with volume expansion-induced changes in SV (r = -0.64).ConclusionsThese results suggest that RF spectral analysis of dynamic preload variables may enable the detection of volume change and fluid responsiveness in SB hypovolemic patients performing PB activity.

Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk1 (2f)) to the Alk1-null allele (Alk1 (1f)) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2.

The subcutaneous tissue of rats after implantation of polypropylene materials with adsorbed bone marrow-derived mesenchymal multipotent stromal cells (MMSCs) was studied using light microscopy. Inflammation in response to implantation was mild, and the foreign material was encapsulated into a thin strip of dense fibrous connective tissue with multinucleated macrophages. By 1 year after introduction of the monofilament and 6 and 12 months after implantation of the mesh product, some threads were deformed, broken, and had sharp edges. Small fragments of foreign material appeared in the adjacent tissues surrounded by their own relatively thick acellular capsule. As a result of preliminary adsorption of MMSCs on polypropylene, the thickness of the connective tissue capsule decreased, its vascularization increased, and the severity of inflammatory infiltration decreased. However, all effects of MMSCs adsorption in rats were transient and disappeared within 1 week., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine., Methods: We conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database., Results: Six single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10 - 7 ): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10 - 9 ). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure., Conclusion: The identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology., Trial Registration: Not applicable., (© 2024. The Author(s).)

Graphene oxide (GO) is a two-dimensional metastable nanomaterial. Interestingly, GO formed oxygen clusterings in addition to oxidized and graphitic phases during the low-temperature thermal annealing process, which could be further used for biomolecule bonding. By harnessing this property of GO, we created a bio-interface with patterned structures with a common laboratory hot plate that could tune cellular behavior by physical contact. Due to the regional distribution of oxygen clustering at the interface, we refer to it as patterned annealed graphene oxide (paGO). In addition, since the paGO was a heterogeneous interface and bonded biomolecules to varying degrees, arginine-glycine-aspartic acid (RGD) was modified on it and successfully regulated cellular-directed growth and migration. Finally, we investigated the FRET phenomenon of this heterogeneous interface and found that it has potential as a biosensor. The paGO interface has the advantages of easy regulation and fabrication, and the one-step thermal reduction method is suitable for biological applications. We believe that this low-temperature thermal annealing method would make GO interfaces more accessible, especially for the development of nano-interfacial modifications for biological applications, revealing its potential for biomedical applications.

Context.—: Many drugs can induce liver injury; however, vaccine-induced liver injury is a rare phenomenon. SARS-CoV-2 messenger RNA (mRNA) vaccines are now widely administered, and clinical evidence of liver injury has been reported., Objective.—: To characterize the histologic features of SARS-CoV-2 mRNA vaccine-associated liver injury., Design.—: Thirteen liver biopsies from 12 patients with elevated liver enzymes clinically favored to be secondary to SARS-CoV-2 mRNA vaccine were identified between 2021 and 2022. Demographics, clinical information, and histologic features of liver biopsies were reviewed., Results.—: All patients (median age, 58 years; M:F = 4:8) received at least 1 dose of SARS-CoV-2 mRNA vaccines (7 Pfizer and 5 Moderna). Four patients had a history of liver disease. Nine patients developed symptoms between 1 day and 2 months after receiving the vaccine dose. Viral serologies were negative. Drug-induced liver injury was thought to be less likely clinically in the 3 patients who had started new medications. Autoimmune antibodies were detected in 9 patients. Moderate to severe active hepatitis was the dominant histologic pattern of injury (9 of 13 biopsies; 69%). Resolving hepatitis, cholestatic hepatitic injury, and bile duct injury were identified in 1 biopsy each. All patients recovered spontaneously or with steroid therapy except one patient who developed autoimmune hepatitis., Conclusions.—: Moderate to severe active hepatitis is commonly observed in SARS-CoV-2 mRNA vaccine-associated liver injury, and female patients may be more susceptible to injury. Liver injury resolves spontaneously or with steroid treatment. In rare cases, these vaccines may trigger an underlying immune condition., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Viruses are dependent on the host factors for their replication and survival. Therefore, identification of host factors that druggable for antiviral development is crucial. The actin cytoskeleton plays an important role in the virus infection. The dynamics change of actin and its function are regulated by multiple actin-associated proteins (AAPs). However, the role and mechanism of various AAPs in the life cycle of virus are still enigmatic. In this study, we analyzed the roles of actin and AAPs in the replication of pseudorabies virus (PRV). Using a library of compounds targeting AAPs, our data found that multiple AAPs, such as Rho-GTPases, Rock, Myosin and Formin were involved in PRV infection. Besides, our result demonstrated that the actin-binding protein Drebrin was also participated in PRV infection. Further studies are necessary to elucidate the molecular mechanism of AAPs in the virus life cycle, in the hope of mining host factors for antiviral developments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Supramolecular macrocycles, renowned for their remarkable capabilities in molecular recognition and complexation, have emerged as pivotal elements driving advancements across various innovative research fields. Cocrystal materials, an important branch within the realm of crystalline organic materials, have garnered considerable attention owing to their simple preparation methods and diverse potential applications, particularly in optics, electronics, chemical sensing and photothermal conversion. In recent years, macrocyclic entitles have been successfully brought into this field, providing an essential and complementary channel to create novel functional materials, especially those with multiple functionalities and smart stimuli-responsiveness. In this Review, we present an overview of the research efforts on functional cocrystals constructed with macrocycles, covering their design principles, preparation strategies, assembly modes, and diverse functions and applications. Finally, the remaining challenges and perspectives are outlined. We anticipate that this review will serve as a valuable and timely reference for researchers interested in supramolecular crystalline materials and beyond, catalyzing the emergence of more original and innovative studies in related fields.

As an important CXC chemokine, CXCL8 plays pleiotropic roles in immunological response. In teleost, CXCL8 is involved in cell migration and bacterial invasion. However, the immune antibacterial function of CXCL8 in Japanese flounder (Paralichthys olivaceus) (PoCXCL8) is largely scarce. In this research, we investigated the antibacterial property and leukocyte activation of PoCXCL8. PoCXCL8 consists of 100 amino acid residues, with a conserved chemokine CXC domain. PoCXCL8 was expressed in various tissues, with the highest level in liver and the lowest level in muscle, and sharply induced by V. harveyi or E. tarda in liver, spleen, and head kidney. In vitro, the recombinant PoCXCL8 (rPoCXCL8) could bind to Bacillus subtilis, Edwardsiella tarda, Escherichia coli, Pseudomonas fluorescens, Vibrio anguillarum, Vibrio harveyi, Staphylococcus aureus, and Micrococcus luteus, affect the growth of E. coli, E. tarda, M. luteus, and P. fluorescens, and have a direct bactericidal effect on E. coli and E. tarda. Moreover, rPoCXCL8 was able to bind the outer membranal protein rPilA of E. tarda. In addition, rPoCXCL8 could bind to PBLs, activating the PBLs activity including chemotaxis, proliferation, phagocytosis, reactive oxygen species, acid phosphatase activity. At same time, rPoCXCL8 could induce neutrophil to generate neutrophil extracellular traps (NETs) and promote the expression of inflammatory genes including IL-1β, IL6, MMP13, TNF-α, and NF-κB. In flounder, the presence of rPoCXCL8 could enhance the in vivo resistance to E. tarda in liver, spleen, and head kidney. Moreover, the PoCXCL8-deficient could attenuate the fish defense against E. tarda infection in in spleen and head kidney. In conclusion, these results provided new insights into the antibacterial properties of CXCL8 in P. olivaceus., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively impact quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy., Objective: We performed a multi-site, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE., Methods: Patients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary endpoint was symptom improvement by Pediatric EoE Symptom Score (PEESSv2.0). Secondary endpoints were proportion achieving histologic remission (<15 eosinophils/high-power field [eos/hpf]); change in histologic features (histology scoring system [HSS]), endoscopic severity (endoscopic reference score [EREFS]), transcriptome (EoE diagnostic panel [EDP]), and QoL scores; and predictors of remission., Results: 63 patients were randomly assigned to 1FED (n=38) and 4FED (n=25). In 4FED versus 1FED, mean PEESSv2.0 improved -25.0 versus -14.5 (p=0.04) but remission rates (41% versus 44%; p=1.00), HSS (-0.25 versus -0.29; p=0.77), EREFS (-1.10 versus -0.58; p=0.47) and QoL scores were similar between groups. The EoE transcriptome normalized in histologic responders to both diets. Baseline peak eosinophil count predicted remission (OR 0.975, 95% CI 0.953-0.999, p=0.04; cut-off ≤42 eos/hpf). The 4FED withdrawal rate (32%) exceeded 1FED (11%) (p=0.0496)., Conclusions: Although 4FED moderately improved symptoms compared to 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first choice therapy for pediatric EoE given its effects, tolerability, and relative simplicity., (Copyright © 2024. Published by Elsevier Inc.)

In laboratory conditions, composite sutures based on polylactide (PLA) containing chitin nanofibrils modified with polyethylene glycol (CN-PEG) and poviargol (silver nanoparticles stabilized with poly(N-vinylpyrrolidone)) were obtained, studied, and used as a prototype. Surgical sutures threads with the addition of CN-PEG have stable mechanical properties both in air and in a buffer simulating the environment of a living organism. The yield strength of oriented threads decreased by an average of 15%, whereas for non-oriented threads the decrease was 3-4 times. The strength values in simple units of unfilled PLA, PLA containing 5 wt % CN-PEG, and PLA with 1 wt % Poviargol were on average 50% higher than the national standard 31620-2012. The results of in vivo experiments on albino rats (cross-linking skin and muscle tissue in the linea alba area) showed that composite sutures are best for suturing muscle tissue, whereas unfilled PLA sutures are more suitable for suturing skin. When suturing muscle tissue, suturing with composite sutures increased the number of collagen fibers of different diameters., (© 2024 Wiley Periodicals LLC.)

Objectives: We aimed to evaluate the histopathological alterations in human salivary glands after radioactive iodine (RAI) treatment for thyroid diseases., Study Design: We retrospectively selected patients with a history of RAI treatment for thyroid diseases from a database of patients who underwent surgery for oral and maxillofacial diseases and had specimens of salivary glands at Peking University School of Stomatology between December 2012 and July 2023. The patients' clinical records and histopathological slides of the salivary glands were carefully reviewed., Results: Sixteen patients were included. Three symptomatic patients showed duct cell cytoplasmic vacuolization and increased numbers of disordered duct cell layers (3/3), severe duct stenosis and dilation (2/3), and exfoliated epithelial cells in the duct lumen (1/3). The glandular parenchyma showed severe acinar atrophy (2/2), fat content enhancement (2/2), and severe periductal fibrosis (3/3). Thirteen asymptomatic patients showed duct cell cytoplasmic vacuolization (5/13), acinar atrophy and increased fat content in the parenchyma (5/13), and periductal fibrosis (5/13)., Conclusion: Main histopathologic changes in the salivary glands after RAI treatment for thyroid diseases are cytoplasmic vacuolization of duct cells, acinar atrophy, fat content enhancement, and periductal fibrosis. These changes were evident in symptomatic cases, and were also seen in some asymptomatic patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Recurrence within one or two years is common after Crohn's disease (CD) resection. In this study, we seek to identify histologic features in CD resections that may predict earlier (≤18 months) recurrence to potentially guide post-operative management. A single-institution, retrospective review was performed on patients with first-time CD bowel resection specimens (2002-2007). Patient demographics and CD course were also documented. Slides were reviewed for inflammatory distribution and composition, small bowel (SB) pyloric metaplasia (PM), and presence and characteristics of submucosal fibrosis and granulomas. In our cohort, 14 of 41 patients experienced earlier clinical or endoscopic recurrence after initial resection. In the 38 patients who underwent SB resection (3 were colon only), PM was less common in those with earlier recurrence (6/12 [50%]) compared to those with later (>18 months) or no known recurrence (22/26 [85%]) (P = 0.045). PM was present even in patients with <1 year of known CD. Additionally, therapy with anti-tumor necrosis factor (TNF) prior to surgery was more common in earlier recurrence patients (7/14 [50%]) than later or no recurrence patients (4/27 [15%]) (P = 0.026). There was no significant difference in age, sex, smoking status, duration of CD, post-operative CD medication, distribution or features of inflammation, granulomas, or fibrosis. Overall, our results indicate that SB PM and pre-surgical anti-TNF therapy are possible helpful clinicopathologic features to evaluate for recurrence risk., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven esophageal disorder. Connective tissue disorders (CTDs) and esophageal connective tissue alterations are associated with EoE. Therefore, angiotensin II type 1 receptor blockade with losartan, an accepted CTD treatment, is a potential EoE treatment., Objective: We evaluated losartan's effects on esophageal pathology, symptoms, and safety in patients with EoE with and without a CTD in an open-label, non-placebo controlled multisite study., Methods: Fifteen participants with EoE, aged 5 to 23 years, underwent treatment with per-protocol titrated doses of losartan in an open-label, 16-week pilot trial. Losartan was added to standard of care therapy and 14 patients completed the study. Eosinophil counts served as the primary end point, whereas we also assessed the EoE Histology Scoring System, Endoscopic Reference Scores, EoE Diagnostic Panel, and patient-reported outcomes., Results: Esophageal eosinophilia was not reduced after losartan. The peak eosinophil count was not reduced for the proximal (median [interquartile range]: -3 [-22 to 3]; P = .49) and distal esophagus (median [interquartile range]: -18 [-39 to -1]; P = .23). There were no differences in losartan response in EoE with or without CTD (n = 7 and 8, respectively). Regardless, in a small subset of four participants esophageal eosinophilia was resolved with a concomitant reduction in EoE Histology Scoring System score and Endoscopic Reference Score. Across all subjects, the Pediatric EoE Symptom Score, Pediatric Quality of Life Inventory EoE Module, and EoE Diagnostic Panel improved after losartan (P < .05)., Conclusions: Losartan treatment was associated with improved patient-reported outcome scores and EoE Diagnostic Panel biomarkers although without a reduction in esophageal eosinophilia overall. A subset of patients demonstrated improved histopathologic and endoscopic features that could not be tied to a specific feature predicting response to treatment., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Sialadenitis is a prevalent salivary gland disease resulting in decreased salivary flow rate. To date, little is known about the exact changes and mechanism of ductal cells in sialadenitis. This study aims to establish an efficient method to identify and isolate ductal cells, thereby facilitating further research on this specific cell type. Immunofluorescence for cytokeratin 13 and cytokeratin 19 was conducted in salivary glands to confirm their specificity as ductal cell markers. The dissected ducts were assessed through PCR and Western blot of cytokeratin 19 and digested by dispase and collagenase. The functionality of the isolated ductal cells was determined by measuring intracellular calcium. Cytokeratin 19 and cytokeratin 13 were expressed in all segments of human ducts. Cytokeratin 19 was limited to ducts excluding granular convoluted tubules in rat and mouse. The purities of the obtained ductal cells were approximately 98% in humans and 93% in rats. Furthermore, intracellular free calcium increased with time and concentration of carbachol treatment. Cytokeratin 19 serves as a dependable marker for identifying ductal cells in salivary glands, except for granular convoluted tubules. Moreover, we have successfully developed an efficient method for isolating ductal cells from salivary glands., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The LEPR gene encodes a leptin hormone receptor, and its mutations are associated with morbid obesity, dysregulation of lipid metabolism, and fertility defects in humans. Spontaneous Lepr mutations have been described in rodents, and Lepr knockout animals have been generated, in particular, using the CRISPR/Cas9 system. Lipid metabolism in rodents significantly differs from that in humans or rabbits, and rabbits are therefore considered as the most relevant model of morbid obesity and lipid metabolism dysregulation in humans. LEPR knockout rabbits have not been reported so far. In this work a LEPR knockout rabbit was generated by introducing a deletion of the region around LEPR exon 10 using the CRISPR/Cas9 system. The body weight of the knockout rabbit was significantly higher than the average body weight of the wild type rabbits. CRISPR/Cas9-mediated generation of LEPR knockout rabbits will allow the development of a model of morbid obesity and endocrine defects due to leptin receptor mutations in humans., (© 2024. Pleiades Publishing, Ltd.)

Soluble HIV-1 envelope (Env) trimers may serve as effective vaccine immunogens. The widely utilized SOSIP trimers have been paramount for structural studies, but the disulfide bond they feature between gp120 and gp41 constrains intersubunit mobility and may alter antigenicity. Here, we report an alternative strategy to generate stabilized soluble Env trimers free of covalent gp120-gp41 bonds. Stabilization was achieved by introducing an intrasubunit disulfide bond between the inner and outer domains of gp120, defined as interdomain lock (IDL). Correctly folded IDL trimers displaying a native-like antigenic profile were produced for HIV-1 Envs of different clades. Importantly, the IDL design abrogated CD4 binding while not affecting recognition by potent neutralizing antibodies to the CD4-binding site. By cryoelectron microscopy, IDL trimers were shown to adopt a closed prefusion configuration, while single-molecule fluorescence resonance energy transfer documented a high prevalence of native-like conformation. Thus, IDL trimers may be promising candidates as vaccine immunogens., Competing Interests: Declaration of interests P.L. and P.Z. applied for a patent describing HIV-1 envelope trimers stabilized in a native-like, non-CD4-binding conformation (US Provisional Patent Application No. 62/306,006, filed on March 9, 2016, entitled “Recombinant HIV-1 envelope proteins and their use”)., (Published by Elsevier Inc.)

This letter addresses the review titled "Wharton's jelly mesenchymal stem cells: Future regenerative medicine for clinical applications in mitigation of radiation injury". The review highlights the regenerative potential of Wharton's jelly mesenchymal stem cells (WJ-MSCs) and describes why WJ-MSCs will become one of the most probable stem cells for future regenerative medicine. The potential plausible role of WJ-MSCs for diabetic bone regeneration should be noticeable, which will provide a new strategy for improving bone regeneration under diabetic conditions., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The confused gene expressions and molecular mechanisms for mitochondrial dysfunction of traditional nanoenzymes is a challenge for tumor therapy. Herein, a nano-bacilliform-enzyme obtains the ability to inhibit p52-ZER6 signal pathway, regulate the genes related to mitochondrial metabolism, and possess the GOx/CAT/POD-like property. NBE acquires catalytic activity from the electronic energy transition. The tannin of NBE as a mitochondrial (Mito)-targeting guide overloads MitoROS, and then metabolic disorder and lipid peroxidation of Mito membrane occurs, thus leading to a novel death pathway called PAFerroptosis (pyroptosis, apoptosis, and Ferroptosis). Simultaneously, in order to refrain from mitophagy, hydroxychloroquine is mixed with NBE to form a combo with strength pyroptosis. As a result, NBE/combo improves the PAFerroptosis obviously by activation of CD8+T cells and inactivation of MDSC cells, up-regulating expression of caspase-3 signal pathway, intercepting DHODH pathway to arrive excellent antitumor effect (93%). Therefore, this study establishes a rational nanoenzyme for mitochondrial dysfunction without mitophagy for effective antitumor therapy., (© 2024 Wiley‐VCH GmbH.)

As the burgeoning field of Artificial Intelligence (AI) continues to permeate the fabric of healthcare, particularly in the realms of patient surveillance and telemedicine, a transformative era beckons. This manuscript endeavors to unravel the intricacies of recent AI advancements and their profound implications for reconceptualizing the delivery of medical care. Through the introduction of innovative instruments such as virtual assistant chatbots, wearable monitoring devices, predictive analytic models, personalized treatment regimens, and automated appointment systems, AI is not only amplifying the quality of care but also empowering patients and fostering a more interactive dynamic between the patient and the healthcare provider. Yet, this progressive infiltration of AI into the healthcare sphere grapples with a plethora of challenges hitherto unseen. The exigent issues of data security and privacy, the specter of algorithmic bias, the requisite adaptability of regulatory frameworks, and the matter of patient acceptance and trust in AI solutions demand immediate and thoughtful resolution .The importance of establishing stringent and far-reaching policies, ensuring technological impartiality, and cultivating patient confidence is paramount to ensure that AI-driven enhancements in healthcare service provision remain both ethically sound and efficient. In conclusion, we advocate for an expansion of research efforts aimed at navigating the ethical complexities inherent to a technology-evolving landscape, catalyzing policy innovation, and devising AI applications that are not only clinically effective but also earn the trust of the patient populace. By melding expertise across disciplines, we stand at the threshold of an era wherein AI's role in healthcare is both ethically unimpeachable and conducive to elevating the global health quotient., (© 2024. The Author(s).)

Two Ni-added poly(polyoxometalate)s built of Keggin-type {Ni 6 PW 9 } and Anderson-type NiW 6 O 24 units via WO 4 /Sb 2 O bridges and Ni-O-W linkages, Na 4 H 8 [Ni(enMe) 2 ][(Sb 2 O) 2 (NiW 6 O 24 )-{Ni 12 O 2 (OH) 4 (enMe) 4 (H 2 O) 3 (WO 4 ) 2 (B-α-PW 9 O 34 ) 2 } 2 ]·39H 2 O (1) and H 9 [Ni(en) 2 (H 2 O)][Ni 0.5 (en) 2 (H 2 O)][Ni-(enMe) 2 (H 2 O)][(Sb 2 O) 2 (NiW 6 O 24 ){Ni 12 O 2 (OH) 4 (en) 2 (enMe) 2 (H 2 O) 3 (WO 4 ) 2 }-{Ni 12 O 2 (OH) 4 (en) 4 (H 2 O) 3 (WO 4 ) 2 }(B-α-PW 9 O 34 ) 4 ]·45H 2 O (2), have been hydrothermally synthesized and characterized, in which the {Ni 12 (WO 4 ) 2 (PW 9 ) 2 } subunit was obtained by the synergistic directing effect of 2 lacunary PW 9 O 34 (PW 9 ) fragments and further linked by a central Anderson-type (Sb 2 O) 2 (NiW 6 O 24 ) bridge. Both compounds represent the first example of Ni-added polyoxometalates (POMs) simultaneously based on Keggin-type and Anderson-type POM components. Photocatalytic studies revealed that 2 can work as an efficient heterogeneous catalyst towards a light-driven H 2 evolution reaction, achieving a hydrogen evolution rate of as high as 19 214 μmol g -1 h -1 (TON = 1500), which is superior to most of the reported POM-based heterogeneous catalysts.

Cluster headache (CH) is a debilitating neurological disorder characterized by severe, unilateral pain and ipsilateral autonomic symptoms. Chronic CH is exceedingly rare in Taiwan, constituting approximately 1% of all CH cases. This narrative review provides an up-to-date overview of the acute and preventive treatment strategies for CH in Taiwan, focusing on currently available pharmacological options in the country. The treatment approach for CH in Taiwan involves a stepwise strategy. High-flow oxygen and triptan nasal sprays are the mainstays of acute treatment, providing rapid relief and good tolerability. Transitional treatments, such as oral steroids and suboccipital steroid injections, serve as a crucial bridge between acute and long-term preventive therapies, offering temporary relief while minimizing side effects through a carefully limited duration. For preventive treatment, verapamil is the first-line option, with lithium and topiramate being the second-line alternatives. Among the CGRP monoclonal antibodies, galcanezumab has demonstrated efficacy in the prevention of episodic CH. Preventive treatments are personalized to individual patients, starting with low doses and close monitoring for adverse effects. Neuromodulatory therapies, such as non-invasive vagus nerve stimulation, show promise for chronic and refractory CH but have limited availability in Taiwan. In conclusion, despite the availability of various acute and preventive treatment options, unmet needs in the management of CH in Taiwan remain. In particular, increased awareness and education among healthcare professionals to improve the diagnosis and management of CH in Taiwan should be implemented., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)