Transforming growth factor-ß1 protects against white matter injury and reactive astrogliosis via the p38 MAPK pathway in rodent demyelinating model.

In central nervous system (CNS), demyelination is a pathological process featured with a loss of myelin sheaths around axons, which is responsible for the diseases of multiple sclerosis, neuromyelitis optica, and so on. Transforming growth factor-beta1 (TGF-ß1) is a multifunctional cytokine participating in abundant physiological and pathological processes in CNS. However, the effects of TGF-ß1 on CNS demyelinating disease and its underlying mechanisms are controversial and not well understood. Herein, we evaluated the protective potential of TGF-ß1 in a rodent demyelinating model established by lysophosphatidylcholine (LPC) injection. It was identified that supplement of TGF-ß1 evidently rescued the cognitive deficit and motor dysfunction in LPC modeling mice assessed by novel object recognition and balance beam behavioral tests. Besides, quantified by luxol fast blue staining, immunofluorescence, and western blot, administration of TGF-ß1 was found to significantly ameliorate the demyelinating lesion and reactive astrogliosis by suppressing p38 MAPK pathway. Mechanistically, the results of in vitro experiments indicated that treatment of TGF-ß1 could directly promote the differentiation and migration of cultured oligodendrocytes. Our study revealed that modulating TGF-ß1 activity might serve as a promising and innovative therapeutic strategy in CNS demyelinating diseases.

Astrocyte-Derived Exosomes Contribute to Pathologies of Neuromyelitis Optica Spectrum Disorder in Rodent Model.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin-4 autoantibodies (AQP4-IgG, named as NMO-IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO-IgG, the pathogenic astrocyte-derived exosomes are released and injure the neighboring cells. METHODS: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte-derived exosomes (AST-ExosNMO vs AST-ExosCON ) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST-ExosNMO . The microRNA (miRNA) sequencing of AST-Exos and verification were performed to identify the key pathogenic miRNA. The custom-designed adeno-associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. RESULTS: AST-ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR-129-2-3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR-129-2-3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR-129-2-3p level was significantly elevated in NMOSD patients and correlated with disease severity. INTERPRETATION: Astrocytes targeted by NMO-IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163-181.

Risk factors associated with lymph node metastasis in early-stage distal gastric cancer.

OBJECTS: This study was designed to explore the risk factors of lymph node metastasis (LNM) in distal gastric cancer with early stage, and to provide reference for the choice of treatment protocols. METHODS: In this retrospective observational study, 824 early distal gastric cancer (EDGC) cases who treated at our unit from 2010 to 2020 were selected as research objects. Subsequently, univariate and multivariate logistic regression analyses were conducted to investigate the associations between LNM and clinicopathological features. RESULTS: Of these 824 EDGC cases, 140 (17.0%) developed LNM, including 72 N1 stage and 68 N2-3 stage LNM. Multivariate logistic regression analysis identified the tumor diameter ≥1.75 cm (odds ratio (OR) = 2.361, p < 0.001), tumor location (OR = 1.552, p = 0.046), histological classification (p = 0.004), tumor infiltration depth (OR = 2.154, p = 0.001), and vascular infiltration (OR = 4.354, p < 0.001) as independent predictors for LNM. Logistic regression analyses based on 756 N0-1 LNM cases identified the smoking history (OR = 0.507, p = 0.043), tumor diameter ≥1.75 cm (OR = 2.265, p = 0.010), tumor location (OR = 1.834, p = 0.036), histological classification (p = 0.018), tumor infiltration depth (OR = 1.939, p = 0.034), and vascular infiltration (OR = 3.225, p < 0.001) as independent predictors for N1 LNM. Moreover, preoperative hypoalbuminemia (OR = 7.087, p = 0.015), significant preoperative weight loss (OR = 2.724, p = 0.023), tumor diameter ≥1.75 cm (OR = 5.484, p = 0.001), multiple tumors (OR = 9.986, p = 0.038), histological classification (p = 0.029), and vascular infiltration (OR = 33.704, p < 0.001) were proved to be associated with LNM for T1a tumors. CONCLUSIONS: The tumor diameter, location and infiltration depth, histological classification, and vascular infiltration were expected to be used as predictors of LNM in EDGC, and preoperative hypoalbuminemia, significant weight loss, tumor diameter and number, histological classification, and vascular infiltration were associated with LNM for T1a tumors.

Surgical outcomes after reoperation for patients with recurrent presacral tumors: a retrospective study.

BACKGROUND: Relevant reports on the surgical resection and prognosis of recurrent presacral tumors are limited. The objective of this study was to explore the outcomes associated with surgical resection of recurrent presacral tumors. METHODS: The data of patients with recurrent presacral tumors who received surgical resection in our hospital between June 2009 and November 2018 were retrospectively analyzed. RESULTS: Thirty-one patients, comprising 22 females and 9 males, with recurrent presacral lesions were included in our study. A posterior approach was utilized in 27 patients, an anterior approach in 1 patient, and a combined approach in 3 patients. Intraoperative complications occurred in 13 patients (41.9%), while postoperative complications occurred in 6 patients (19.4%). The length of hospital stay was significantly shorter in patients who underwent the posterior approach compared to those who underwent the anterior and combined approaches (P = 0.002). The operative time for the posterior approach was significantly shorter compared to both the anterior and combined approaches (P = 0.006). Temporary tamponade was performed for hemostasis in 4 patients, while staged resection was performed in 2 patients during the surgical treatment process. After a median follow-up period of 115.5 months, 5 patients with recurrent malignant presacral tumors succumbed to tumor recurrence after reoperation in our hospital. CONCLUSIONS: Surgical resection remains the mainstream treatment for recurrent presacral tumors. The outcomes for recurrent benign presacral tumors after surgery demonstrate favorable results, whereas further enhancements are required to improve the outcomes for recurrent malignant presacral tumors after surgery.

Identification of predictors for short-term recurrence: comprehensive analysis of 296 retroperitoneal liposarcoma cases.

BACKGROUND: The short-term (≤ 1 year) recurrence (STR) is the primary determinant impacting both the life quality and survival duration in patients who have undergone surgical resection for retroperitoneal liposarcoma (RPLS), a condition with intricate and ambiguous pathogenesis. The purpose of this study was to analyze the risk factors associated with STR in cases of RPLS and primary retroperitoneal liposarcoma (PRPLS). METHODS: For this retrospective observational study, a total of 296 RPLS cases were selected as research subjects, who experienced tumor recurrence during the follow-up period. The Local recurrence-free survival (LRFS) rates were estimated using the Kaplan-Meier method and subsequently compared between groups utilizing the log-rank test. The subsequent analyses involved univariate and multivariate logistic regression to identify predictors of STR in RPLS cases. Additionally, a logistic regression model was constructed for PRPLS. RESULTS: The 1-, 3-, and 5-year LRFS rates of the 296 RPLS cases were 51.7%, 16.9%, and 7.1%, respectively. In the univariate analysis, several factors were found to be associated with STR, including preoperative neutrophil/lymphocyte ratio (NLR), smoking history, surgical frequency, combined organ excision, operative time, intraoperative bleeding, transfer to the intensive care unit (ICU), multiple primary tumors, tumor shape and capsule characteristics, histological subtype, and presence of tumor necrosis. The elevated preoperative NLR, surgical frequency of ≥ 3 times, transfer to the ICU, presence of multiple primary tumors, and tumor necrosis were identified as independent risk factors for STR in surgically resected RPLS. Conversely, diabetes, intact tumor capsule, and well-differentiated histological subtype appeared to be independent protective factors. Analysis for PRPLS revealed that tumor capsule and tumor necrosis were independent predictors of STR. CONCLUSIONS: The elevated preoperative NLR, surgical frequency of ≥ 3 times, transfer to the ICU, presence of multiple primary tumors, tumor necrosis, and tumor capsule were expected to serve as predictive factors of STR for surgical resected RPLS and PRPLS.

Knockout of microglial Hv1 proton channel reduces neurotoxic A1 astrocytes and neuronal damage via the ROS/STAT3 pathway after spinal cord injury.

Spinal cord injury (SCI) causes severe functional deficits and neuronal damage, accompanied by intense glial activation. The voltage-gated proton channel Hv1, selectively expressed on microglia, is associated with SCI progression. However, the effect of Hv1 on the phenotypes and functions of reactive astrocytes after SCI remains unclear. Here, we combined Hv1 knockout (Hv1-/- ) mice and T10 spinal cord contusion to investigate the effects of microglial Hv1 on SCI pathophysiology and the phenotypes and functions of reactive astrocytes. After SCI, astrocytes proliferated and activated in the peri-injury area and exhibited an A1-dominant phenotype. Hv1 knockout reduced neurotoxic A1 astrocytes and shifted the dominant phenotype of reactive astrocytes from A1 to A2, enhancing synaptogenesis promotion, phagocytosis, and neurotrophy of astrocytes. Moreover, synaptic and axonal remodeling as well as motor recovery after SCI benefited from the improved astrocytic functions of Hv1 knockout. Furthermore, exogenous and endogenous reactive oxygen species (ROS) in astrocytes after SCI were reduced by Hv1 knockout. Our in vitro results showed that inhibition of ROS reduced the neurotoxic A1 phenotype in primary astrocytes via the STAT3 pathway. Similar to the effect of Hv1 knockout, the application of the ROS scavenger N-acetylcysteine reduced SCI-induced neurotoxic A1 astrocytes in vivo. Based on the in vivo and vitro results, we elucidated that microglial Hv1 knockout promotes synaptic and axonal remodeling in SCI mice by decreasing neurotoxic A1 astrocytes and increasing neuroprotective A2 astrocytes via the ROS/STAT3 pathway. Therefore, the Hv1 proton channel is a promising target for the treatment of SCI.

Ectopic lymphoid structures in the aged lacrimal glands.

Aging is a complex biological process in which many organs are pathologically affected. We previously reported that aged C57BL/6J had increased lacrimal gland (LG) lymphoid infiltrates that suggest ectopic lymphoid structures. However, these ectopic lymphoid structures have not been fully investigated. Using C57BL/6J mice of different ages, we analyzed the transcriptome of aged murine LGs and characterized the B and T cell populations. Age-related changes in the LG include increased differentially expressed genes associated with B and T cell activation, germinal center formation, and infiltration by marginal zone-like B cells. We also identified an age-related increase in B1+ cells and CD19+B220+ cells. B220+CD19+ cells were GL7+ (germinal center-like) and marginal zone-like and progressively increased with age. There was an upregulation of transcripts related to T follicular helper cells, and the number of these cells also increased as mice aged. Compared to a mouse model of Sjögren syndrome, aged LGs have similar transcriptome responses but also unique ones. And lastly, the ectopic lymphoid structures in aged LGs are not exclusive to a specific mouse background as aged diverse outbred mice also have immune infiltration. Altogether, this study identifies a profound change in the immune landscape of aged LGs where B cells become predominant. Further studies are necessary to investigate the specific function of these B cells during the aged LGs.

Elevated RANTES levels are associated with increased risk of cerebral atherosclerotic stenosis.

BACKGROUND: Cerebral atherosclerotic stenosis (CAS) is a significant factor in the development of acute ischemic stroke (AIS). Previous studies have reported that cytokines are involved in atherosclerotic diseases, although the relationship between serum levels of the chemokine RANTES (regulated on activation, normal T-cell expressed and secreted) and the presence of CAS remains unclear. METHODS: In total, 127 participants (65 non-AIS controls and 62 patients with AIS) were involved in this study. CAS was defined as the presence of ≥ 50% stenosis in major intracranial or extracranial artery by a Digital Substraction Angiography (DSA) examination, and we classified all participants into four groups according to stroke and CAS status. Serum concentrations of 8 cytokines, including RANTES, were measured by the Human ProcartaPlex Multiplex Immunoassay Kit. RESULTS: Seventy-eight participants (61.41%) had CAS, of which 39 cases with AIS and 39 case with non-AIS. Patients with CAS had higher RANTES levels compared to non-CAS patients in both the non-AIS group (10.54 ± 0.80 vs. 13.20 ± 0.71, p = 0.016) and stroke group (11.96 ± 0.87 vs. 15.03 ± 0.75, p = 0.011), and multivariate logistic regression analysis showed that the RANTES level is independently associated with CAS in both the non-AIS group (adjusted odds ratio (OR), 1.07; 95% CI, 1.02-1.12, P = 0.004) and stroke group (adjusted OR, 1.32; 95% CI, 1.10-1.58, P = 0.003). CONCLUSION: Patients with CAS have higher levels of serum RANTES than non-CAS patients regardless of stroke status suggesting that RANTES may play an important role in the formation of CAS.

MiR196a-5p in extracellular vesicles released from human nasopharyngeal carcinoma enhance the phagocytosis and secretion of microglia by targeting ROCK1.

The microenvironment of the brain has become increasingly recognized as an essential regulator in metastatic and primary brain tumors. Recent studies demonstrate that circulating tumor-derived exosomes are critical for the brain tumor microenvironment. Nasopharyngeal carcinoma (NPC), a malignant tumor of the head and neck, often invades the skull base but infrequently extends to brain parenchyma. Neurobiological communication between microglia and tumor-derived extracellular vesicles (EVs) has been extensively studied, but how NPC cells regulate the immune microenvironment in the brain remains unknown. Here, we report that NPC derived EVs lead to increased microglial phagocytosis and proliferation, and heightened levels of IL-6, IL-8, CXCL1 and TGF-ß1. Analysis of microRNAs in EVs reveal that miR196a-5p is the major effector microRNA. Moreover, we demonstrate an enrichment of miR196a-5p in the plasmatic EVs of NPC patients. Further investigation demonstrated that miR196a-5p was transferred to microglia and regulated microglial structure and functions by downregulating the expression of ROCK1. Therefore, these data indicate that NPC-derived EVs are potent modulators of microglial functions in brain microenvironment. Regardless of brain colonization, EVs-mediated functional changes in microglia may be a universal phenomenon that results in the alteration of the tumor host's microenvironment in the brain.

Correlation Analysis Between Demographic, Surgical, and Pathological Characteristics with Local Recurrence-Free Survival for Surgical Resected Retroperitoneal Liposarcoma.

BACKGROUND: As the leading cause of mortality for retroperitoneal liposarcoma (RPLS) cases, postoperative recurrence has complicated and unclear risk factors. This study was conducted to explore the correlations between demographic, surgical, and pathological characteristics with local recurrence-free survival (LRFS) for surgical resected RPLS. METHODS: RPLS cases that underwent radical operation were considered to be included in this analysis. LRFS rates were estimated based on the Kaplan-Meier method and were compared between groups by the log-rank test. Cox proportional hazard regression models were constructed to identified the predictors of LRFS. Subsequently, the independent predictors acquired from multivariate analyses were used to construct a nomogram. RESULTS: 348 RPLS cases who underwent radical operation were included. Of the 348 cases, 333 had tumor recurrence or with a follow-up period ≥5 years. Thus, 296 (88.9%) of the 333 cases had recurrent disease, and the median LRFS duration of 296 recurrence cases was 17.0 (95% confidence interval (CI) 13.2-20.8) months. Multivariate analysis identified the preoperative neutrophil/lymphocyte ratio (NLR), surgical frequency, operative time, tumor shape, histological subtype, and tumor necrosis as independent predictors of LRFS. Based on above independent predictors, a nomogram was constructed to predict the 1-, 3-, and 5-year LRFS of surgical resected RPLS. CONCLUSION: Elevated preoperative NLR, ≥2nd time surgical frequency, extended operation time, irregular tumor shape, no well-differentiated histological subtype, and tumor necrosis could be used as predictors of LRFS for surgical resected RPLS.

Electric double layer contribution to sum frequency generation signal from Au electrode.

Understanding the electric double layer (EDL) of the metal electrode-electrolyte interface is essential to electrochemistry and relevant disciplines. In this study, potential-dependent electrode Sum Frequency Generation (SFG) intensities of polycrystalline gold electrodes in HClO4 and H2SO4 electrolytes were thoroughly analyzed. The potential of zero charges (PZC) of the electrodes was -0.06 and 0.38 V in HClO4 and H2SO4, respectively, determined from differential capacity curves. Without specific adsorption, the total SFG intensity was dominated by the contribution from the Au surface and increased similar to that of the visible (VIS) wavelength scanning, which pushed the SFG process closer to the double resonant condition in HClO4. However, the EDL contributed about 30% SFG signal with specific adsorption in H2SO4. Below PZC, the total SFG intensity was dominated by the Au surface contribution and increased with potential at a similar slope in these two electrolytes. Around PZC, as the EDL structure became less ordered and the electric field changed direction, there would be no EDL SFG contribution. Above PZC, the total SFG intensity increased much more rapidly with potential in H2SO4 than in HClO4, which suggested that the EDL SFG contribution kept increasing with more specific adsorbed surface ions from H2SO4.

Application of Iodine as a Catalyst in Aerobic Oxidations: A Sustainable Approach for Thiol Oxidations.

Iodine is a well-known oxidant that is widely used in organic syntheses. Thiol oxidation by stoichiometric iodine is one of the most commonly employed strategies for the synthesis of valuable disulfides. While recent advancements in catalytic aerobic oxidation conditions have eliminated the need for stoichiometric oxidants, concerns persist regarding the use of toxic or expensive catalysts. In this study, we discovered that iodine can be used as a cheap, low-toxicity catalyst in the aerobic oxidation of thiols. In the catalytic cycle, iodine can be regenerated via HI oxidation by O2 at 70 °C in EtOAc. This protocol harnesses sustainable oxygen as the terminal oxidant, enabling the conversion of primary and secondary thiols with remarkable efficiency. Notably, all 26 tested thiols, encompassing various sensitive functional groups, were successfully converted into their corresponding disulfides with yields ranging from >66% to 98% at a catalyst loading of 5 mol%.

Multidisciplinary treatment for locally advanced gastric cancer: A systematic review and network meta-analysis.

Introduction: This study aimed to evaluate the efficacy of multidisciplinary treatment for patients with locally advanced gastric cancer (LAGC) who underwent radical gastrectomy. Patients and Methods: Randomised controlled trials (RCTs) comparing the effectiveness of surgery alone, adjuvant chemotherapy (CT), adjuvant radiotherapy (RT), adjuvant chemoradiotherapy (CRT), neoadjuvant CT, neoadjuvant RT, neoadjuvant CRT, perioperative CT and hyperthermic intraperitoneal chemotherapy (HIPEC) for LAGC were searched. Overall survival (OS), disease-free survival (DFS), recurrence and metastasis, long-term mortality, adverse events (grade ≥3), operative complications and R0 resection rate were used as outcome indicators for meta-analysis. Results: Forty-five RCTs with 10077 participants were finally analysed. Adjuvant CT had higher OS (hazard ratio [HR] = 0.74, 95% credible interval [CI] = 0.66-0.82) and DFS (HR = 0.67, 95% CI = 0.60-0.74) than surgery-alone group. Perioperative CT (odds ratio [OR] = 2.56, 95% CI = 1.19-5.50) and adjuvant CT (OR = 0.48, 95% CI = 0.27-0.86) both had more recurrence and metastasis than HIPEC + adjuvant CT, while adjuvant CRT tended to have less recurrence and metastasis than adjuvant CT (OR = 1.76, 95% CI = 1.29-2.42) and even adjuvant RT (OR = 1.83, 95% CI = 0.98-3.40). Moreover, the incidence of mortality in HIPEC + adjuvant CT was lower than that in adjuvant RT (OR = 0.28, 95% CI = 0.11-0.72), adjuvant CT (OR = 0.45, 95% CI = 0.23-0.86) and perioperative CT (OR = 2.39, 95% CI = 1.05-5.41). Analysis of adverse events (grade ≥3) showed no statistically significant difference between any two adjuvant therapy groups. Conclusion: A combination of HIPEC with adjuvant CT seems to be the most effective adjuvant therapy, which contributes to reducing tumour recurrence, metastasis and mortality - without increasing surgical complications and adverse events related to toxicity. Compared with CT or RT alone, CRT can reduce recurrence, metastasis and mortality but increase adverse events. Moreover, neoadjuvant therapy can effectively improve the radical resection rate, but neoadjuvant CT tends to increase surgical complications.

Transforming growth factor-ß1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways.

BACKGROUND: Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-ß1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-ß1 on demyelinating diseases and its underlying mechanisms have not been well investigated. METHODS: A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-ß1 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism. RESULTS: The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-ß1. Besides, TGF-ß1 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1ß, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-ß1. Mechanistically, TGF-ß1 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1ß. Activation of ERK1/2 and NF-κB pathways largely abolished the protective effects of TGF-ß1, which indicated that TGF-ß1 alleviated the pyroptosis possibly via regulating NF-κB/ERK1/2 signal pathways. CONCLUSIONS: Our studies demonstrated TGF-ß1 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1/2 and NF-κB pathways. Targeting TGF-ß1 activity might serve as a promising therapeutic strategy in demyelinating diseases.

Modulation of Oxidative Stress and Inflammation in the Aged Lacrimal Gland.

Inflammation and oxidative stress accompany aging. This study investigated the interplay between oxidative stress and inflammation in the lacrimal gland. C57BL/6 mice were used at 2 to 3, 12, and 24 months of age. Nuclear factor erythroid derived-2-related factor 2 (Nrf2)-/- and corresponding wild-type mice were used at 2 to 3 and 12 to 13 months of age. A separate group of 15.5 to 17 months of age C57BL/6 mice received a diet containing an Nrf2 inducer (Oltipraz) for 8 weeks. Aged C57BL/6 lacrimal glands showed significantly greater lymphocytic infiltration, higher levels of MHC II, IFN-γ, IL-1ß, TNF-α, and cathepsin S (Ctss) mRNA transcripts, and greater nitrotyrosine and 4-hydroxynonenal protein. Young Nrf2-/- mice showed an increase in IL-1ß, IFN-γ, MHC II, and Ctss mRNA transcripts compared with young wild-type mice and greater age-related changes at 12 to 13 months of age. Oltipraz diet significantly decreased nitrotyrosine and 4-hydroxynonenal and decreased the expression of IL-1ß and TNF-α mRNA transcripts, while decreasing the frequency of CD45+CD4+ cells in lacrimal glands and significantly increasing conjunctival goblet cell density compared with a standard diet. The findings provide novel insight into the development of chronic, low-grade inflammation and oxidative stress in age-related dry eye. New therapies targeting oxidative stress pathways will be valuable in treating age-related dry eye.

Cathepsin S is a novel target for age-related dry eye.

Cathepsin S (Ctss) is a protease that is proinflammatory on epithelial cells. The purpose of this study was to investigate the role of Ctss in age-related dry eye disease. Ctss-/- mice [in a C57BL/6 (B6) background] of different ages were compared to B6 mice. Ctss activity in tears and lacrimal gland (LG) lysates was measured. The corneal barrier function was investigated in naïve mice or after topical administration of Ctss eye drops 5X/day for two days. Eyes were collected, and conjunctival goblet cell density was measured in PAS-stained sections. Immunoreactivity of the tight junction proteins, ZO-1 and occludin, was investigated in primary human cultured corneal epithelial cells (HCEC) without or with Ctss, with or without a Ctss inhibitor. A significant increase in Ctss activity was observed in the tears and LG lysates in aged B6 compared to young mice. This was accompanied by higher Ctss transcripts and protein expression in LG and spleen. Compared to B6, 12 and 24-month-old Ctss-/- mice did not display age-related corneal barrier disruption and goblet cell loss. Treatment of HCEC with Ctss for 48 h disrupted occludin and ZO-1 immunoreactivity compared to control cells. This was prevented by the Ctss inhibitor LY3000328 or Ctss-heat inactivation. Topical reconstitution of Ctss in Ctss-/- mice for two days disrupted corneal barrier function. Aging on the ocular surface is accompanied by increased expression and activity of the protease Ctss. Our results suggest that cathepsin S modulation might be a novel target for age-related dry eye disease.

Abnormalities of retinal structure and microvasculature are associated with cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Whilst retinal microvasculature represents cerebral small vessels, the retinal nerve fiber layer is the extended white matter of the brain. The aim was to investigate the correlation between changes in retina and white matter hyperintensities (WMHs). METHODS: Sixty-four candidates with WMHs received an optical coherence tomography angiography examination. WMHs were divided into mild or moderate/severe groups according to the Fazekas score. After imaging the superficial capillary plexus (SCP) and deep capillary plexus (DCP), the microvascular density parameters (vascular perfusion density [VPD], vascular length density [VLD] and fovea avascular zone area) and morphological parameters (vessel diameter index [VDI], fractal dimension [FD] and vessel tortuosity) were identified. A software algorithm measured the thickness of the peripapillary retina nerve fiber layer (PRNFL). RESULTS: Thirty-two were classified as having mild WMHs and 32 were moderate/severe. The median (interquartile range) ages of the two groups were 58 (54-64) and 61 (57-67) years, respectively. A decrease of FD, VPD and VLD in either SCP or DCP appeared with an increased risk of moderate/severe WMHs. Although changes of capillary plexus were not associated with paraventricular WMHs, decreased FD, VPD, VLD and fovea avascular zone area in either SCP or DCP were associated with an increased risk of moderate/severe deep WMHs (DWMHs). Participants with moderate/severe WMHs demonstrated reduced PRNFL thickness, particularly in the DWMHs, compared with mild WMHs. CONCLUSIONS: Abnormalities of retinal microvascular density, morphological parameters and PRNFL thickness are correlated with the incidence of moderate/severe WMHs, particularly the DWMHs, suggesting that arteriosclerosis and hypoperfusion are the causes of DWMHs.

A new direct band gap Si-Ge allotrope with advanced electronic and optical properties.

Direct-band silicon materials have been a sought-after material for potential applications in silicon photonics and solar cells. Accordingly, methodologies like nanostructure engineering, alloy engineering and strain engineering have been developed. In this work, the particle swarm optimization (PSO) algorithm is used to design direct-band Si-Ge alloys. The findings of phonon computations demonstrate that all these structures are dynamically stable. In addition, ab initio molecular dynamics and elastic constant calculations are carried out, with results indicating these structures are thermodynamically stable at 300 K, as well as being mechanically stable. All of these materials exhibit semiconductor behavior with band gaps of 1.03, 0.68 and 1.37 eV for α, ß and γ phases, respectively, at the HSE06 level. The results of effective mass and mobility of carriers that are important in applications show that holes are more easily transported in all structures, with higher concentration of holes accompanied by lower carrier mobility. Different concentrations of holes nh lead to different limits in the scattering process. When nh is lower than the value of around 1016 cm-3, deformation potential scattering is dominant, while the ionized impurity scattering process limits overall mobility when nh is higher than such a value. Finally, the absorption spectra shows that both α and ß phases have isotropic optical properties in the X- and Y-directions while strong anisotropy can be seen in the Z-direction. However, the γ phase exhibits no notable isotropy. This investigation finds three direct-band and potentially CMOS compatible materials, a finding which will benefit the development of high efficiency emitters or solar cells.

Serum Trimethylamine N-oxide and the Diversity of the Intestinal Microbial Flora in Type 2 Diabetes Complicated by Diabetic Kidney Disease.

BACKGROUND: Trimethylamine N-oxide (TMAO) serves as a metabolite of intestinal bacteria as well as a urotoxin influencing the prognosis of chronic kidney disease (CKD), which has become a research hotspot in the field of kidney disease. This study preliminarily explored the alternations of the microbial flora and serum TMAO in patients with type 2 diabetes mellitus (T2DM) complicated with diabetic kidney disease (DKD). METHODS: Seventeen T2DM patients at the Affiliated Hospital of Zunyi Medical University between September 2018 and February 2019 were included. Among these patients, 8 patients had T2DM complicated with DKD. Eight healthy volunteers constituted the control group. Fresh stool was collected for Illumina sequencing. Based on the sequencing outcomes, the flora diversity and species differences were analyzed. Serum TMAO, cystatin C, urinary albumin/urine creatinine ratios (ACRs), and routine biochemical outcomes were also compared. RESULTS: The DKD group exhibited a significantly higher TMAO level than the remaining groups. The high-TMAO group had a significantly increased ACR level compared with the low-TMAO group. TMAO positively correlated with the ACR. Compared with the control group, the DKD group exhibited a decreased flora diversity. At the genus level, both the T2DM group and the DKD group showed decreased numbers of Alloprevotella and Megasphaera compared with the control group. The difference in Megasphaera between the DKD group and the control group was significant. CONCLUSIONS: The alternation of the intestinal microbial flora may participate in the development of DKD, and TMAO and chronic inflammation might be important factors for DKD development.

Higher exposure to childhood adversity associates with lower adult flourishing.

BACKGROUND: Adverse childhood experiences (ACEs) are prevalent and associated with negative health and social outcomes. However, our understanding of how patterns of ACEs exposure relate to positive outcomes in adulthood remains limited. This study aims to identify patterns of ACEs and examine associations with flourishing in a sample of Chinese young adults. METHODS: This cross-sectional study was conducted from August to November 2020. Young adults, ages 18-35, enrolled in undergraduate or graduate programs at universities in Mainland China were recruited through convenience and snowball sampling to participate in a survey. The exposure to ACEs was measured by the twelve-item Chinese version of the ACE-International Questionnaire. Additional measures included six domains of flourishing assessed using the Chinese version of the Flourishing Measure, and demographic covariates (i.e., gender, age, year in university, marital status). Descriptive statistical analysis and latent class analysis (LCA) were performed using SPSS 27 and Mplus 8.5. RESULTS: Participants included 9468 young adults (mean age = 20.1 years). Majority of participants were female (75.3%), undergraduate students (96.4%), and single (79.8%). Approximately 56% of participants reported at least one ACE; 7.0% reported four or more ACEs. Emotional neglect (33.2%), household violence (20.6%), and parental separation/divorce (13.9%) were the most frequently reported ACEs. LCA identified three ACEs classes: multiple maltreatment and household violence (4.7%), emotional neglect and household violence (16.2%), and low ACEs (79.1%). Individuals in the low ACEs class had the highest level of flourishing whereas individuals in multiple maltreatment and household violence had the lowest level of flourishing in all six domains. There were no significant differences in flourishing between the multiple maltreatment and household violence and the emotional neglect and household violence classes except in the physical and mental health (means = 6.17 vs 6.51, p = 0.02) and the financial and material stability domains (means = 5.25 vs 5.66, p = 0.04). CONCLUSIONS: Patterns of multiple ACEs exposures were associated with lower levels of flourishing. Our findings have implications for efforts to prevent ACEs exposure through monitoring and promoting family well-being and routine screening to identify those with ACEs exposure to prevent negative social and health sequelae.