Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43.

Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases1. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills2. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity3. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP4. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.

Cryo-EM structures of the D290V mutant of the hnRNPA2 low-complexity domain suggests how D290V affects phase separation and aggregation.

Heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) is a human ribonucleoprotein that transports RNA to designated locations for translation via its ability to phase separate. Its mutated form, D290V, is implicated in multisystem proteinopathy known to afflict two families, mainly with myopathy and Paget's disease of bone. Here, we investigate this mutant form of hnRNPA2 by determining cryo-EM structures of the recombinant D290V low complexity domain. We find that the mutant form of hnRNPA2 differs from the WT fibrils in four ways. In contrast to the WT fibrils, the PY-nuclear localization signals in the fibril cores of all three mutant polymorphs are less accessible to chaperones. Also, the mutant fibrils are more stable than WT fibrils as judged by phase separation, thermal stability, and energetic calculations. Similar to other pathogenic amyloids, the mutant fibrils are polymorphic. Thus, these structures offer evidence to explain how a D-to-V missense mutation diverts the assembly of reversible, functional amyloid-like fibrils into the assembly of pathogenic amyloid, and may shed light on analogous conversions occurring in other ribonucleoproteins that lead to neurological diseases such as amyotrophic lateral sclerosis and frontotemporal dementia.

The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity.

Pseudomonas aeruginosa is an opportunistic pathogen that predominantly causes nosocomial and community-acquired lung infections. As a member of ESKAPE pathogens, carbapenem-resistant P. aeruginosa (CRPA) compromises the limited therapeutic options, raising an urgent demand for the development of lead compounds against previously-unrecognized drug targets. Biotin is an important cofactor, of which the de novo synthesis is an attractive antimicrobial target in certain recalcitrant infections. Here we report genetic and biochemical definition of P. aeruginosa BioH (PA0502) that functions as a gatekeeper enzyme allowing the product pimeloyl-ACP to exit from fatty acid synthesis cycle and to enter the late stage of biotin synthesis pathway. In relative to Escherichia coli, P. aeruginosa physiologically requires 3-fold higher level of cytosolic biotin, which can be attributed to the occurrence of multiple biotinylated enzymes. The BioH protein enables the in vitro reconstitution of biotin synthesis. The repertoire of biotin abundance is assigned to different mouse tissues and/or organ contents, and the plasma biotin level of mouse is around 6-fold higher than that of human. Removal of bioH renders P. aeruginosa biotin auxotrophic and impairs its intra-phagosome persistence. Based on a model of CD-1 mice mimicking the human environment, lung challenge combined with systemic infection suggested that BioH is necessary for the full virulence of P. aeruginosa. As expected, the biotin synthesis inhibitor MAC13772 is capable of dampening the viability of CRPA. Notably, MAC13772 interferes the production of pyocyanin, an important virulence factor of P. aeruginosa. Our data expands our understanding of P. aeruginosa biotin synthesis relevant to bacterial infectivity. In particular, this study represents the first example of an extracellular pathogen P. aeruginosa that exploits biotin cofactor as a fitness determinant, raising the possibility of biotin synthesis as an anti-CRPA target.

Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation.

In neurodegenerative diseases including Alzheimer's and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms in autopsied brains. Evidence suggests that RNA aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at the level of atomic structure. Here, we present the 3.4-Å resolution structure of fibrils of full-length recombinant tau protein in the presence of RNA, determined by electron cryomicroscopy (cryo-EM). The structure reveals the familiar in-register cross-ß amyloid scaffold but with a small fibril core spanning residues Glu391 to Ala426, a region disordered in the fuzzy coat in all previously studied tau polymorphs. RNA is bound on the fibril surface to the positively charged residues Arg406 and His407 and runs parallel to the fibril axis. The fibrils dissolve when RNase is added, showing that RNA is necessary for fibril integrity. While this structure cannot exist simultaneously with the tau fibril structures extracted from patients' brains, it could conceivably account for the nucleating effects of RNA cofactors followed by remodeling as fibrils mature.

Whole-exome sequencing reveals a comprehensive germline mutation landscape and identifies twelve novel predisposition genes in Chinese prostate cancer patients.

Prostate cancer is the most inheritable cancer with approximately 42% of disease risk attributed to inherited factors by studies of twins, indicating the importance of additional genetic screening to identify predisposition variants. However, only DNA damage repair (DDR) genes have been investigated thoroughly in prostate cancer. To determine the comprehensive germline mutation landscape in Chinese prostate cancer patients, we performed whole exome sequencing in 100 Han Chinese patients with prostate cancer in Hong Kong and identified deleterious germline mutations. A total of 36 deleterious germline variants in 25 genes were identified in 29% patients. Variants were found in eight pathways, including DNA methylation, DDR, and tyrosine-protein kinase. These findings were validated in an independent Chinese cohort of 167 patients with prostate cancer in Shanghai. Seven common deleterious-variant-containing genes were found in discovery cohort (7/25, 28%) and validation cohort (7/28, 25%) with three genes not described before (LDLR, MYH7 and SUGCT) and four genes previously reported (FANCI, ITGA6, PABPC1 and RAD54B). When comparing with that of a cohort of East Asian healthy individuals, 12 non-DDR novel potential predisposition genes (ADGRG1, CHD4, DNMT3A, ERBB3, GRHL1, HMBS, LDLR, MYH7, MYO6, NT5C2, NUP98 and SUGCT) were identified using the discovery and validation cohorts, which have not been previously reported in prostate cancer patients in all ethnic groups. Taken together, this study reveals a comprehensive germline mutation landscape in Chinese prostate cancer patients and discovers 12 novel non-DDR predisposition genes to lay the groundwork for the optimization of genetic screening.

Oxide Ion Conduction in Ca-Doped Yb3Ga5O12 Garnet.

Developing oxide ion conductors with new structural families is important for many energy conversion and storage techniques. Herein, a series of Ca-doped Yb3Ga5O12 garnet-type materials are prepared through a traditional solid-state reaction method, with their oxide ion conduction properties being reported for the first time. The results revealed that Ca substitution for Yb would significantly improve the conductivity of Yb3Ga5O12 from 3.57 × 10-7 S/cm at 900 °C under air to 1.66 × 10-4 S/cm, with an oxide ion transporting number of ∼0.52. The oxygen vacancy defect formation energy (∼0.127 eV) and the local structure around an oxygen vacancy were studied by atomic-level static lattice simulations based on the interatomic potential method. The oxide ion conducting mechanism was studied by the bond-valence-based method, which revealed three-dimensional pathways for oxide ion migration in both the parent and Ca-doped structures. The simulated activation energy of oxide ion migration decreased slightly from ∼0.358 eV in the parent structure to 0.346 eV in the doped one. These discoveries in the Ca-doped Yb3Ga5O12 will stimulate extensive exploitation and fundamental research on garnet-type materials.

Genome assembly and annotation of Periplaneta americana reveal a comprehensive cockroach allergen profile.

BACKGROUND: One of the most common cockroach types in urban areas, the American cockroach (Periplaneta americana), has been reported to impose an increased risk of allergies and asthma. Limited groups of allergens (Per a 1-13) have been identified in this species due to the lack of genome-related information. METHODS: To expand the allergen profile of P. americana, genomic, transcriptomic, and proteomic approaches were applied. With the support of a high-quality genome assembled using nanopore, Illumina, and Hi-C sequencing techniques, potential allergens were identified based on protein homology. Then, using enzyme-linked immunosorbent assay, selected allergens were tested in Thai patients allergic to P. americana. RESULTS: A chromosomal-level genome of P. americana (3.06 Gb) has been assembled with 94.6% BUSCO completeness, and its contiguity has been significantly improved (N50 = 151 Mb). A comprehensive allergen profile has been characterized, with seven novel groups of allergens, including enolase (Per a 14), cytochrome C (Per a 15), cofilin (Per a 16), alpha-tubulin (Per a 17), cyclophilin (Per a 18), porin3 (Per a 19), and peroxiredoxin-6 (Per a 20), showing IgE sensitivity in enzyme-linked immunosorbent assay. A new isoallergen of tropomyosin (Per a 7.02) and multiple potential isoallergens of Per a 5 were revealed using bioinformatics and proteomic approaches. Additionally, comparative analysis of P. americana with the closely related Blattodea species revealed the possibility of cross-reaction. CONCLUSION: The high-quality genome and proteome of P. americana are beneficial in studying cockroach allergens at the molecular level. Seven novel allergen groups and one isoallergen in Per a 7 were identified.

Transcriptomic and Functional Analyses of Two Cadmium Hyper-Enriched Duckweed Strains Reveal Putative Cadmium Tolerance Mechanisms.

Cadmium (Cd) is one of the most toxic metals in the environment and exerts deleterious effects on plant growth and production. Duckweed has been reported as a promising candidate for Cd phytoremediation. In this study, the growth, Cd enrichment, and antioxidant enzyme activity of duckweed were investigated. We found that both high-Cd-tolerance duckweed (HCD) and low-Cd-tolerance duckweed (LCD) strains exposed to Cd were hyper-enriched with Cd. To further explore the underlying molecular mechanisms, a genome-wide transcriptome analysis was performed. The results showed that the growth rate, chlorophyll content, and antioxidant enzyme activities of duckweed were significantly affected by Cd stress and differed between the two strains. In the genome-wide transcriptome analysis, the RNA-seq library generated 544,347,670 clean reads, and 1608 and 2045 differentially expressed genes were identified between HCD and LCD, respectively. The antioxidant system was significantly expressed during ribosomal biosynthesis in HCD but not in LCD. Fatty acid metabolism and ethanol production were significantly increased in LCD. Alpha-linolenic acid metabolism likely plays an important role in Cd detoxification in duckweed. These findings contribute to the understanding of Cd tolerance mechanisms in hyperaccumulator plants and lay the foundation for future phytoremediation studies.

Low C/N promotes stable partial nitrification by enhancing the cooperation of functional microorganisms in treating high-strength ammonium landfill leachate.

Partial nitrification is an effective process for treating high-strength ammonium landfill leachate with low C/N ratio, for the cooperation with denitrification can save almost 40% carbon addition in biological nitrogen removal. However, high ammonia loading often causes the instability of partial nitrification process. Less carbon addition can promote the stability of partial nitrification and increase the nitrite accumulation ratio (NAR). Nevertheless, the microbial mechanisms within remain further elusive. In this study, two laboratory-scale sequencing batch reactors were constructed and operated for 125 days, which were fed with ammonia synthetic wastewater with C/N of 0.6 (CN system) and C/N of 0.0 as the control (N system). CN system performed more stably and had the highest NAR of 100%. Extracellular polymeric substances (EPS) generated from carbon source provided spatial and nutrient niches to tighten the cooperation of functional microorganisms, thus, enhanced the stability and efficiency of partial nitrification. Thauera was the dominant denitrifier in CN system. Nitrosomonas was one of the most important autotrophic ammonia oxidizing bacteria, while Paracoccus and Flavobacterium were the main heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria in CN system. The enrichment of HN-AD bacteria outcompeted nitrite oxidizing bacteria (NOB), therefore leaded to higher nitrite accumulation in CN system. The findings of this study may be conducive to increasing the understanding of the microbial collaboration mechanisms of partial nitrification, thereby provides theoretical support for the improvement of biological nitrogen removal technology.

Single-cell RNA-seq dissecting heterogeneity of tumor cells and comprehensive dynamics in tumor microenvironment during lymph nodes metastasis in gastric cancer.

Lymph node metastasis is the common metastasis route of gastric cancer. However, until now, heterogeneities of tumor cells and tumor microenvironment in primary tumors (PT) and metastatic lymph nodes (MLN) of gastric cancer (GC) remains uncharacterized. In our study, single cell RNA sequencing was performed on tissues from PT and MLN of gastric cancer. Trajectory analysis and function enrichment analyses were conducted to decode the underlying mechanisms contributing to LN metastasis of gastric cancer. Heterogeneous composition of immune cells and distinct intercellular interactions in PT and MLN were analyzed. Based on the generated single cell transcriptome profiles, dynamics of gene expressions in cancer cells between PT and MLN were characterized. Moreover, we reconstructed the developmental trajectory of GC cells' metastasis to LN and identified two subtypes of GC cells with distinct potentials of having malignant biological behaviors. We characterized the repression of neutrophil polarization associated genes, like LCN2, which would contribute to LN metastasis, and histochemistry experiments validated our findings. Additionally, heterogeneity in neutrophils, rather than macrophages, was characterized. Immune checkpoint associated interaction of SPP1 was found active in MLN. In conclusion, we decode the dynamics of tumor cells during LN metastasis in GC and to identify a subtype of GC cells with potentials of LN metastasis. Our data indicated that the disordering the neutrophils polarization and maturation and the activation of immune checkpoint SPP1 might contribute to LN metastasis in GC, providing a novel insight on the mechanism and potential therapeutic targets of LN metastasis in GC.

Shaping the nebulous enhancer in the era of high-throughput assays and genome editing.

Since the 1st discovery of transcriptional enhancers in 1981, their textbook definition has remained largely unchanged in the past 37 years. With the emergence of high-throughput assays and genome editing, which are switching the paradigm from bottom-up discovery and testing of individual enhancers to top-down profiling of enhancer activities genome-wide, it has become increasingly evidenced that this classical definition has left substantial gray areas in different aspects. Here we survey a representative set of recent research articles and report the definitions of enhancers they have adopted. The results reveal that a wide spectrum of definitions is used usually without the definition stated explicitly, which could lead to difficulties in data interpretation and downstream analyses. Based on these findings, we discuss the practical implications and suggestions for future studies.

MRI-visible enlarged perivascular spaces: imaging marker to predict cognitive impairment in older chronic insomnia patients.

OBJECTIVE: Perivascular spaces (PVS), components of the glymphatic system in the brain, have been known to be important conduits for clearing metabolic waste, and this process mainly increases during sleep. Sleep disruption might result in PVS dysfunction and cognitive impairment. In this study, we aim to explore whether MRI-visible enlarged perivascular spaces (EPVS) could be imaging markers to predict cognitive impairment in chronic insomnia patients. METHOD: We obtained data from 156 patients with chronic insomnia and 79 age-matched healthy individuals. Using T2-weighted MRI images, visible EPVS in various brain regions were measured and analyzed. The associations between EPVS numbers and cerebrospinal fluid (CSF) ß-amyloid 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) level in chronic insomnia patients were evaluated. RESULT: Our results showed that MRI-visible EPVS in the frontal cortex, centrum semiovale, basal ganglia, and hippocampus of chronic insomnia patients with impaired cognition (ICG) significantly increased than that in normal cognition (NCG) patients. The increased MRI-visible EPVS in the frontal cortex, centrum semiovale, and basal ganglia were also associated with the increased CSF Aß42, t-tau, and p-tau level in ICG patients. MRI-visible EPVS in the basal ganglia and centrum semiovale had high sensitivity and specificity in distinguishing ICG chronic insomnia patients from those with NCG. CONCLUSION: Our study indicated that MRI-visible EPVS in the basal ganglia and centrum semiovale might be valuable imaging markers to predict cognitive impairment in chronic insomnia patients. It will be meaningful to discern those cognitive decline patients in preclinical stage and take some measures to prevent disease progression. KEY POINTS: • Increased MRI-visible EPVS were associated with the increased CSF Aß42, t-tau, and p-tau level in older chronic insomnia patients with impaired cognition.

Aflatoxin B1 causes oxidative stress and apoptosis in sheep testes associated with disrupting rumen microbiota.

Aflatoxin B1 (AFB1) is an unavoidable environmental pollutant commonly found in feed and foodstuffs. It is the most toxic one of all the aflatoxins, which can cause severe impairment to testicular development and function. Yet, the underlying mechanisms of reproductive toxicity in rams sheep remain inconclusive. The study was designed to explore the effects of AFB1 on sheep testes through rumen-microbiota, oxidative stress and apoptosis. Six-month-old male Dorper rams (n = 6) were orally administrated with 1.0 mg/kg AFB1 (dissolved in 20 mL 4% ethanol) 24 h before the experiment. At the same time, rams in the control group (n = 6) were intragastrically administrated with 20 mL 4% ethanol. It was observed that acute AFB1 poisoning had significant (p < 0.05) toxin residue in the testis and could cause testicular histopathological damage. AFB1 stimulated the secretion of plasma testosterone level through regulating testosterone synthesis-related genes (StAR, 3ß-HSD, CYP11A1, and CYP17A1), which are accompanied by the increase of oxidative stress and testicular apoptosis that had a close relationship with the regulation of testosterone secretion. Interestingly, we observed rumen dysbacteriosis and decreased the abundances of Prevotella, Succiniclasticum, CF231, Ruminococcus, and Pseudobutyrivibrio in AFB1-exposed sheep, which were negatively correlated to the testosterone synthesis-related gene levels. Taken together, our findings indicated that AFB1 induced testicular damage and testicular dysfunction, which is related to testicular oxidative stress and apoptosis involved in rumen dysbacteriosis in sheep.

The inhibition of cellular toxicity of amyloid-ß by dissociated transthyretin.

The protective effect of transthyretin (TTR) on cellular toxicity of ß-amyloid (Aß) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aß, a protein associated with Alzheimer's disease. TTR binds Aß, alters its aggregation, and inhibits its toxicity both in vitro and in vivo In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aß oligomers. These findings suggest that the Aß-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aß aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aß oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aß catalyzed by Aß fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

Metabolic analysis of early nonalcoholic fatty liver disease in humans using liquid chromatography-mass spectrometry.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease that affects 20-30% of individuals worldwide. Liver puncture remains the gold standard for the diagnosis of liver diseases despite limitations regarding invasive nature and sample variability. It is of great clinical significance to find noninvasive biomarkers to detect and predict NAFLD. OBJECTIVE: The aims of this study were to identify potential serum markers in individuals with early-stage NAFLD and to advance the mechanistic understanding of this disease using a high-throughput mass spectrometry-based untargeted metabolomics approach. METHODS: One hundred and twelve patients with early-stage NAFLD aged 18-55 were recruited according to the guidelines. The control group included 112 healthy participants. The demographic, anthropometric, clinical and laboratory data of all participants were systematically collected. Serum samples were obtained after an overnight fast. The comprehensive serum metabolomic analysis was performed by ultra-performance liquid chromatography-Orbitrap mass spectrometry. The resultant data was processed by Compound Discover and SIMCA-P software to validate the potential biomarkers. Significantly altered metabolites were evaluated by variable importance in projection value (VIP > 1) and ANOVA (p < 0.01). Pathway analysis was performed using MetaboAnalyst 4.0. RESULTS: The liver function test of early NAFLD patients showed no statistical differences to control group (p > 0.05). However, obvious differences in blood lipids were observed between subjects with NAFLD and controls (p < 0.001). In total, 55 metabolites showed significant changes in experimental group were identified. The area under curve (AUC) values deduced by receiver operating curve (ROC) analysis indicated that these newly identified biomarkers have high predictability and reliability. Of these, 15 metabolites with AUC greater than 0.9 were of great diagnostic value in early NAFLD patients. CONCLUSION: In this study, a total of 15 serum metabolites were found to strongly associate with early NAFLD. These biomarkers may have great clinical significance in the early diagnosis of NAFLD, as well as to follow response to therapeutic interventions.

Regulation of ROS in myeloid-derived suppressor cells through targeting fatty acid transport protein 2 enhanced anti-PD-L1 tumor immunotherapy.

Despite the remarkable success and efficacy of immune checkpoint blockade (ICB) therapy against the PD-1/PD-L1 axis, it induces sustained responses in a sizeable minority of cancer patients due to the activation of immunosuppressive factors such as myeloid-derived suppressor cells (MDSCs). Inhibiting the immunosuppressive function of MDSCs is critical for successful cancer ICB therapy. Interestingly, lipid metabolism is a crucial factor in modulating MDSCs function. Fatty acid transport protein 2 (FATP2) conferred the function of PMN-MDSCs in cancer via the upregulation of arachidonic acid metabolism. However, whether regulating lipid accumulation in MDSCs by targeting FATP2 could block MDSCs reactive oxygen species (ROS) production and enhance PD-L1 blockade-mediated tumor immunotherapy remains unexplored. Here we report that FATP2 regulated lipid accumulation, ROS, and immunosuppressive function of MDSCs in tumor-bearing mice. Tumor cells-derived granulocyte macrophage-colony stimulating factor (GM-CSF) induced FATP2 expression in MDSCs by activation of STAT3 signaling pathway. Pharmaceutical blockade of FATP2 expression in MDSCs by lipofermata decreased lipid accumulation, reduced ROS, blocked immunosuppressive activity, and consequently inhibited tumor growth. More importantly, lipofermata inhibition of FATP2 in MDSCs enhanced anti-PD-L1 tumor immunotherapy via the upregulation of CD107a and reduced PD-L1 expression on tumor-infiltrating CD8+T-cells. Furthermore, the combination therapy blocked MDSC's suppressive role on T- cells thereby enhanced T-cell's ability for the production of IFN-γ. These findings indicate that FATP2 plays a key role in modulating lipid accumulation-induced ROS in MDSCs and targeting FATP2 in MDSCs provides a novel therapeutic approach to enhance anti-PD-L1 cancer immunotherapy.

Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infection has been deemed as a global pandemic by the World Health Organisation. While diffuse alveolar damage (DAD) is recognised to be the primary manifestation of COVID-19 pneumonia, there has been little emphasis on the progression to the fibrosing phase of DAD. This topic is of great interest, due to growing concerns regarding the potential long-term complications in prolonged survivors. METHODS AND RESULTS: Here we report a detailed histopathological study of 30 autopsy cases with COVID-19 virus infection, based on minimally invasive autopsies performed between February and March, 2020. The mean age was 69 years, with 20 (67%) males and 10 (33%) females and frequent (70.0%) underlying comorbidities. The duration of illness ranged from 16 to 82 (median = 42) days. Histologically, the most common manifestation was diffuse alveolar damage (DAD) in 28 (93.3%) cases which showed predominantly acute (32%), organising (25%) and/or fibrosing (43%) patterns. Patients with fibrosing DAD were one decade younger (P = 0.034) and they had a longer duration of illness (P = 0.033), hospitalisation (P = 0.037) and mechanical ventilation (P = 0.014) compared to those with acute DAD. Patients with organising DAD had a longer duration of illness (P = 0.032) and hospitalisation (P = 0.023) compared to those with acute DAD. CONCLUSIONS: COVID-19 pneumonia patients who develop DAD can progress to the fibrosing pattern. While we observed fibrosing DAD in fatal cases, whether or not surviving patients are at risk for developing pulmonary fibrosis and the frequency of this complication will require further clinical and radiological follow-up studies.

MicroRNA-183 exerts a protective role in lupus nephritis through blunting the activation of TGF-ß/Smad/TLR3 pathway via reducing Tgfbr1.

PURPOSE: The role of microRNA (miR)-183 has been elucidated in systemic lupus erythematosus, while whether it is also engaged in the lupus nephritis (LN) development remains opaque. The intention of this study is to examine the relevance of miR-183 downregulation in the pathogenesis of LN. METHODS: The expression of miR-183 was first detected in MRL/lpr mice at weeks 8 and 12, followed by the assessment the effects of miR-183 on renal fibrosis and inflammatory response after overexpression or silencing of miR-183 in mice with LN. We further overexpressed or knocked-down miR-183 in human renal glomerular endothelial cells (HRGECs), and detected the expression patterns of inflammatory factors and Vimentin and α-SMA in the cells. Differentially expressed genes in HRGECs overexpressing miR-183 by microarrays were intersected with targeting mRNAs of miR-183 predicted by bioinformatics websites. The effects of transforming growth factor beta receptor 1 (Tgfbr1) and TGF-ß/Smad/TLR3 pathway on renal damage in mice were verified by rescue experiments. RESULTS: miR-183 expression was notably lower in MRL/lpr mice, and increased miR-183 expression inhibited renal fibrosis and inflammatory response in mice with LN. Moreover, miR-183 inhibitor in HRGECs remarkably promoted the expression of Vimentin and α-SMA and the secretion of inflammatory factors. miR-183 protected the mouse kidney from pathological damages by targeting and inhibiting Tgfbr1 expression. CONCLUSION: miR-183 inhibited the expression of Tgfbr1 by direct targeting to disrupt the TGF-ß/Smad/TLR3 pathway, thus repressing renal fibrosis and the secretion of inflammatory factors in LN.

Comparative effects on pain arising from injury to the knee meniscus in adults: A systematic review and network meta-analysis.

OBJECTIVE: To identify the most effective pain management method for meniscus injuries by comparing pain relief observed with several common interventions including combined different combinations of surgery and exercise, surgery alone, supervised exercise alone and home exercise alone. METHODS: PubMed, Embase, CINAHL, Cochrane Library, Web of Science, SportDiscus, and PEDro were searched from database inception through October 15, 2020. Randomized controlled trials investigating the effect of surgery and exercise for meniscus injuries by using the visual analogue scale (VAS) assessment were eligible for inclusion. Primary outcome was mean change in VAS score from baseline. Comparisons between interventions were made through use of random-effects network meta-analysis over the short-term (three months) and mid-term (12 months). Relative ranking of therapies was assessed by the surface-under-the-cumulative ranking possibilities. All reference lists of included studies were hand-searched. RESULTS: We investigated six RCTs (total n = 796 patients). No significant difference was found between different treatments of pain control in three months and 12 months. The surface under the cumulative ranking curves suggested that supervised exercise combined with surgery was considered most likely to overshadow other treatments in reducing short-term pain (surface under cumulative ranking curve (SUCRA) values: 98.1; mean ranks: 1.1) and mid-term pain (SUCRA values: 97.2; mean rank: 1.1). CONCLUSION: There is not sufficient evidence to identify any preferred or more effective surgical and/or exercise-based treatment program.

Aflatoxin B1 alters meat quality associated with oxidative stress, inflammation, and gut-microbiota in sheep.

Aflatoxin B1 (AFB1) is an unavoidable contaminant in animal feed and agricultural products. AFB1 has been found to impair the liver and kidney function of sheep. However, few data are available, which explain the toxic damage of AFB1 exposure on meat quality. In the study, male Dorper RAMS sheep (6-month-old) were orally administrated with AFB1 at the dose of 1 mg/kg body weight once. The body temperature, serum biochemistry, meat quality-related parameters, oxidation indicators in meat and serum, the mRNA expression of pro-inflammatory cytokines and anti-inflammatory, and microbiota composition of feces were measured 24 h after AFB1 exposure. The results showed that the body temperature was slightly increased, the mental state of mutton sheep was suppressed, and biochemical indicators were significantly changed after AFB1 exposure. AFB1 impaired mutton quality reflected by the structure of muscle fibers was changed, and increased muscle drip loss and lightness (L*), and decreased muscle redness (a*). Moreover, we found that AFB1 caused changes in the oxidative stress indicators T-SOD, T-AOC, MDA, GSH level, and GSH/GSSG ratio, and inflammation damage of mutton reflected by increasing pro-inflammatory TNF-α and reducing anti-inflammatory IL-10 mRNA levels, disrupts the secretion of inflammatory factors, and changed the composition of gut microbiota reflected by significantly increased Firmicutes/Bacteroidetes ratio and decreased the abundances of Butyrivibrio, which are related to the quality of the mutton. In summary, gut microbiota participates in AFB1 to damage mutton quality, which may be co-mediated by oxidative stress, inflammation, and gut microbiota.