CX-5461 is a first-in-class selective RNA polymerase I inhibitor. Previously we found that CX-5461 had anti-inflammatory activities. In this study we characterized potential immunosuppressive effects of CX-5461 and explored the underlying mechanisms. Allogeneic skin transplantation model (BALB/c to C57BL/6 mice) and heterotopic heart transplantation model (F344 to Lewis rats) were used. We showed that CX-5461 was a potent inhibitor of alloimmunity which prevented acute allograft rejections. CX-5461 treatment was invariably associated with expansion of the regulatory T cell population. In vitro, CX-5461 inhibited agonists-induced T cell activation. CX-5461 consistently inhibited the expression of interferon-γ and interleukin – 2, key mediators of T cell-mediated alloimmunity. Mechanistically, CX-5461-induced immunosuppression was, at least partly, dependent on the p53-DUSP5 (dual-specificity phosphatase 5) axis and subsequent antagonism of the Erk1/2 mitogen-activated protein kinase pathway. In conclusion, our results suggest that CX-5461 is a promising candidate of a novel class of immunosuppressant which may be used as an alternative to the currently approved anti-rejection therapies.Congenital superior oblique (SO) palsy is often associated with anomalies of its tendon, increased tendon laxity being the most common. Rarely, the tendon lies in an abnormal location nasal to the superior rectus (SR) muscle, either attaching to the sclera or to Tenon’s capsule. We describe a case of a child who presented with abnormal head posture and exotropia. The orthoptic evaluation revealed a left hypertropia and V-pattern exotropia. The motility pattern and the Parks three-step test were suggestive of left-sided SO palsy. Intraoperatively, the left SO tendon was very lax and was absent from its usual insertion. Further exploration revealed it to be inserted entirely to the nasal border of the SR muscle, with no scleral attachment. This tendon was advanced to its normal attachment to the sclera, and 11 mm inferior oblique recession was also performed. Postoperative alignment was satisfactory.Alterations in metabolic pathways are a hallmark of cancer. A deeper understanding of the contribution of different metabolites to carcinogenesis is thus vitally important to elucidate mechanisms of tumor initiation and progression to inform therapeutic strategies. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide and its altered metabolic landscape is beginning to unfold with the advancement of technologies. In particular, characterization of the lipidome of human HCCs has accelerated, and together with biochemical analyses, are revealing recurrent patterns of alterations in glycerophospholipid, sphingolipid, cholesterol and bile acid metabolism. These widespread alterations encompass a myriad of lipid species with numerous roles affecting multiple hallmarks of cancer, including aberrant growth signaling, metastasis, evasion of cell death and immunosuppression. In this review, we summarize the current trends and findings of the altered lipidomic landscape of HCC and discuss their potential biological significance for hepatocarcinogenesis.Gingivobuccal oral squamous cell carcinoma (OSCC-GB) occurs among persons who excessively chew smokeless tobacco in India. To understand the role of cancer stem cells (CSCs) in the disease, we have performed transcriptomics analysis on RNA-seq data from OSCC-GB primary tumors. The mutational signature analysis of the identified novel and Catalogue of Somatic Mutations in Cancer (COSMIC) variants reveals DNA damage associated etiology based on identified COSMIC signatures showing a higher prevalence of C > T mutations and 1 bp T/(A) nucleotide insertions, pointing to the role of smokeless tobacco carcinogens. The differential somatic mutational, functional impact predictions, and survival analysis reveals the role of DNA damage response-related genes, with the CREBBP gene as a major player. The new CSC somatic variants identified in the study may play a crucial role in cancer metastasis, local-regional recurrence, chemo- and/or radioresistance that contributes to high mortality of the Indian OSCC-GB patients.We sequenced 13 Neisseria gonorrhoeae isolates exhibiting distinct susceptibility profiles and which were recovered over 12 years in the metropolitan region of São Paulo, Brazil. Whole Genome Sequencing (WGS) was performed on an Illumina MiSeq™ 2 × 300 bp paired-end reads. Bioinformatics analyses were carried out using CGE, PATRIC, and BLAST databases for manual curation of obtained genomes. Multilocus sequence typing (MLST) analysis identified seven STs, namely ST1580, ST1590, ST1901, ST1902, ST8161, ST9363, and ST15640. Moreover, a diversity of mutations was observed in MtrR/G45D-A39T, PIB/G120K-A121S, and PBP1/L421P. Mutations associated with sulfonamides (DHPS/R228S) and rifampicin (RNAP/H552N) were also detected, as well as tetracycline resistance determinants, namely rpsJ/V57M and tet(M). The results presented herein can contribute to the knowledge of N. gonorrhoeae strains circulating in Sao Paulo, Brazil.Daphnia sinensis is a widespread freshwater microcrustacean. The assembled D. sinensis genome totaled 131.58 Mb with 92.23% of the assembly anchored onto 10 chromosomes. Based on the whole genome information, we further compared the transcriptomic and epigenomic characterization among parthenogenetic females, sexual females and males in D. sinensis. Transcriptomic analysis showed that the up-regulated genes in males were mainly grouped into the cuticle, sex differentiation and methyl farnesoate synthesis, which might play a pivotal role in steering development and reproduction processes. By comparison, the highly expressed genes in parthenogenetic females were mainly grouped into energy metabolism, mitosis, and DNA replication, which might contribute to maintaining rapid production of parthenogenetic females, and nutrient uptake for the growth of neonates. The whole-genome DNA methylation analysis showed that the methylation rate in parthenogenetic females was higher than that in sexual females and males, which might contribute to its rapid response to environment stress.Spotted seals (Phoca largha) are a critically endangered pinniped in China. Artificial rescue of newborn pups is a conventional method to enhance their survival and maintain the population. However, little is known about the variations in the physiological state of spotted seal pups following artificial rescue. Here, an integrated proteomics and metabolomics study was performed on spotted seal pups by using whole blood samples to characterize the molecular response to artificial rescue. The proteome was characterized as having 1165 proteins that were predominantly associated with the metabolic pathways, and the complement and coagulation cascades. Remarkable variation was found in spotted seal pup blood following artificial rescue, whereby the levels of 193 proteins and 32 metabolites significantly varied in some metabolic pathways, including glycosylphosphatidylinositol-anchor biosynthesis, focal adhesion, cardiac muscle contraction, and fatty acid beta-oxidation. After rescue, spotted seal pups had a higher risk to mild hemolytic disorder due to the energy metabolism in the red blood cells was possibly suppressed. Moreover, spotted seal pups after rescue could have stronger anaerobic exercise abilities, while their capacity for long-term high-intensity exercise was weaker.Condyloma acuminata (CA) is a prevalent sexually transmitted disease, associated with human papilloma viruses (HPV) infections and host immune status. In this present study, we aimed to explore immune landscape and biomarkers for CA prevention and treatment. We obtained differentially expressed genes (DEGs) of CA vs normal tissues in GSE140662 and screened out hub genes from the protein-protein interaction (PPI) network. Hub genes were then subjected to microRNA (miRNA) analysis. Besides, CCK-8, transwell, flow cytometry assays were employed to assess the cell proliferation, migration and apoptosis in Hela cells. ImmuCellAI was firstly applied to identify immune cell infiltration levels of CA. We obtained 275 DEGs, 23 hub genes and key miRNAs. Subsequently, we verified four up-regulated hub genes IFIT1, IFI27, OASL, SAMD9L and down-regulated mir-146a-5p in CA tissues by RT-qPCR. Moreover, over-expression of miR-146a-5p reduced Hela cells proliferation, migration, blocked cell cycle and induced apoptosis. Up-regulated miR-146a-5p attenuated PI3K/AKT and activated p38/ MAPK signaling pathway. Proportions of Monocyte, NK cells, Gamma delta cells, Th17 cells were relatively low, while Th1 and CD8+ T cells were relatively high in CA skin. Our study revealed that mir-146a-5p contribute to CA progression through PI3K/AKT and p38/MAPK signaling pathway.Melon is a popular fruit vegetable crop worldwide with diverse morphological variation. We report a high-density genetic map of melon and nine major QTLs with physical region ranging from 43.47 kb to 1.89 Mb. Importantly, two seed-related trait QTLs were repeatedly detected in two environments, and the mapping region was narrowed to 522 kb according to a regional linkage analysis. A total of 40 annotated genes were screened for nonsynonymous variations, of which EVM0009818, involved in cytokinin-activated signaling, was differentially expressed in the young fruits of parents based on RNA-seq. Selective sweep analysis identified 152 sweep signals for seed size, including the two seed-related QTLs and nine homologs that have been verified to regulate seed size in Arabidopsis or rice. This work illustrates the power of a joint analysis combining resequencing-based genetic map for QTL mapping and a combination of KASP genotyping and RNA-seq analysis to facilitate QTL fine mapping.Nelore cattle breed was farmed worldwide due to its economic importance in the beef market and adaptation to the tropics. In Brazil, purebred Nelore animals (PO) receive a certificate from the breeders’ association based on the animal’s genealogy and morphological characterization. The top 20 to 30% of the superior animals are eligible to receive the Special Certificate of Identification and Production (CEIP), meaning animals from this category were selected and evaluated in a breeding program to improve economically important traits. We used whole-genome sequencing and approaches based on haplotype differentiation and allelic differentiation to detect regions of selection signatures in Nelore cattle by comparing animals from PO and CEIP categories. From a total of 150 animals, a hierarchical clustering analysis was performed to choose the more unrelated animals from each category (16 PO and 40 CEIP). The hapFLK statistic was performed, and extensions of hapFLK values were investigated considering continuous 23 are part of the Bovine Major Histocompatibility Complex (MHC) Class II gene family, representing good candidates for immune response and adaptation to tropical conditions. The BoLA family genes and the interaction of ROBO1 with SLIT genes appeared in the enrichment results. Genomic regions located in intronic regions were also identified and might play a regulatory role in traits under selection in PO and CEIP subpopulations. The regions here identified contribute to our knowledge regarding genes and variants that have an important role in complex traits selected in this breed.The subfamily Ototretinae represents an important and unusual lineage of fireflies. Here, we sequenced and annotated three mitogenomes for this subfamily, with two Stenocladius species and one Drilaster species as representatives. The mitogenome of Stenocladius exhibits a rearranged gene order between trnC and trnW caused by transposition, which is a novel finding in Lampyridae. Meanwhile, a long intergenic space (241 to 376 bp) exists between the two rearranged genes, and some remnants (23 bp) of trnW are present within this non-coding region. Moreover, phylogenetic analyses did not recover the monophyly of Ototretinae, in which Drilaster is shown at a basal lineage in Lampyridae, but Stenocladius seems more related to Luciolinae. Therefore, the gene rearrangement in Stenocladius is presumed to result from independent evolutionary events, suggesting that this genus should be placed in a separate lineage. Nevertheless, more representative mitogenomes from different groups are required to verify the present results.Fascioliasis is a foodborne zoonotic disease generally caused by the parasitic flukes Fasciola gigantica and Fasciola hepatica in class Trematoda. An „intermediate” Fasciola forms between F. gigantica and F. hepatica has been shown to exist. However, the relationships among F. gigantica, F. hepatica, and „intermediate” Fasciola forms remain unclear. In this study, we found five new polymorphic positions in 18S and 28S rDNAs sequences of „intermediate” Fasciola forms. According to the high-throughput sequencing results, all known 16 polymorphic positions of „intermediate” Fasciola forms show a clear and consistent tendency for F. gigantica or F. hepatica, and the percentages of the most frequently occurring bases were different in specimens. In the three ITS sequence fragments, hybrid-type base combinations of the polymorphic positions were detected, and the percentages of the most frequent base combinations were different in specimens too. In addition, interestingly, the newly detected ITS-802 position was not a traditional polymorphic position in „intermediate” Fasciola forms, and the bases in ITS-802 position are not same as the allele bases of F. gigantica or F. hepatica. Our results will be helpful to investigations into the molecular taxonomy, population genetics, and ecology of F. gigantica, F. hepatica, and „intermediate” Fasciola forms.Fall webworm, Hyphantria cunea, is a global invasive forest pest that causes serious damage to the economy and ecosystem of agriculture and forestry. Due to the extent of the problem and the difficulty of conventional chemical control, new technologies must be pursued, such as genetic-based inheritable insect sterile technology (gSIT), which exhibits promise for pest control. In the present study, we established a piggyBac-based transgenic system in fall webworm and generated a dominant male-sterile strain by targeting the seminal fluid protein serine protease 2 (Hcser2), displaying an outstanding trait of gSIT. First, an RNA polymerase type III (Pol III) promoter, the HcU62 small nuclear RNA (snRNA) gene promoter, was identified and characterized through direct injection of RNAi plasmids in vivo. Quantitative real-time PCR revealed that HcU62 had the greatest knockdown efficiency of the Hcyellow gene among five short hairpin RNA (shRNA) plasmids tested, designated HcU61-HcU65. Second, subsequent application of piggyBac-based transgenic RNAi (HcU62 shHcyellow, Ysh2) significantly reduced the expression level of the Hcyellow gene, resulting in a stable yellow observable phenotype from the larval to pupal stages in Ysh2 transgenic mutants. Finally, an HcU62-driven transgenic RNAi strain targeting the Hcser2 gene was obtained, resulting in a dominant male-sterile phenotype. Significantly, this process did not affect the growth, development, mating behavior or egg laying of the mutants, and the dominant sterile trait could be inherited in the next generation through female Hcser2 mutants. Furthermore, CRISPR/Cas9-mediated disruption of the Hcser2 gene further confirmed the dominant sterile phenotype, supporting it as a generalized target for genetic control of H. cunea. This study reports the first piggyBac-mediated transgenic system in H. cunea, providing a promising genetic method for controlling this pest by targeting Hcser2 gene.Two kinds of amphiphilic block copolymers of TfR-T12-PEG-PLGA and TATH7-PEG-PLGA were synthesized to self-assembly nano-composite micelles for encapsulating paclitaxel and imiquimod synchronously. TfR-T12 peptide modified nano-composite micelles can pass through BBB in a TfR-mediated way to achieve targeted delivery of chemotherapeutic drugs, and pH sensitive TATH7 peptide modified nano-composite micelles enhanced uptake efficiency more significantly under pH 5.5 medium than pH 7.4 medium. The results of pharmacodynamic evaluation in vivo showed that the nano-composite micelles had achieved good anti-tumor effect in subcutaneous and normotopia glioma models, and effectively prolonged the life cycle of tumor-bearing mice. The nano-composite micelles regulated the immunosuppression phenomenon of tumor microenvironment significantly, and promoted the M1 polarization of TAMs, then enhanced the proliferation and activation of CD8+ T cells in tumor microenvironment. It comes to conclusion that the nano-composite micelle achieves the purpose of effective treatment of glioma by chemotherapy combined with immunotherapy.Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, core body-temperature during cold stress or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.

To assess whether meta-analyses include older randomized controlled trials (RCTs) and whether intervention effect differ between older and recent RCTs.

In this meta-epidemiological study of 295 meta-analyses (2940 RCTs) published in 2017-2018, we evaluated the difference in intervention effects between older (i.e., published before 2000) and recent RCTs. We also compared effects by quarters of publication year within each meta-analysis (from quarter 1 including the 25% oldest trials to quarter 4 including the 25% most recent trials). A ratio of odds ratio (ROR) <1 indicates larger effects in older than recent RCTs.

Trials published before 2000 and before 1990 represented 25% and 10% of all trials, respectively. Intervention effects were significantly larger for old than recent RCTs (ROR=0.92, 95% confidence interval [CI] 0.85-1.00, I

=22%). Compared with the most recent trials (quarter 4), intervention effects were significantly larger for the oldest trials (quarter 1) (ROR=0.85, 95% CI 0.79-0.92) and for trials in quarter 2 (ROR=0.89, 95% CI 0.83-0.96) but not for trials in quarter 3 (ROR=0.98, 95% CI 0.91-1.05).

Intervention effects were larger for older than recent RCTs. Meta-analyses including older trials should be interpreted cautiously.

Intervention effects were larger for older than recent RCTs. Meta-analyses including older trials should be interpreted cautiously.In the central nervous system (CNS), many neurons develop axonal arbors that are crucial for information processing. Previous studies have demonstrated that premature axons contain motile and stationary mitochondria, and their balance is important for axonal arborization. However, the mechanisms by which neurons determine the positions of stationary mitochondria as well as their turnover remain to be elucidated. We observed that the distribution of stationary mitochondrial spots along the unmyelinated and nonsynaptic axons is not random but rather relatively uniform both in primary cultured neurons and in tissues. Intriguingly, whereas the positions of each mitochondrial spot changed over time, the overall distribution remained uniform. In addition, local inactivation of mitochondria by KillerRed mediated chromophore-assisted light inactivation (CALI) inhibited the translocation of mitochondrial spots in adjacent axonal regions, suggesting that functional mitochondria enhance the motility of other mitochondria in the vicinity. Signals of ATPADP sensor, PercevalHR indicated that the ATPADP ratio was relatively high around mitochondria, and treating axons with phosphocreatine (PCr), which supplies ATP, reduced the immobile mitochondria induced by the local mitochondrial inactivation. In a mathematical model, we found that the ATP gradient generated by mitochondria, and ATP dependent regulation of mitochondrial motility could establish uniform mitochondrial distribution. These observations suggest that axons in the CNS possess the system that distributes mitochondria uniformly, and intermitochondrial signaling contribute to the regulation. In addition, our results suggest the possibility that ATP might be one of the molecules mediating the signaling.Purple non-sulfur bacteria (PNSB) form an interesting group of microbes for resource recovery from wastewater. Solid/liquid separation is key for biomass and value-added products recovery, yet insights into PNSB aggregation are thus far limited. This study explored the effects of organic loading rate (OLR), hydraulic retention time (HRT) and water composition on the aggregation of Rhodobacter capsulatus in an anaerobic upflow photobioreactor. Between 2.0 and 14.6 gCOD/(L.d), the optimal OLR for aggregation was 6.1 gCOD/(L.d), resulting in a sedimentation flux of 5.9 kgTSS/(m2.h). With HRT tested between 0.04 and 1.00 d, disaggregation occurred at the relatively long HRT (1 d), possibly due to accumulation of thus far unidentified heat-labile metabolites. Chemical oxygen demand (COD) to nitrogen ratios (6-35 gCOD/gN) and the nitrogen source (ammonium vs. glutamate) also impacted aggregation, highlighting the importance of the type of wastewater and its pre-treatment. These novel insights to improve purple biomass separation pave the way for cost-efficient PNSB applications.This study investigated the effects of adding polyvinyl alcohol (PVA) beads on the performance of methanogenic reactors and the fouling behavior of a two-stage thermophilic anaerobic membrane bioreactor (ThAnMBR) for treating wastewater at a feed chemical oxygen demand (COD) of 10 g/L. The PVA-added methanogenic reactor exhibited stable operation performance and offered a relatively low volatile fatty acid concentration effluent with a higher COD removal than the system without PVA addition. The predominant microbial communities in both methanogenic reactors were similar and were assigned to the genus Methanosaeta, followed by Clostridia, which was the predominant genus in the hydrolytic reactor. Ultrafiltration in the PVA-added system offered higher effluent quality and lower fouling resistance. The system was able to operate with hydraulically removable fouling, without any chemical cleaning requirements; however, an elevated flux caused the system to suffer from hydraulically irreversible fouling. PVA beads exhibit their structural stability over long-term operation.The current work focuses on studying the aqueous phase reforming (APR) of pine and birch hydrolysate obtained from waste wood by using organic acids available from biorefineries. Processing of representative synthetic mixtures was utilized in the work in order to support data interpretation related to the influence of different chemical compound and processing parameters on the APR of the actual hydrolysates. It was shown, that hydrogenation of the hydrolysates prior to APR was not feasible in the presence of formic acid, which ruled out one potential processing route. However, it was successfully demonstrated that birch and pine hydrolysates could be directly processed obtaining close to full conversion. The best results were obtained with tailored bimetallic Pd-Pt/sibunit catalyst in a trickle bed reactor system in the temperature range 175 °C-225 °C.Based on features extracted from Raman spectra, regularization algorithms, SVR, DT, RF, LightGBM, CatBoost, and XGBoost were used to develop prediction models for lignin content in poplar. Firstly, Raman features extracted from FT-Raman spectra after data processing were used as input of models and determined lignin contents were output. Secondly, grid-search combined with cross-validation was used to adjust the hyper-parameters of models. Finally, the predictive models were built by aforementioned algorithms. The results indicated regularization algorithms, SVR, DT held test R2 were >0.80 which means the predictive values from model still deviate from measured ones. Meanwhile, RF, LightGBM, CatBoost, and XGBoost were better than above algorithms, and their test R2 were >0.91 which suggesting the predictive values was nearly close to measured ones. Therefore, fast and accurate methods for predicting lignin content were obtained and will be useful for screening suitable lignocellulosic resource with expected lignin content.To explore the effect of microelement selenium on greenhouse gas emission, nitrogen loss and related functional genes during the composting. Selenite and selenate were respectively mixed with goat manure and wheat straw and then composted the mixture without selenium regarded as control. The results indicated adding selenite prolonged the thermophilic phase and improved the organic matter degradation, while the selenate presented the opposite results. Selenite and selenate influenced ammonium transformation while prompting the formation of nitrate. Compared to the control, adding selenite and selenate both decreased NH3 emissions (by 26.7%-53.1%) and increased the total nitrogen content of compost. The addition of selenium increased mcrA in the early phase of composting, thereby promoting CH4 emission (by 3.5-18.4%). Meanwhile, adding selenate significantly reduced nirK abundance and consequently reduced N2O emission. Moreover, selenate added treatment presented the highest compost maturity (88.77%) and the lowest global warm potential (117.46 g/kg CO2-eq.) among all treatments.An acetic acid-mediated bio-oxidation strategy with Gluconobacter oxydans was developed to produce valuable 2-ketogluconic acid from lignocellulosic biomass. Metabolically, glucose is firstly oxidized to gluconic acid and further oxidized to 2-keto-gluconic acid by Gluconobacter oxydans. As a specific inhibitor for microbial fermentation generated from pretreatment, acetic acid was validated to have a down-regulated effect on bio-oxidizing glucose to gluconic acid. Nevertheless, it significantly facilitated 2-keto-gluconic acid accumulation and improved gluconate dehydrogenase activity. In the presence of 5.0 g/L acetic acid, the yield of 2-keto-gluconic acid increased from 38.0% to 80.5% using pure glucose as feedstock with 1.5 g/L cell loading. Meanwhile, 44.6 g/L 2-keto-gluconic acid with a yield of 83.5% was also achieved from the enzymatic hydrolysate. 2-keto-gluconic acid production, found in this study, laid a theoretical foundation for the industrial production of 2-keto-gluconic acid by Gluconobacter oxydans using lignocellulosic materials.The decomposition and transformation of organic matters during composting process are performed by various microorganisms. However, the bacterial communities and their functions usually vary with composting materials. Here the dominant bacterial genera and their functions were identified at the thermophilic phase during composting of mulberry branches with silkworm excrement (MSE), pig manure (MPM) and cow manure (MCD). The activities of β-glucosidase and endoglucanase were highest for MCD (1.31 and 17.15 µg g-1 min-1) and lowest for MPM (0.92 and 14.22 µg g-1 min-1). Random Forest model and correlation analysis revealed that Stenotrophomonas, Bacillus, and Sinibacillus were the dominant bacterial genera involved in lignocellulose degradation regardless of composting materials. Carbohydrate metabolism, amino acid metabolism, and DNA replication and repair were primary functions of the bacterial communities for the three types of composting. The quantification of lignocellulose degradation genes further verified the dominant functions of the bacterial communities.The removal of nitrate (NO3–N) under the low carbon to nitrogen (C/N) ratio is a widespread issue. Here in, a modified biochar (MRHB) was prepared by combining rice husk and magnetite to promote the denitrification performance of Aquabacterium sp. XL4 under low C/N ratio. In addition, when the modified H2O2 concentration was 0.6 mM, the dosage was 5.0 g L-1, the C/N ratio was 1.5, and the pH was neutral, the nitrate removal efficiency is 97.9%. Fluorescence excitation-emission matrix spectra (3D-EEM) showed that the metabolism of strain XL4 was stable under optimal conditions. Furthermore, the results of flow cytometry (FC) showed that the amounts of intact cells with MRHB was excellent. The measurement of cytochrome c concentration, total membrane permeability (Tmp), electron transport system activity (ETSA), and cyclic voltammetry curve (CV) confirmed that the MRHB improved the electron transfer and membrane activity of strain XL4.This study researched denitrification performance and mechanism of denitrification biofilm reactor with different HRTs and carbon sources dosages. Experimental group (EG) had better nitrate and COD removal performance than control group (CG) with different HRTs or carbon doses, and the maximum nitrate-to-nitrite transformation ratio (NTR) of them reached 7.91 ± 1.60% and 17.50 ± 1.92%, respectively. Because organic carbon sources were added to the carrier’s interior in EG, forming high local concentrations in biofilms and counter-diffusional with nitrate. By contrast, carbon sources and nitrate were provided from the aqueous phase in CG. Thus, the EG system has more active regions of the biofilm than CG. In addition, EG had higher proportions of microorganisms and enzymes related to denitrification and carbon metabolism. The most dominant phylum, genus, and species were Proteobacteria, Thaurea, and Thauera_sp._27, respectively. The transcript of acetyl-CoA synthetase (K01895) and denitrification (M00529) was mainly originated from unclassified_g__Pseudomonas and unclassified_g__Thauera, respectively.Design for fermentation bioreactor controllers is challenged by the nonlinear process kinetics and the lack of online measurements for key variables. This work developed a multi-input, multi-output advanced nonlinear control structure for a continuous, non-isothermal, constant volume fermentation bioreactor. Utilizing feedback linearization control for the bioreactor feed to regulate glucose concentration, and backstepping control for the cooling jacket feed to regulate reactor temperature. A developed novel estimator for biomass concentration was incorporated to provide online estimates for the unmeasurable state variable. Simulation results showed the control structure ability in efficiently establishing a combination of dynamic and fixed set points, despite disturbances in the bioreactor feed temperature and glucose concentration. Expanded bioreactor control authority increased operational flexibility and enhanced the potential for performance improvements. This work illustrated the effectiveness of feedback linearization and backstepping control in designing controllers for biological systems with nonlinear dynamics, complex interactions, and input disturbances.Activation of signal transducer and activator of transcription 3 (STAT3) is associated with hypoxia-induced epithelial-mesenchymal transition (EMT). Activation of STAT3 requires its phosphorylated form, and STAT3 can also be post-translationally modified by O-GlcNAcylation. Dynamic regulation of STAT3 O-GlcNAcylation in relation to STAT3 phosphorylation remains poorly understood. We observed, based on chemical enzyme labeling and click chemistry methods in combination with mass spectrometric analysis, that O-GlcNAcylation of STAT3 is significantly reduced under hypoxia. Results of functional experiments indicated that O-GlcNAcylation maintains stability of STAT3 and prevents its degradation via ubiquitination during hypoxia-induced EMT. O-GlcNAcylation of STAT3 facilitated its phosphorylation. Following STAT3 phosphorylation, existing STAT3 O-GlcNAcylation was antagonistically released. Our experimental findings, in combination with structure modeling, indicate that O-GlcNAcylation of STAT3 at residue T717 is essential for its phosphorylation at Y705. In contrast, mutation of STAT3 at phosphorylation site Y705 had no effect on its O-GlcNAcylation. O-GlcNAcylation and phosphorylation of STAT3 evidently occur in a strict sequential order under hypoxia-induced EMT. Dynamic regulation of STAT3 function clearly involves crosstalk between O-GlcNAcylation and phosphorylation. O-GlcNAcylation of STAT3 at T717 facilitates EMT process by promoting STAT3 phosphorylation, and provides a potential therapeutic target that may be useful in anticancer drug design.The postrhinal cortex (POR) serves as a key input area to the hippocampal system. It receives highly processed information from the ventral visual stream and other limbic areas including the retrosplenial cortex, parahippocampal areas, and portions of the limbic thalamus. The POR was studied early on by David Bucci and colleagues who first postulated that the POR plays a major role in contextual learning. Here we review a number of approaches and experimental studies that have explored POR’s role in contextual processing. We discuss POR lesion studies that monitored deficits in fear conditioning tasks and the effects that these lesions had on processing visual landmark information. We then review the types of spatial correlates encoded by POR cells. A large number of head direction (HD) cells are present, although recent findings suggest that many of them are more accurately characterized as landmark modulated-HD cells as opposed to classic HD cells. A significant number of POR cells are also tuned to egocentric properties of the environment, such as the spatial relationship of the animal to the center of its environment, or the distance between the animal and either the environment’s center or its boundaries. We suggest potential frameworks through which these functional cell types might support contextual processing. We then discuss deficits seen in humans who have damage to the homologous parahippocampal cortex, and we finish by reviewing functional imaging studies that found activation of this area while human subjects performed various tasks. A preponderance of evidence suggests that the POR, along with its interactions with retrosplenial cortex, plays a key role in contextual information processing.

The phase III IMspire150 study (NCT02908672) demonstrated significantly improved progression-free survival (PFS) with atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) versus placebo, vemurafenib, and cobimetinib (control group) in patients with BRAF

-mutated advanced melanoma. We report exploratory biomarker analyses to optimize targeting of patients who are more likely to benefit from triplet combination therapy.

Five hundred fourteen patients were randomized to atezolizumab (n= 256) or control (n= 258). Outcomes were evaluated in subgroups defined by key biomarkers, including programmed death-ligand 1 (PD-L1) expression, lactate dehydrogenase (LDH) level, tumor mutational burden (TMB), and interferon-γ (IFN-γ) gene signature. Exploratory recursive partitioning analysis was then used to model associations between PFS and baseline covariates, including key biomarkers.

PFS benefit for atezolizumab versus control was greater in patients with high TMB [≥10 mutations/Mb; hazard ratio (HR) 0.zumab, vemurafenib, and cobimetinib.

Treatment benefits in the atezolizumab group seemed to be most evident in patients with elevated LDH and PD-L1- tumors. LDH remains the primary predictor of outcomes regardless of treatment. IFN-γ and TMB further differentiate outcomes for patients treated with atezolizumab, vemurafenib, and cobimetinib.Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disease caused primarily by autoantibodies (PV-IgG) against the desmosomal cadherins desmoglein (Dsg) 1 and Dsg 3. Pemphigus is a model disease to study desmosome regulation because patient lesions are characterized by ultrastructural hallmarks including loss, shrinkage and splitting of desmosomes as well as by retraction of keratin filaments. The mechanisms underlying the disease are not completely understood but involve several intracellular signaling pathways triggered by autoantibody binding. Recently, we demonstrated that Phosphoinositid-Phospholipase C (PLC) and Ca2+ signaling are required for acantholysis in human epidermis. Here, we used transmission electron microscopy to characterize the role of PLC and Ca2+ signaling with regard to the pathogenic effects of PV-IgG on desmosome ultrastructure in human ex vivo skin model. First, we observed that the PV-IgG used in this study significantly reduced desmosome length and caused uncoupling of desmosomes from keratin filaments. Moreover, PV-IgG enhanced the number of split desmosomes but did not cause a significant loss of desmosomes. We found that inhibition of PLC and Ca2+ signaling significantly blocked keratin filament uncoupling but not shrinkage of desmosomes. Blocking Ca2+ flux prevented desmosome splitting. The ultrastructural analysis revealed that for preventing skin blistering it is sufficient to enhance keratin filament insertion, which is regulated by PLC/ Ca2+. Here, we underscore the unique role of electron microscopy to investigate the underlying mechanisms by which a signaling pathway regulates desmosome ultrastructure in pemphigus.It is difficult to measure the dimensions of the anterior cruciate ligament (ACL) in vivo, which makes choosing an individualized graft size for ACL reconstruction particularly troublesome. The morphology and function of porcine ACL have been reported to be similar to the native human ACL. This study aimed to identify bony morphological parameters on X-ray images that were significantly correlated with features of the native ACL. Anteroposterior X-ray images of 19 porcine knees were obtained. The width, height and area of the femoral notch, the widths of the femoral and tibial condyles and the width and area of the interspinal fossa of the tibia were measured. ACL length was measured using a caliper. The ACL was then resected and the outline of the bone insertion sites were marked and photographed for measuring the areas of the insertion sites. The excised ACL substance was scanned using X-ray microscopy and reconstructed to measure the medial-lateral (ML) and anterior-posterior (AP) widths, the long and shorthe width of the femoral condyle measured from X-ray images might be used to estimate the shape and size of the ACL, which might be helpful for choosing a suitable graft size for ACL reconstruction. DATA STATEMENT All data relevant to the study are included in the article.Bilateral deficits in sensorimotor function have been observed in unilateral musculoskeletal pain conditions. Altered interhemispheric inhibition (IHI) between primary sensory cortices (S1s) is one mechanism that could explain this phenomenon. However, IHI between S1s in response to acute muscle pain, and the relationship between IHI and pressure pain sensitivity in the unaffected limb have not been examined. In 21 healthy individuals, IHI was assessed using somatosensory evoked potentials in response to paired median nerve electrical stimulation at 1) baseline; 2) immediately following pain resolution; and 3) at 30-minutes follow-up. Acute muscle pain was induced by injection of hypertonic saline into the right abductor pollicis brevis (APB) muscle. Pressure pain thresholds were assessed at the right and left APB muscles before and 30-minutes after pain resolution. Compared to baseline, IHI from the affected to unaffected S1 was unaltered in response to acute muscle pain immediately following pain resolution, or at 30-minutes follow-up. Pressure pain thresholds were reduced over the right (P = .001) and left (P = .001) APB muscles at 30-minutes follow-up. These findings suggest IHI between S1s is unaffected by acute, short-lasting muscle pain, despite the development of increased sensitivity to pressure in the unaffected APB muscle. PERSPECTIVE IHI from the affected S1 (contralateral to the side of pain) to unaffected S1 is unaltered following the resolution of acute muscle pain. This finding suggests that IHI between S1s may not be relevant in the development of bilateral sensorimotor symptoms in unilateral pain conditions.Cognitive factors are thought to contribute and maintain pain experiences in young people. However, most of these factors have been assessed in isolation. Considering more than 1 cognitive factor could increase explanatory power and identify multiple targets for intervention. Here, we tested a Combined Cognitive Bias Hypothesis (CCBH) that suggests information-processing factors associate with each other and exert either additive and/or interactive influences on pain outcomes. We conducted secondary analysis of data from 243 adolescents aged 16 to 19 years, who had completed a task measuring pain-related attention control impairments (emotion-priming visual search task) and a task measuring biased interpretations towards threatening cues (Adolescent Interpretation of Bodily Threat task). These young people also completed measures of recent pain experiences and pain catastrophizing, which served as primary and secondary outcomes, respectively. Regression analyses revealed that difficulties with attention control (following presentation of pain-related stimuli) and tendencies to endorse threatening interpretations of ambiguous situations had significant additive effects on both pain outcomes. However, correlations between these factors were non-significant. They also did not interact to influence pain outcomes. These findings require replication in broader age ranges and clinical samples but potentially suggest that, measuring multiple cognitive factors increases explanatory power of youth pain outcomes. PERSPECTIVE Weak attention control following exposure to pain cues and tendencies to endorse threat interpretations, uniquely and additively associate with self-reported pain experiences and pain catastrophizing in community youth. Measuring several cognitive factors simultaneously could improve our ability to explain pain outcomes in adolescent populations.Unravelling how reactive oxygen species regulate fundamental biological processes is hampered by the lack of an accessible microplate technique to quantify target-specific protein thiol redox state in percentages and moles. To meet this unmet need, we present RedoxiFluor. RedoxiFluor uses two spectrally distinct thiol-reactive fluorescent conjugated reporters, a capture antibody, detector antibody and a standard curve to quantify target-specific protein thiol redox state in relative percentage and molar terms. RedoxiFluor can operate in global mode to assess the redox state of the bulk thiol proteome and can simultaneously assess the redox state of multiple targets in array mode. Extensive proof-of-principle experiments robustly validate the assay principle and the value of each RedoxiFluor mode in diverse biological contexts. In particular, array mode RedoxiFluor shows that the response of redox-regulated phosphatases to lipopolysaccharide (LPS) differs in human monocytes. Specifically, LPS increased PP2A-, SHP1-, PTP1B-, and CD45-specific reversible thiol oxidation without changing the redox state of calcineurin, PTEN, and SHP2. The relative percentage and molar terms are interpretationally useful and define the most complete and extensive microplate redox analysis achieved to date. RedoxiFluor is a new antibody technology with the power to quantify relative target-specific protein thiol redox state in percentages and moles relative to the bulk thiol proteome and selected other targets in a widely accessible, simple and easily implementable microplate format.Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2-/- mice. In silico docking simulations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR-opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.Vaccination is an effective public health measure, yet vaccine efficacy varies across different populations. Adjuvants improve vaccine efficacy but often increase reactogenicity. An unconventional behavioral „adjuvant” is physical exercise at the time of vaccination. Here, in separate experiments, we examined the effect of 90-minute light- to moderate-intensity cycle ergometer or outdoor walk/jog aerobic exercise performed once after immunization on serum antibody response to three different vaccines (2009 pandemic influenza H1N1, seasonal influenza, and COVID-19). Exercise took place after influenza vaccination or after the first dose of Pfizer-BioNTech COVID-19 vaccine. A mouse model of influenza A immunization was used to examine the effect of exercise on antibody response and the role of IFNα as a potential mechanism by treating mice with anti-IFNα antibody. The results show that 90 min of exercise consistently increased serum antibody to each vaccine four weeks post-immunization, and IFNα may partially contribute to the exercise-related benefit. Exercise did not increase side effects after the COVID-19 vaccination. These findings suggest that adults who exercise regularly may increase antibody response to influenza or COVID-19 vaccine by performing a single session of light- to moderate-intensity exercise post-immunization.

Childhood maltreatment (CM) has long-term consequences for dysregulation of the immune system which is particularly pronounced when mental and physical health sequelae have manifested. Higher proinflammatory state has been shown in non-pregnant state in association with CM as well as with depression, one of the most frequent and pernicious psychiatric sequelae of CM. During pregnancy, however, this association is less clear. Given the important role of maternal inflammatory state during pregnancy for fetal, pregnancy, and birth outcomes, we sought to examine the association between CM and proinflammatory state during pregnancy considering the moderating role of maternal depressive symptoms characterized serially across pregnancy.

A prospective, longitudinal study of 180 healthy pregnant women was conducted with serial assessments in early (12.98±1.71weeks gestation), mid (20.53±1.38weeks gestation) and late (30.42±1.4weeks gestation) pregnancy. Maternal history of CM was assessed with the Childhood Traumahe timely assessment of both CM exposure and depressive symptoms which might allow for the development of targeted and individualized interventions to impact inflammation during pregnancy and to ameliorate the detrimental long-term effects of CM. The current findings add to a better understanding of the prenatal biological pathways that may underlie intergenerational transmission of maternal CM.

Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions.

Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profilnd polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids.

The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

Physical and psychological stress alter gut-brain axis activity, potentially causing intestinal barrier dysfunction that may, in turn, induce cognitive and mood impairments through exacerbated inflammation and blood brain barrier (BBB) permeability. These interactions are commonly studied in animals or artificial laboratory environments. However, military survival training provides an alternative and unique human model for studying the impacts of severe physical and psychological stress on the gut-brain axis in a realistic environment.

To determine changes in intestinal barrier and BBB permeability during stressful military survival training and identify relationships between those changes and markers of stress, inflammation, cognitive performance, and mood state.

Seventy-one male U.S. Marines (25.2±2.6years) were studied during Survival, Evasion, Resistance, and Escape (SERE) training. Measurements were conducted on day 2 of the 10-day classroom phase of training (PRE), following completion of the 7.5-day field-based simulation phase of the training (POST), and following a 27-day recovery period (REC).