Search

Objective: To compare the risk of infection in inflammatory arthritis patients treated with tumor necrosis factor (TNF) inhibitors.Methods: PubMed, Embase, and the Cochrane Library were systematically searched from inception to 28 December 2023 for randomized controlled trials (RCTs) assessing TNF inhibitors and reporting infections. Subsequently, pairwise and network meta-analyses were conducted to determine odds ratios (ORs) and the corresponding 95% confidence intervals (CIs).Results: A total of 61 RCTs involving 20,458 patients were included. Pairwise meta-analysis revealed that certolizumab pegol was significantly associated with an increased risk of serious infection compared to placebo (OR:2.28, 95% CI: 1.13–4.62). Both adalimumab and certolizumab pegol were also significantly associated with an increased risk of any infection compared to placebo (OR:1.18, 95% CI: 1.06 to 1.30 and OR:1.40, 95% CI: 1.11 to 1.76, respectively). Moreover, a network meta-analysis indicated that certolizumab pegol and infliximab were associated with a higher risk of serious infection compared to other TNF inhibitors. In the cumulative ranking of any infection risk, certolizumab pegol had the highest risk compared with others. TNF inhibitors increased the risk of tuberculosis but not that of herpes zoster.Conclusion: Available evidence indicates etanercept and golimumab are likely associated with a lower risk of infection compared to other TNF inhibitors in inflammatory arthritis. For patients at a heightened risk of infection, prioritizing the use of etanercept and golimumab may be advisable to minimize patient risk.Systematic Review Registration: identifier CRD42022316577

IntroductionPeripartal cows are susceptible to a negative energy balance due to inadequate nutrient intake and high energy requirements for lactation. Improving the energy metabolism of perinatal dairy cows is crucial in increasing production in dairy cows.MethodsIn this study, we investigated the impact of rumen-protected branched-chain amino acid (RPBCAA) on the production performance, energy and lipid metabolism, oxidative stress, and immune function of primiparous dairy cows using metabolomics through a single-factor experiment. Twenty healthy primiparous Holstein cows were selected based on body condition scores and expected calving date, and were randomly divided into RPBCAA (n = 10) and control (n = 10) groups. The control group received a basal diet from calving until 21 d in milk, and the RPBCAA group received the basal diet and 44.6 g/d RPLeu, 25.14 g/d RPIle, and 25.43 g/d RPVal.ResultsIn comparison to the control group, the supplementation of RPBCAA had no significant effect on milk yield and milk composition of the dairy cows. Supplementation with RPBCAA significantly increased the concentrations of insulin, insulin growth factor 1, glucagon, and growth hormones, which are indicators of energy metabolism in postpartum cows. The very low density lipoprotein, fatty acid synthase, acetyl coenzyme A carboxylase, and hormone-sensitive lipase contents of the RPBCAA group were significantly greater than that of the control group; these metrics are related to lipid metabolism. In addition, RPBCAA supplementation significantly increased serum glutathione peroxidase and immunoglobulin G concentrations and decreased malondialdehyde concentrations. Liquid chromatography–mass spectrometry (LC-MS) analysis revealed 414 serum and 430 milk metabolic features. Supplementation with RPBCAA primarily increased concentrations of amino acid and lipid metabolism pathways and upregulated the abundance of serotonin, glutamine, and phosphatidylcholines.DiscussionIn summary, adding RPBCAA to the daily ration can influence endocrine function and improve energy metabolism, regulate amino acid and lipid metabolism, mitigate oxidative stress and maintain immune function on primiparous cows in early lactation.

Circular RNAs (circRNAs) play an important role in regulating the mammalian reproductive system, especially testicular development and spermatogenesis. However, their functions in testicular development and spermatogenesis in the Qianbei Ma goat, the Guizhou endemic breed are still unclear. In this study, tissue sectioning and circRNAs transcriptome analysis were conducted to compare the changes of morphology and circular RNAs gene expression profile at four different developmental stages (0Y, 0-month-old; 6Y, 6-month-old; 12Y, 12-month-old; 18Y, 18-month-old). The results showed that the circumferences and area of the seminiferous tubule gradually increased with age, and the lumen of the seminiferous tubule in the testis differentiated significantly. 12,784 circRNAs were detected from testicular tissues at four different developmental stages by RNA sequencing, and 8,140 DEcircRNAs (differentially expressed circRNAs) were found in 0Y vs. 6Y, 6Y vs. 12Y, 12Y vs. 18Y and 0Y vs. 18Y, 0Y vs. 12Y, 6Y vs. 18Y Functional enrichment analysis of the source genes showed that they were mainly enriched in testicular development and spermatogenesis. In addition, the miRNAs and mRNAs associated with DECircRNAs in 6 control groups were predicted by bioinformatics, and 81 highly expressed DECircRNAs and their associated miRNAs and mRNAs were selected to construct the ceRNA network. Through functional enrichment analysis of the target genes of circRNAs in the network, some candidate circRNAs related to testicular development and spermatogenesis were obtained. Such as circRNA_07172, circRNA_04859, circRNA_07832, circRNA_00032 and circRNA_07510. These results will help to reveal the mechanism of circRNAs in testicular development and spermatogenesis, and also provide some guidance for goat reproduction.

PurposeIn this study, we aimed to investigate whether Programmed cell death 1 ligand 1/programmed cell death 1 ligand 2 (PD-L1/PD-L2) double knockout (dKO) has a protective effect on RGCs in a mouse model of chronic ocular hypertension (COHT).MethodsWe used superparamagnetic iron oxide to induce COHT in mice. Apoptosis of retinal ganglion cells (RGCs) and activation of microglia were evaluated using western blotting (WB) and immunofluorescence staining of the mouse retina. In addition, we also conducted transcriptome sequencing and further gene expression analyses using the gene ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) database.ResultsIn the mouse model of COHT, PD-L1/PD-L2 prevented the apoptosis of RGCs to some extent. Blocking the programmed cell death 1 (PD-1) pathway also increased the number of anti-inflammatory M2-activated microglia and enhanced the phosphorylation of its related pathway signal transducer and activator of transcription (STAT)6. Sequencing results showed that this protective effect may have been achieved by regulating the NF−B, tumour necrosis factor (TNF), PI3K/Akt and toll-like receptor signaling pathway etc.ConclusionBlocking the PD-1 pathway has a protective effect on RGCs in the mouse model of COHT induced by superparamagnetic iron oxide.

Endophytic microbial communities of lichen are emerging as novel microbial resources and for exploration of potential biotechnological applications. Here, we focused on a medicinal lichen Usnea longissima, and investigated its bacterial and fungal endophytes. Using PacBio 16S rRNA and ITS amplicon sequencing, we explored the diversity and composition of endophytic bacteria and fungi in U. longissima collected from Tibet at five altitudes ranging from 2,989 to 4,048 m. A total of 6 phyla, 12 classes, 44 genera, and 13 species of the bacterial community have been identified in U. longissima. Most members belong to Alphaproteobacteria (42.59%), Betaproteobacteria (33.84%), Clostridia (13.59%), Acidobacteria (7%), and Bacilli (1.69%). As for the fungal community, excluding the obligate fungus sequences, we identified 2 phyla, 15 classes, 65 genera, and 19 species. Lichen-related fungi of U. longissima mainly came from Ascomycota (95%), Basidiomycota (2.69%), and unidentified phyla (2.5%). The presence of the sequences that have not been characterized before suggests the novelty of the microbiota. Of particular interest is the detection of sequences related to lactic acid bacteria and budding yeast. In addition, the possible existence of harmful bacteria was also discussed. To our best knowledge, this is the first relatively detailed study on the endophytic microbiota associated with U. longissima. The results here provide the basis for further exploration of the microbial diversity in lichen and promote biotechnological applications of lichen-associated microbial strains.

BackgroundBlindness and stroke resulting from hyaluronic acid (HA) fillers are not frequently reported complications. Reports on stroke recovery after HA injection are limited. In the current study, the recovery process, task-based functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and neurophysiological changes of a patient with monocular blindness and ipsilateral motor cortical stroke after forehead injection of HA are explored.Case-reportThe study comprised a 34-year-old female patient who presented with left eye blindness and a stroke after receiving an HA injection a month before admission. The lesion was mainly limited to the left precentral gyrus, and the patient had pure arm monoparesis. For 3 weeks, the patient received conventional rehabilitation treatments and ten sessions of repetitive transcranial magnetic stimulation (rTMS) intervention. Clinical assessments, neurophysiological evaluation, task-based fMRI, and DTI examinations were conducted to assess her motor improvement and the possible neuro mechanism.Clinical rehabilitation impactThe patient's right upper limb motor function was almost completely restored after receiving rehabilitation therapy. However, the vision in her left eye did not show significant improvement. The neurophysiological evaluation showed partial recovery of the ipsilesional motor evoked potentials (MEPs). DTI results showed that the ipsilesional corticospinal tract (CST) was intact. Task-based fMRI results indicated that the activation pattern of the affected hand movement was gradually restored to normal.ConclusionA case of good motor recovery after stroke due to HA injection with a lesion mainly restricted to the precentral gyrus but without CST damage is presented in the current study. Further studies should be conducted to explore the efficacy and the mechanisms of rehabilitation and neuromodulation approaches to motor cortical stroke.

ATR is a PI3K-like kinase protein, regulating checkpoint responses to DNA damage and replication stress. Apart from its checkpoint function in the nucleus, ATR actively engages in an antiapoptotic role at mitochondria following DNA damage. The different functions of ATR in the nucleus and cytoplasm are carried out by two prolyl isomeric forms of ATR: trans- and cis-ATR, respectively. The isomerization occurs at the Pin1 Ser428-Pro429 motif of ATR. Here, we investigated the structural basis of the subcellular location-specific functions of human ATR. Using a mass spectrometry-based footprinting approach, the surface accessibility of ATR lysine residues to sulfo-NHS-LC-biotin modification was monitored and compared between the cis- and the trans-isomers. We have identified two biotin-modified lysine residues, K459 and K469, within the BH3-like domain of cis-ATR that were not accessible in trans-ATR, indicating a conformational change around the BH3 domain between cis- and trans-ATR. The conformational alteration also involved the N-terminal domain and the middle HEAT domain. Moreover, experimental results from an array of complementary assays show that cis-ATR with the accessible BH3 domain was able to bind to tBid while trans-ATR could not. In addition, both cis- and trans-ATR can directly form homodimers via their C-terminal domains without ATRIP, while nuclear (trans-ATR) in the presence of ATRIP forms dimer–dimer complexes involving both N- and C-termini of ATR and ATRIP after UV. Structural characteristics around the Ser428-Pro429 motif and the BH3 domain region are also analyzed by molecular modeling and dynamics simulation. In support, cis conformation was found to be significantly more energetically favorable than trans at the Ser428-Pro429 bond in a 20-aa wild-type ATR peptide. Taken together, our results suggest that the isomerization-induced structural changes of ATR define both its subcellular location and compartment-specific functions and play an essential role in promoting cell survival and DNA damage responses.

In this study, we investigated cell physiological and biochemical responses to copper (Cu) accumulation in the marine diatom Phaeodactylum tricornutum under different nitrogen (N) and phosphorus (P) conditions. Cells with sufficient N and P (+N+P) showed the highest total Cu concentrations and displayed a higher metal-tolerance ability. In the +N+P treatments, 36.5% of dissolved Cu was adsorbed on the frustules (cell walls), 54.9% was occluded in organelles, and 8.6% was in the soluble fraction. In comparison, cells with N and/or P shortages (+N−P, −N+P, and −N−P) adsorbed 10.8–13.1% of the total Cu onto their cell walls, 74.5–80% was occluded in organelles, and 9.2–12.4% was in the soluble fraction. The Cu2+ influx on the +N+P cell wall was faster due to sufficient metal ligands on the cell walls and up-regulated metal-related transporters. A significant increase in protein content occurred under N and/or P shortages, which was accompanied by the inhibition of the antioxidative enzymatic system and cell membrane damage. Our findings indicate that N and P play an important role in both Cu adsorption (cell surface) and uptake (intracellular), and they provide multifaceted evidence of the Cu acquisition mechanism in P. tricornutum under different macronutrient conditions.

It remains poorly understood how brain causal connectivity networks change following hearing loss and their effects on cognition. In the current study, we investigated this issue. Twelve patients with long-term bilateral sensorineural hearing loss [mean age, 55.7 ± 2.0; range, 39–63 years; threshold of hearing level (HL): left ear, 49.0 ± 4.1 dB HL, range, 31.25–76.25 dB HL; right ear, 55.1 ± 7.1 dB HL, range, 35–115 dB HL; the duration of hearing loss, 16.67 ± 4.5, range, 3–55 years] and 12 matched normally hearing controls (mean age, 52.3 ± 1.8; range, 42–63 years; threshold of hearing level: left ear, 17.6 ± 1.3 dB HL, range, 11.25–26.25 dB HL; right ear, 19.7 ± 1.3 dB HL, range, 8.75–26.25 dB HL) participated in this experiment. We constructed and analyzed the causal connectivity networks based on functional magnetic resonance imaging data of these participants. Two-sample t-tests revealed significant changes of causal connections and nodal degrees in the right secondary visual cortex, associative visual cortex, right dorsolateral prefrontal cortex, left subgenual cortex, and the left cingulate cortex, as well as the shortest causal connectivity paths from the right secondary visual cortex to Broca’s area in hearing loss patients. Neuropsychological tests indicated that hearing loss patients presented significant cognitive decline. Pearson’s correlation analysis indicated that changes of nodal degrees and the shortest causal connectivity paths were significantly related with poor cognitive performances. We also found a cross-modal reorganization between associative visual cortex and auditory cortex in patients with hearing loss. Additionally, we noted that visual and auditory signals had different effects on neural activities of Broca’s area, respectively. These results suggest that changes in brain causal connectivity network are an important neuroimaging mark of cognitive decline. Our findings provide some implications for rehabilitation of hearing loss patients.

Ataxia telangiectasia and Rad3-related protein (ATR) is a serine/threonine-protein kinase of the PI3K family and is well known for its key role in regulating DNA damage responses in the nucleus. In addition to its nuclear functions, ATR also was found to be a substrate of the prolyl isomerase Pin1 in the cytoplasm where Pin1 isomerizes cis ATR at the Ser428-Pro429 motif, leading to formation of trans ATR. Cis ATR is an antiapoptotic protein at mitochondria upon UV damage. Here we report that Pin1’s activity on cis ATR requires the phosphorylation of the S428 residue of ATR and describe the molecular mechanism by which Pin1-mediated ATR isomerization in the cytoplasm is regulated. We identified protein phosphatase 2A (PP2A) as the phosphatase that dephosphorylates Ser428 following DNA damage. The dephosphorylation led to an increased level of the antiapoptotic cis ATR (ATR-H) in the cytoplasm and, thus, its accumulation at mitochondria via binding with tBid. Inhibition or depletion of PP2A promoted the isomerization by Pin1, resulting in a reduction of cis ATR with an increased level of trans ATR. We conclude that PP2A plays an important role in regulating ATR’s anti-apoptotic activity at mitochondria in response to DNA damage. Our results also imply a potential strategy in enhancing cancer therapies via selective moderation of cis ATR levels.

Peptidyl-prolyl isomerization is an important post-translational modification of protein because proline is the only amino acid that can stably exist as cis and trans, while other amino acids are in the trans conformation in protein backbones. This makes prolyl isomerization a unique mechanism for cells to control many cellular processes. Isomerization is a rate-limiting process that requires a peptidyl-prolyl cis/trans isomerase (PPIase) to overcome the energy barrier between cis and trans isomeric forms. Pin1, a key PPIase in the cell, recognizes a phosphorylated Ser/Thr-Pro motif to catalyze peptidyl-prolyl isomerization in proteins. The significance of the phosphorylation-dependent Pin1 activity was recently highlighted for isomerization of ATR (ataxia telangiectasia- and Rad3-related). ATR, a PIKK protein kinase, plays a crucial role in DNA damage responses (DDR) by phosphorylating hundreds of proteins. ATR can form cis or trans isomers in the cytoplasm depending on Pin1 which isomerizes cis-ATR to trans-ATR. Trans-ATR functions primarily in the nucleus. The cis-ATR, containing an exposed BH3 domain, is anti-apoptotic at mitochondria by binding to tBid, preventing activation of pro-apoptotic Bax. Given the roles of apoptosis in many human diseases, particularly cancer, we propose that cytoplasmic cis-ATR enables cells to evade apoptosis, thus addicting cancer cells to cis-ATR formation for survival. But in normal DDR, a predominance of trans-ATR in the nucleus coordinates with a minimal level of cytoplasmic cis-ATR to promote DNA repair while preventing cell death; however, cells can die when DNA repair fails. Therefore, a delicate balance/equilibrium of the levels of cis- and trans-ATR is required to ensure the cellular homeostasis. In this review, we make a case that this anti-apoptotic role of cis-ATR supports oncogenesis, while Pin1 that drives the formation of trans-ATR suppresses tumor growth. We offer a potential, novel target that can be specifically targeted in cancer cells, without killing normal cells, to significantly reduce the adverse effects usually seen in cancer treatment. We also raise important issues regarding the roles of phosphorylation-dependent Pin1 isomerization of ATR in diseases and propose areas of future studies that would shed more understanding on this important cellular mechanism.

HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends—telomeres, leading to accelerated telomere erosion—a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated (ATM) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, ATM/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following ATM knockdown or exposure to the ATM inhibitor KU60019 in vitro, recapitulating the biological effects observed in HIV-derived CD4 T cells in vivo. Importantly, ectopic expression of ATM was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to ATM deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.

T cells in chronic viral infections are featured by premature aging with accelerated telomere erosion, but the mechanisms underlying telomere attrition remain unclear. Here, we employed human CD4 T cells treated with KML001 (a telomere-targeting drug) as a model to investigate the role of telomere integrity in remodeling T cell senescence. We demonstrated that KML001 could inhibit cell proliferation, cytokine production, and promote apoptosis via disrupting telomere integrity and DNA repair machineries. Specifically, KML001-treated T cells increased dysfunctional telomere-induced foci (TIF), DNA damage marker γH2AX, and topoisomerase cleavage complex (TOPcc) accumulation, leading to telomere attrition. Mechanistically, KML001 compromised telomere integrity by inhibiting telomeric repeat binding factor 2 (TRF2), telomerase, topoisomerase I and II alpha (Top1/2a), and ataxia telangiectasia mutated (ATM) kinase activities. Importantly, these KML001-induced telomeric DNA damage and T cell senescent phenotype and machineries recapitulated our findings in patients with clinical HCV or HIV infection in that their T cells were also senescent with short telomeres and thus more vulnerable to KML001-induced apoptosis. These results shed new insights on the T cell aging network that is critical and essential in protecting chromosomal telomeres from unwanted DNA damage and securing T cell survival during cell crisis upon genomic insult.