Safety and effectiveness evaluation of a uterine direct visualization system in induced abortion. A multicenter clinical trial.

OBJECTIVES: While the decision of abortion is undeniably complex, there are situations where it becomes a necessary choice. In such circumstances, a secure abortion procedure is essential to safeguard the physical and mental well-being of women. A uterine direct visualization system was designed to fulfill the requirements and this study undertook an assessment of the system's safety and effectiveness within a medical facility setting. MATERIALS AND METHODS: Induced abortion requested women in 17 institutions across the country between December 2016 and February 2017 were enrolled. Subjects were separated to the study and control group randomly. Induced abortion was conducted by a uterine direct visualization system and an ultrasound-guided system in the study and control group, respectively. The clinical indexes collected during intra- and post-procedures were analyzed and compared between groups. RESULTS: Overall, 392 and 339 subjects were included in the study and control group, respectively. The baseline demographic and clinical characteristics were similar between two groups. Subjects in the study group had significant smaller number of uterine cavity entry (p < 0.001), less 2-h and 14-days postoperative bleeding (all p < 0.001), and less 14-days postoperative abdominal pain (p < 0.001). Significantly higher ratio of normal menstruation, in terms of incidence and duration after 60-days of operation, was observed in the study group (all p < 0.001). CONCLUSIONS: Induced abortion with uterine direct visualization system generate better outcome and less complication than the conventional ultrasound-guided abortion procedures.

Neuropeptide Calcitonin Gene-Related Peptide Promotes Immune Homeostasis of Bacterial Meningitis by Inducing Major Histocompatibility Complex Class II Ubiquitination.

BACKGROUND: Calcitonin gene-related peptide (CGRP), an immunomodulatory neuropeptide, is important for regulating pain transmission, vasodilation, and the inflammatory response. However, the molecular mechanisms of the CGRP-mediated immune response remain unknown. METHODS: The effects of CGRP on bacterial meningitis (BM) and its underlying mechanisms were investigated in BM mice in vivo and macrophages in vitro. RESULTS: Peripheral injection of CGRP attenuated cytokine storms and protected mice from fatal pneumococcal meningitis, marked by increased bacterial clearance, improved neuroethology, and reduced mortality. When the underlying mechanisms were investigated, we found that CGRP induces proteasome-dependent degradation of major histocompatibility complex class II (MHC-II) in macrophages and then inhibits CD4+ T-cell activation. MARCH1 was identified as an E3 ligase that can be induced by CGRP engagement and promote K48-linked ubiquitination and degradation of MHC-II in macrophages. These results provide new insights into neuropeptide CGRP-mediated immune regulation mechanisms. CONCLUSIONS: We conclude that targeting the nervous system and manipulating neuroimmune communication is a promising strategy for treating intracranial infections like BM.

Dual Oxytocin Receptor-G Protein Signaling in the Autoregulation of Activities of Oxytocin Neurons.

Oxytocin (OT), a hypothalamic nonaneuropeptide, can extensively modulate mental and physical activities; however, the regulation of its secretion from hypothalamic OT neurons remains poorly understood. OT neuronal activity is generally modulated by neurochemical environment, synaptic inputs, astrocytic plasticity, and interneuronal interactions. By changing intracellular signals and ion channel activity, these extracellular factors dynamically regulate OT neuronal activity and OT release in a microdomain-specific manner. In this process, OT receptor (OTR) and OTR-coupled G proteins are pivotal, typically observed during lactation. Suckling-elicited somatodendritic release of OT causes sequential activation of Gq and Gs proteins to increase the firing rate gradually and trigger burst firing transiently, and then of Gi/o protein to cause post-burst inhibition as a result of potential bolus somatodendritic release of OT during the burst-like discharges. Under chronic social stress like mother-baby separation and cesarean section, excessive somatodendritic secretion of OT and over-excitation of OT neurons cause post-excitation inhibition of OT neuronal activity and reduction of OT secretion. In this process, dominance of G protein that couples to OTR is switched from Gq to Gi/o type because of inhibition of OTR-Gq signaling following negative feedback of downstream Gq signaling or crosstalk of Gq with Gs and Gi signals. This review summarizes our current understandings of OT/OTR signaling in the autoregulation of OT neuronal activity under physiological and pathological conditions.

Interactions between the Astrocytic Volume-Regulated Anion Channel and Aquaporin 4 in Hyposmotic Regulation of Vasopressin Neuronal Activity in the Supraoptic Nucleus.

We assessed interactions between the astrocytic volume-regulated anion channel (VRAC) and aquaporin 4 (AQP4) in the supraoptic nucleus (SON). Acute SON slices and cultures of hypothalamic astrocytes prepared from rats received hyposmotic challenge (HOC) with/without VRAC or AQP4 blockers. In acute slices, HOC caused an early decrease with a late rebound in the neuronal firing rate of vasopressin neurons, which required activity of astrocytic AQP4 and VRAC. HOC also caused a persistent decrease in the excitatory postsynaptic current frequency, supported by VRAC and AQP4 activity in early HOC; late HOC required only VRAC activity. These events were associated with the dynamics of glial fibrillary acidic protein (GFAP) filaments, the late retraction of which was mediated by VRAC activity; this activity also mediated an HOC-evoked early increase in AQP4 expression and late subside in GFAP-AQP4 colocalization. AQP4 activity supported an early HOC-evoked increase in VRAC levels and its colocalization with GFAP. In cultured astrocytes, late HOC augmented VRAC currents, the activation of which depended on AQP4 pre-HOC/HOC activity. HOC caused an early increase in VRAC expression followed by a late rebound, requiring AQP4 and VRAC, or only AQP4 activity, respectively. Astrocytic swelling in early HOC depended on AQP4 activity, and so did the early extension of GFAP filaments. VRAC and AQP4 activity supported late regulatory volume decrease, the retraction of GFAP filaments, and subside in GFAP-VRAC colocalization. Taken together, astrocytic morphological plasticity relies on the coordinated activities of VRAC and AQP4, which are mutually regulated in the astrocytic mediation of HOC-evoked modulation of vasopressin neuronal activity.

Contribution of inwardly rectifying K+ channel 4.1 of supraoptic astrocytes to the regulation of vasopressin neuronal activity by hypotonicity.

Astrocytic morphological plasticity and its modulation of adjacent neuronal activity are largely determined by astrocytic volume regulation, in which glial fibrillary acidic protein (GFAP), aquaporin 4 (AQP4), and potassium channels including inwardly rectifying K+ channel 4.1 (Kir4.1) are essential. However, associations of astrocyte-dominant Kir4.1 with other molecules in astrocytic volume regulation and the subsequent influence on neuronal activity remain unclear. Here, we report our study on these issues using primary cultures of rat pups' hypothalamic astrocytes and male adult rat brain slices. In astrocyte culture, hyposmotic challenge (HOC) significantly decreased GFAP monomer expression and astrocytic volume at 1.5 min and increased Kir4.1 expression and inwardly rectifying currents (IRCs) at 10 min. BaCl2 (100 µmol/l) suppressed the HOC-increased IRCs, which was simulated by VU0134992 (2 µmol/l), a Kir4.1 blocker. Preincubation of the astrocyte culture with TGN-020 (10 µmol/l, a specific AQP4 blocker) made the HOC-increased Kir4.1 currents insignificant. In hypothalamic brain slices, HOC initially decreased and then increased the firing rate of vasopressin (VP) neurons in the supraoptic nucleus. In the presence of BaCl2 or VU0134992, HOC-elicited rebound increase in VP neuronal activity was blocked. GFAP was molecularly associated with Kir4.1, which was increased by HOC at 20 min; this increase was blocked by BaCl2 . These results suggest that HOC-evoked astrocytic retraction or decrease in the volume and length of its processes is associated with increased Kir4.1 activity. Kir4.1 involvement in HOC-elicited astrocytic retraction is associated with AQP4 activity and GFAP plasticity, which together determines the rebound excitation of VP neurons.

CircSMARCC1 and CircLRBA are potential biomarkers in forensic postmortem diagnosis of acute myocardial infarction.

Postmortem diagnosis of acute myocardial infarction (AMI), especially early AMI, is a challenge for forensic scientists. Circular RNAs (circRNA) are a unique type of RNA with a closed loop structure and more stability, compared with linear RNA. We aimed at evaluating whether circRNAs are ideal postmortem diagnostic markers for AMI. We employed bioinformatics methods to screen for target circRNAs. Divergent and convergent primers were used to confirm the loop structure. Ribonuclease R (RNaseR) digestion and artificial simulated room temperature test were performed to evaluate the stability of circRNAs. Furthermore, RT-PCR analysis was performed to assess the expressions of target circRNAs in a mouse model of AMI and in autopsy cases, while the diagnostic significance of circRNAs was evaluated by the receiver-operator characteristic (ROC) curve. The bioinformatics analysis screened out circSMARCC1 and circLRBA as target circRNAs. Agarose gel electrophoresis revealed the loop structure of target circRNAs. RNaseR digestion and the artificial simulated room temperature test showed that the stability of circRNAs was good. In mouse AMI model, circSMARCC1 levels were elevated while circLRBA levels were suppressed. Finally, in forensic autopsy cases, circSMARCC1 levels were significantly elevated, while circLRBA levels were significantly suppressed in the MI and early-MI group, relative to the normal control group. The ROC curve analysis showed that both circSMARCC1 and circLRBA can distinguish between AMI and normal control cases. Futher, a combination of the two circRNAs can increase the diagnostic efficacy of AMI. Thus, circSMARCC1 and circLRBA are potential biomarkers for postmortem diagnosis of AMI.

Negative Regulation of RIG-I by Tim-3 Promotes H1N1 Infection.

The mechanisms by which retinoic acid-inducible gene I (RIG-I), a critical RNA virus sensor, is regulated in many biological and pathological processes remain to be determined. Here, we demonstrate that T cell immunoglobulin and mucin protein-3 (Tim-3), an immune checkpoint inhibitor, mediates infection tolerance by suppressing RIG-I-type I interferon pathway. Overexpression or blockade of Tim-3 affects type I interferon expression, virus replication, and tissue damage in mice following H1N1 infection. Tim-3 signaling decreases RIG-I transcription via STAT1 in macrophages and promotes the proteasomal dependent degradation of RIG-I by enhancing K-48-linked ubiquitination via the E3 ligase RNF-122. Silencing RIG-I reversed Tim-3 blockage-mediated upregulation of type I interferon in macrophages. We thus identified a new mechanism through which Tim-3 mediates the immune evasion of H1N1, which may have clinical implications for the treatment of viral diseases.

Excitatory Effects of Astrocytic Hydrogen Sulfide on the Electrical Activity of Oxytocin Neurons in the Supraoptic Nucleus.

INTRODUCTION: In the regulation of oxytocin (OT) neuronal activity, hydrogen sulfide (H2S), a gaseous neurotransmitter, likely exerts an excitatory role. This role is associated with increased expression of astrocytic cystathionine-ß-synthase (CBS), the key enzyme for H2S synthesis. However, it remains unclear whether H2S is mainly produced in astrocytes and contributes to the autoregulation of OT neurons. METHODS: In hypothalamic slices of male rats, OT and H2S-associated drug effects were observed on the firing activity and spontaneous excitatory postsynaptic currents (sEPSCs) of putative OT neurons in the supraoptic nucleus (SON) in whole-cell patch-clamp recording. Expression of glial fibrillary acidic protein (GFAP) in the SON was analyzed in Western blots. In addition, changes in the length of rat pups' hypothalamic astrocytic processes were observed in primary cultures. RESULTS: In brain slices, OT significantly increased the firing rate of OT neurons, which was simulated by CBS allosteric agonist S-adenosyl-L-methionine (SAM) and H2S slow-releasing donor GYY4137 but blocked by CBS inhibitor aminooxyacetic acid (AOAA). L-α-aminoadipic acid (a gliotoxin) blocked SAM-evoked excitation. OT and SAM also increased the frequency and amplitude of sEPSCs; the effect of OT was blocked by AOAA. Both OT and GYY4137 reduced GFAP expression in the SON. Morphologically, OT or GYY4137 time-dependently reduced the length of astrocytic processes in primary cultures. CONCLUSIONS: These findings indicate that the auto-excitatory effect of OT on OT neurons is mediated by H2S from astrocytes at least partially and astrocytic H2S can elicit retraction of astrocytic processes that subsequently increase OT neuronal excitability.

Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses.

Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-α. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity.

RACK1 T50 Phosphorylation by AMPK Potentiates Its Binding with IRF3/7 and Inhibition of Type 1 IFN Production.

The receptor for activated C kinase 1 (RACK1) adaptor protein has been implicated in viral infection. However, whether RACK1 promotes in vivo viral infection in mammals remains unknown. Moreover, it remains elusive how RACK1 is engaged in antiviral innate immune signaling. In this study, we report that myeloid RACK1 deficiency does not affect the development and survival of myeloid cells under resting conditions but renders mice less susceptible to viral infection. RACK1-deficient macrophages produce more IFN-α and IFN-ß in response to both RNA and DNA virus infection. In line with this, RACK1 suppresses transcriptional activation of type 1 IFN gene promoters in response to virus infection. Analysis of virus-mediated signaling indicates that RACK1 inhibits the phosphorylation of IRF3/7. Indeed, RACK1 interacts with IRF3/7, which is enhanced after virus infection. Further exploration indicates that virus infection triggers AMPK activation, which in turn phosphorylates RACK1 at Thr50 RACK1 phosphorylation at Thr50 enhances its interaction with IRF3/7 and thereby limits IRF3/7 phosphorylation. Thus, our results confirm that myeloid RACK1 promotes in vivo viral infection and provide insight into the control of type 1 IFN production in response to virus infection.

Oxytocin Modulation of Maternal Behavior and Its Association With Immunological Activity in Rats With Cesarean Delivery.

Oxytocin (OT), a neuropeptide produced in the supraoptic (SON) and paraventricular (PVN) nuclei, is not only essential for lactation and maternal behavior but also for normal immunological activity. However, mechanisms underlying OT regulation of maternal behavior and its association with immunity around parturition, particularly under mental and physical stress, remain unclear. Here, we observed effects of OT on maternal behavior in association with immunological activity in rats after cesarean delivery (CD), a model of reproductive stress. CD significantly reduced maternal interests to the pups throughout postpartum day 1-8. On postpartum day 5, CD decreased plasma OT levels and thymic index but increased vasopressin, interleukin (IL)-1ß, IL-6 and IL-10 levels. CD had no significant effect on plasma adrenocorticotropic hormone and corticosterone levels. In the hypothalamus, CD decreased corticotropin-releasing hormone contents in the PVN but increased OT contents in the PVN and SON and OT release from hypothalamic implants. CD also increased c-Fos expression, particularly in the cytoplasm of OT neurons. Lastly, CD depolarized resting membrane potential and increased spike width while increasing the variability of the firing rate of OT neurons in brain slices. Thus, CD can increase hypothalamic OT contents and release but reduce pituitary release of OT into the blood, which is associated with depressive-like maternal behavior, increased inflammatory cytokine release and decreased relative weight of the thymus.

Intranasal Oxytocin Restores Maternal Behavior and Oxytocin Neuronal Activity in the Supraoptic Nucleus in Rat Dams with Cesarean Delivery.

Oxytocin (OT) is a key factor for maternal behavior. However, neurochemical regulation of OT neurons, the major source of OT, remains incompletely understood. Here we report the effect of intranasally-applied OT (IAO) on OT neuronal activity in the supraoptic nucleus (SON) and on maternal behavior in a rat model of cesarean delivery (CD) at day 4-5 (stage I) and day 8-9 (stage II) following delivery. We found that at stage I, CD dams exhibited significantly longer latency of pup retrieval, lower number of anogenital licks and smaller acinar area of the mammary glands. In the SON, the number of OT neurons expressing phosphorylated extracellular signal-regulated protein kinase 1/2 (pERK 1/2) decreased significantly. IAO reversed the depressive-like maternal behavior and involution-like change in the mammary glands, and restored the number of pERK1/2-positive OT neurons in CD dams. At stage II, CD did not significantly influence the latency of retrieval and pERK1/2 expression in the SON. However, CD still reduced the number of anogenital licks during suckling, which was reversed by IAO. Notably, IAO but not hypodermic OT application in CD dams significantly increased litter's body weight gains. In brain slices, CD but not CD plus IAO significantly depolarized membrane potential and increased spike duration in OT neurons. In vasopressin neurons, CD, but not CD plus IAO, significantly depolarized membrane potential and increased the firing rate. Thus, decreased OT neuronal activity and increased vasopressin neuronal activity impair maternal behavior in CD dams, which can be prevented by IAO .

Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity.

Nuclear factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering stress granule (SG) formation. However, the regulation of the NF90-SG pathway remains largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SG-mediated antiviral immunity. Vesicular stomatitis virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages, which in turn recruit the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiate a proteasome-dependent degradation via K48-linked ubiquitination at Lys297. Targeted inactivation of Tim-3 enhances the NF90 downstream SG formation by selectively increasing the phosphorylation of protein kinase R and eukaryotic translation initiation factor 2α, the expression of SG markers G3BP1 and TIA-1, and protecting mice from VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.

Peripheral Injection of Tim-3 Antibody Attenuates VSV Encephalitis by Enhancing MHC-I Presentation.

Viral encephalitis is the most common cause of encephalitis. It is responsible for high morbidity rates, permanent neurological sequelae, and even high mortality rates. The host immune response plays a critical role in preventing or clearing invading pathogens, especially when effective antiviral treatment is lacking. However, due to blockade of the blood-brain barrier, it remains unclear how peripheral immune cells contribute to the fight against intracerebral viruses. Here, we report that peripheral injection of an antibody against human Tim-3, an immune checkpoint inhibitor widely expressed on immune cells, markedly attenuated vesicular stomatitis virus (VSV) encephalitis, marked by decreased mortality and improved neuroethology in mice. Peripheral injection of Tim-3 antibody enhanced the recruitment of immune cells to the brain, increased the expression of major histocompatibility complex-I (MHC-I) on macrophages, and as a result, promoted the activation of VSV-specific CD8+ T cells. Depletion of macrophages abolished the peripheral injection-mediated protection against VSV encephalitis. Notably, for the first time, we found a novel post-translational modification of MHC-I by Tim-3, wherein, by enhancing the expression of MARCH9, Tim-3 promoted the proteasome-dependent degradation of MHC-I via K48-linked ubiquitination in macrophages. These results provide insights into the immune response against intracranial infections; thus, manipulating the peripheral immune cells with Tim-3 antibody to fight viruses in the brain may have potential applications for combating viral encephalitis.

Tim-3 Relieves Experimental Autoimmune Encephalomyelitis by Suppressing MHC-II.

Tim-3, an immune checkpoint inhibitor, is widely expressed on the immune cells and contributes to immune tolerance. However, the mechanisms by which Tim-3 induces immune tolerance remain to be determined. Major histocompatibility complex II (MHC-II) plays a key role in antigen presentation and CD4+T cell activation. Dysregulated expressions of Tim-3 and MHC-II are associated with the pathogenesis of many autoimmune diseases including multiple sclerosis. Here we demonstrated that, by suppressing MHC-II expression in macrophages via the STAT1/CIITA pathway, Tim-3 inhibits MHC-II-mediated autoantigen presentation and CD4+T cell activation. As a result, overexpression or blockade of Tim-3 signaling in mice with experimental autoimmune encephalomyelitis (EAE) inhibited or increased MHC-II expression respectively and finally altered clinical outcomes. We thus identified a new mechanism by which Tim-3 induces immune tolerance in vivo and regulating the Tim-3-MHC-II signaling pathway is expected to provide a new solution for multiple sclerosis treatment.

The E3 ubiquitin ligase Itch deficiency promotes antigen-driven B-cell responses in mice.

Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B-cell-specific Itch deficiency promoted antigen-induced B-cell activation and antibody-expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19cre Itchf/f ) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)-like SP 2/0 cells, Itch deficiency promoted B-cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen-induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen-driven B-cell response. This may provide hints for Itch-targeted treatment of patients with autoimmune disease.

T cell immunoglobulin and mucin domain protein 3 inhibits glycolysis in RAW 264.7 macrophages through Hexokinase 2.

T cell immunoglobulin and mucin domain-3 (Tim-3), an immune checkpoint molecule, plays critical roles in maintaining innate immune homeostasis; however, the mechanisms underlying these roles remain to be determined. Here, we determined that Tim-3 controls glycolysis in macrophages and thus contributes to phenotype shifting. Tim-3 signal blockade significantly increases lactate production by macrophages, but does not influence cell proliferation or apoptosis. Tim-3 attenuates glucose uptake by inhibiting hexokinase 2 (HK2) expression in macrophages. Tim-3-mediated inhibition of macrophage glycolysis and the expression of proinflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß are reversed by HK2 silencing. Finally, we demonstrated that Tim-3 inhibits HK2 expression via the STAT1 pathway. We have thus discovered a new way by which Tim-3 modulates macrophage function.

Use and Cost-Effectiveness of a Telehealth Service at a Centralized COVID-19 Quarantine Center in Taiwan: Cohort Study.

BACKGROUND: Telehealth is a recommended method for monitoring the progression of nonsevere infections in patients with COVID-19. However, telehealth has not been widely implemented to monitor SARS-CoV-2 infection in quarantined individuals. Moreover, studies on the cost-effectiveness of quarantine measures during the COVID-19 pandemic are scarce. OBJECTIVE: In this cohort study, we aimed to use telehealth to monitor COVID-19 infections in 217 quarantined Taiwanese travelers and to analyze the cost-effectiveness of the quarantine program. METHODS: Travelers were quarantined for 14 days at the Taiwan Yangmingshan quarantine center and monitored until they were discharged. The travelers' clinical symptoms were evaluated twice daily. A multidisciplinary medical team used the telehealth system to provide timely assistance for ill travelers. The cost of the mandatory quarantine was calculated according to data from the Ministry of Health and Welfare of Taiwan. RESULTS: All 217 quarantined travelers tested negative for SARS-CoV-2 upon admission to the quarantine center. During the quarantine, 28/217 travelers (12.9%) became ill and were evaluated via telehealth. Three travelers with fever were hospitalized after telehealth assessment, and subsequent tests for COVID-19 were negative for all three patients. The total cost incurred during the quarantine was US $193,938, which equated to US $894 per individual. CONCLUSIONS: Telehealth is an effective instrument for monitoring COVID-19 infection in quarantined travelers and could help provide timely disease management for people who are ill. It is imperative to screen and quarantine international travelers for SARS-CoV-2 infection to reduce the nationwide spread of COVID-19.

Hspa13 Promotes Plasma Cell Production and Antibody Secretion.

The generation of large numbers of plasma cells (PCs) is a main factor in systemic lupus erythematosus (SLE). We hypothesize that Hspa13, a member of the heat shock protein family, plays a critical role in the control of PC differentiation. To test the hypothesis, we used lipopolysaccharide (LPS)-activated B cells and a newly established mouse line with a CD19cre-mediated, B cell-specific deletion of Hspa13: Hspa13 cKO mice. We found that Hspa13 mRNA was increased in PCs from atacicept-treated lupus-prone mice and in LPS-stimulated plasmablasts (PBs) and PCs. A critical finding was that PBs and PCs [but not naïve B cells and germinal center (GC) B cells] expressed high levels of Hspa13. In contrast, the Hspa13 cKO mice had a reduction in BPs, PCs, and antibodies induced in vitro by LPS and in vivo by sheep red blood cells (SRCs)- or 4-hydroxy-3-nitrophenylacetyl (NP)-immunization. Accordingly, the Hspa13 cKO mice had reduced class-switched and somatically hypermutated antibodies with defective affinity maturation. Our work also showed that Hspa13 interacts with proteins (e.g., Bcap31) in the endoplasmic reticulum (ER) to positively regulate protein transport from the ER to the cytosol. Importantly, Hspa13 mRNA was increased in B220+ cells from patients with multiple myeloma (MM) or SLE, whereas Hspa13 cKO led to reduced autoantibodies and proteinuria in both pristane-induced lupus and lupus-prone MRL/lpr mouse models. Collectively, our data suggest that Hspa13 is critical for PC development and may be a new target for eliminating pathologic PCs.

Tim-3 Promotes Listeria monocytogenes Immune Evasion by Suppressing Major Histocompatibility Complex Class I.

BACKGROUND: T-cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint inhibitor that has therapeutic implications for many tumors and infectious diseases. However, the mechanisms by which Tim-3 promotes immune evasion remain unclear. METHODS: In this study, we demonstrated that Tim-3 inhibits the expression of major histocompatibility complex class I (MHC-I) in macrophages at both the messenger ribonucleic acid and protein levels by inhibiting the STAT1-NLRC5 signaling pathway. RESULTS: As a result, MHC-I-restricted antigen presentation by macrophages was inhibited by Tim-3 both in vitro and in a Listeria monocytogenes infection model in vivo. Systemic overexpression of Tim-3 or specific knockout of Tim-3 in macrophages significantly attenuated or enhanced CD8+ T-cell activation and infection damage in L monocytogenes-infected mice, respectively. CONCLUSIONS: Thus, we identified a new mechanism by which Tim-3 promotes L monocytogenes immune evasion. Further studies on this pathway might shed new light on the physio-pathological roles of Tim-3 and suggest new approaches for intervention.