Rapid development of double-hit mRNA antibody cocktail against orthopoxviruses.

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses.

Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: A randomized double-blind trial and TMS-EEG study.

It has been 15 years since repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) was approved by the FDA for clinical depression treatment. Yet, the underlying mechanisms for rTMS-induced depression relief are not fully elucidated. This study analyzes TMS-electroencephalogram (EEG) data from 64 healthy control (HC) subjects and 53 patients with major depressive disorder (MDD) before and after rTMS treatment. Prior to treatment, patients with MDD have lower activity in the DLPFC, the hippocampus (HPC), the orbitofrontal cortex (OFC), and DLPFC-OFC connectivity compared with HCs. Following active rTMS treatment, patients with MDD show a significant increase in the DLPFC, HPC, and OFC. Notably, the increase in HPC activity is specifically associated with amelioration of depressive symptoms but not anxiety or sleep quality. The orbitofrontal-hippocampal pathway plays a crucial role in mediating depression relief following rTMS treatment. These findings suggest potential alternative targets for brain stimulation therapy against depression (chictr.org.cn: ChiCTR2100052007).

Functional near-infrared spectroscopy in elderly patients with four types of dementia.

BACKGROUND: Functional near-infrared spectroscopy (fNIRS) is commonly used to study human brain function by measuring the hemodynamic signals originating from cortical activation and provides a new noninvasive detection method for identifying dementia. AIM: To investigate the fNIRS imaging technique and its clinical application in differential diagnosis of subtype dementias including frontotemporal lobe dementia, Lewy body dementia, Parkinson's disease dementia (PDD) and Alzheimer's disease (AD). METHODS: Four patients with different types of dementia were examined with fNIRS during two tasks and a resting state. We adopted the verbal fluency task, working memory task and resting state task. Each patient was compared on the same task. We conducted and analyzed the fNIRS data using a general linear model and Pearson's correlation analysis. RESULTS: Compared with other types of dementias, fNIRS showed the left frontotemporal and prefrontal lobes to be poorly activated during the verbal fluency task in frontotemporal dementia. In Lewy body dementia, severe asymmetry of prefrontal lobes appeared during both verbal fluency and working memory tasks, and the patient had low functional connectivity during a resting state. In PDD, the patient's prefrontal cortex showed lower excitability than the temporal lobe during the verbal fluency task, while the prefrontal cortex showed higher excitability during the working memory task. The patient with AD showed poor prefrontal and temporal activation during the working memory task, and more activation of frontopolar instead of the dorsolateral prefrontal cortex. CONCLUSION: Different hemodynamic characteristics of four types of dementia (as seen by fNIRS imaging) provides evidence that fNIRS can serve as a potential tool for the diagnosis between dementia subtypes.

The effects of childhood maltreatment on adolescent non-suicidal self-injury behavior: mediating role of impulsivity.

Background: Non-suicidal self-injury (NSSI) severely challenges mental health in adolescents. Childhood maltreatment experience acts as high-risk factor for adolescents to engage in NSSI behaviors. On the other hand, impulsivity or loss of control sets the threshold for NSSI execution. Here we examined the effects of childhood maltreatment on adolescent NSSI-related clinical outcomes and the potential role of impulsivity. Methods: We assessed the clinical data of 160 hospitalized NSSI adolescents and recruited 64 age-matched healthy subjects as a control group. The clinical symptoms of NSSI are expressed by the NSSI frequency, depression, and anxiety measured by the Ottawa Self-Injury Inventory, the Beck Depression Inventory, and the Beck Anxiety Inventory. Childhood maltreatment and impulsivity were assessed with Childhood Trauma Questionnaire and Barratt Impulsiveness Scale. Results: The results showed that when compared to HC group, NSSI group is more likely to experience childhood maltreatment. Notably, NSSI group with Childhood maltreatment accompanies higher trait impulsivity and exacerbated clinical outcomes, such as NSSI frequency, depression and anxiety symptoms. Mediation analyses indicated that the association between childhood maltreatment and NSSI-related clinical outcomes was partially explained by impulsivity. Conclusion: We found that NSSI adolescents have a higher proportion of childhood maltreatment. Impulsivity plays a mediating role between childhood maltreatment and NSSI behaviors.

Inhalable vaccine of bacterial culture supernatant extract mediates protection against fatal pulmonary anthrax.

Pulmonary anthrax is the most fatal clinical form of anthrax and currently available injectable vaccines do not provide adequate protection against it. Hence, next-generation vaccines that effectively induce immunity against pulmonary anthrax are urgently needed. In the present study, we prepared an attenuated and low protease activity Bacillus anthracis strain A16R-5.1 by deleting five of its extracellular protease activity-associated genes and its lef gene through the CRISPR-Cas9 genome editing system. This mutant strain was then used to formulate a lethal toxin (LeTx)-free culture supernatant extract (CSE) anthrax vaccine, of which half was protective antigen (PA). We generated liquid, powder, and powder reconstituted formulations that could be delivered by aerosolized intratracheal inoculation. All of them induced strong humoral, cellular, and mucosal immune responses. The vaccines also produced LeTx neutralizing antibodies and conferred full protection against the lethal aerosol challenges of B. anthracis Pasteur II spores in mice. Compared to the recombinant PA vaccine, the CSE anthrax vaccine with equal PA content provided superior immunoprotection against pulmonary anthrax. The preceding results suggest that the CSE anthrax vaccine developed herein is suitable and scalable for use in inhalational immunization against pulmonary anthrax.

H-NS Represses Biofilm Formation and c-di-GMP Synthesis in Vibrio parahaemolyticus.

Objective: This study aimed to investigate the regulation of histone-like nucleoid structuring protein (H-NS) on biofilm formation and cyclic diguanylate (c-di-GMP) synthesis in Vibrio parahaemolyticus RIMD2210633. Methods: Regulatory mechanisms were analyzed by the combined utilization of crystal violet staining, quantification of c-di-GMP, quantitative real-time polymerase chain reaction, LacZ fusion, and electrophoretic-mobility shift assay. Results: The deletion of hns enhanced the biofilm formation and intracellular c-di-GMP levels in V. parahaemolyticus RIMD2210633. H-NS can bind the upstream promoter-proximal DNA regions of scrA, scrG, VP0117, VPA0198, VPA1176, VP0699, and VP2979 to repress their transcription. These genes encode a group of proteins with GGDEF and/or EAL domains associated with c-di-GMP metabolism. Conclusion: One of the mechanisms by which H-NS represses the biofilm formation by V. parahaemolyticus RIMD2210633 may be via repression of the production of intracellular c-di-GMP.

Aerosolized Zika virus infection in Guinea pigs.

Zika virus (ZIKV) is primarily transmitted through mosquito bites and sexual contact, and vertical transmission of ZIKV has also been observed in humans. In addition, ZIKV infection via unknown transmission routes has been frequently reported in clinical settings. However, whether ZIKV can be transmitted via aerosol routes remains unknown. In this study, we demonstrated that aerosolized ZIKV is fully infectious in vitro and in vivo. Remarkably, intratracheal (i.t.) inoculation with aerosolized ZIKV led to rapid viremia and viral secretion in saliva, as well as robust humoral and innate immune responses in guinea pigs. Transcriptome analysis further revealed that the expression of genes related to viral processes, biological regulation and the immune response was significantly changed. Together, our results confirm that aerosolized ZIKV can result in systemic infection and induce both innate and adaptive immune responses in guinea pigs, highlighting the possibility of ZIKV transmission via aerosols.

Advances in neuroimaging studies of alcohol use disorder (AUD).

Alcohol use disorder (AUD) is a worldwide problem and the most common substance use disorder. Chronic alcohol consumption may have negative effects on the body, the mind, the family, and even society. With the progress of current neuroimaging methods, an increasing number of imaging techniques are being used to objectively detect brain impairment induced by alcoholism and serve a vital role in the diagnosis, prognosis, and treatment assessment of AUD. This article organizes and analyzes the research on alcohol dependence concerning the main noninvasive neuroimaging methods, structural magnetic resonance imaging, functional magnetic resonance imaging, and electroencephalography, as well as the most common noninvasive brain stimulation - transcranial magnetic stimulation, and intersperses the article with joint intra- and intergroup studies, providing an outlook on future research directions.

Salvage of vascular graft infections via vacuum sealing drainage and rectus femoris muscle flap transposition: A case report.

BACKGROUND: The management of vascular graft infections continues to be a significant challenge in a clinical situation. The aim of this report is to illustrate the novel vacuum sealing drainage (VSD) technique and rectus femoris muscle flap transposition for vascular graft infections, and to evaluate the prospective of future testing of this surgical procedure. CASE SUMMARY: We report the case of a 32-year-old male patient, who presented a severe infected groin wound with biological vascular graft Acinetobacter baumannii infection resulting in extensive graft exposure. Using the VSD and muscle flap trans-position, the groin wound and vascular graft infection were finally treated successfully. CONCLUSION: Our case report highlights that VSD technique and rectus femoris muscle flap transposition could be considered in patients presenting with a severe infected groin wound with biological vascular graft Acinetobacter baumannii infection resulting in extensive graft exposure, especially in consideration of treatable conditions.

Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Habituation to a Deterrent Plant Alkaloid Develops Faster in the Specialist Herbivore Helicoverpa assulta Than in Its Generalist Congener Helicoverpa armigera and Coincides with Taste Neuron Desensitisation.

The two closely related moth species, Helicoverpa armigera and H. assulta differ strongly in their degree of host-plant specialism. In dual-choice leaf disk assays, caterpillars of the two species that had been reared on standard artificial diet were strongly deterred by the plant-derived alkaloid strychnine. However, caterpillars of both species reared on artificial diet containing strychnine from neonate to the 5th instar were insensitive to this compound. Fifth instar caterpillars of H. assulta and 4th or 5th instars of H. armigera not exposed to strychnine before were subjected to strychnine-containing diet for 24 h, 36 h, 48 h, or 72 h. Whereas H. assulta displayed habituation to strychnine after 48 h, it took until 72 h for H. armigera to become habituated. Electrophysiological tests revealed that a deterrent-sensitive neuron in the medial sensillum styloconicum of both species displayed significantly reduced sensitivity to strychnine that correlated with the onset of habituation. We conclude that the specialist H. assulta habituated faster to strychnine than the generalist H. armigera and hypothesis that desensitization of deterrent-sensitive neurons contributed to habituation.

Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder.

Genetic analyses for bipolar disorder (BD) have achieved prominent success in Europeans in recent years, whereas its genetic basis in other populations remains relatively less understood. We herein report that the leading risk locus for BD in European genome-wide association studies (GWAS), the single-nucleotide polymorphism (SNP) rs9834970 near TRANK1 at 3p22 region, is also genome-wide significantly associated with BD in a meta-analysis of four independent East Asian samples including 5748 cases and 65,361 controls (p = 2.27 × 10-8, odds ratio = 1.136). Expression quantitative trait loci (eQTL) analyses and summary data-based Mendelian randomization (SMR) analyses in multiple human brain samples suggest that lower TRANK1 mRNA expression is a principal BD risk factor explaining its genetic risk signals at 3p22. We also identified another SNP rs4789 in the 3' untranslated region (3'UTR) of TRANK1 showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function of TRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated with TRANK1 are significantly enriched in the biological processes related to dendritic spine, synaptic plasticity, axon guidance and circadian entrainment, and are also more likely to exhibit strong associations in psychiatric GWAS (e.g., the CACNA1C gene). Overall, our results support that TRANK1 is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.

Sinus tarsi approach versus the extended lateral approach for displaced intra-articular calcaneal fractures: a systematic review and meta-analysis.

BACKGROUND: The goal of this study was to review eligible randomized controlled trials to determine the efficacy of the sinus tarsi approach (STA) versus the extended lateral approach (ELA) for the treatment of displaced intra-articular calcaneal fractures (DIACF). METHODS: Using appropriate keywords, we identified relevant studies using PubMed, the Cochrane Library, Embase, CNKI, VANFUN, and VIP. Key pertinent sources in the literature were also reviewed, and all articles published through June 2020 were considered for inclusion. For each study, we assessed odds ratios (ORs), mean difference (MD), and 95% confidence interval (95% CI) to assess and synthesize the outcomes. RESULTS: We included 15 RCTs, with a total of 847 patients in the STA group and 959 in the ELA group. The results found that after STA and ELA, no significant difference in changes of Böhler's angle (WMD: 0.746, 95% CI: - 0.316-1.809), Gissane angle (WMD: - 0.710, 95% CI: - 2.157-0.737), calcaneal heights (WMD: 0.378, 95% CI: - 1.973-2.728), calcaneal widths (SMD: - 0.431, 95% CI: - 1.604- 0.742), calcaneal lengths (WMD: 0.691, 95% CI: - 0.749-2.131). Besides, there was no significant difference in the incidence of complications between the STA group and the ELA group (RR: 0.592, 95% CI: 0.336-1.045). CONCLUSION: There was no difference in clinical efficacy between STA and ELA in treating DIACF. Besides, there is still a need of large-sample, high-quality, long-term randomized controlled trials to confirm the conclusion. LEVEL OF EVIDENCE: Level I-High-Quality Prospective Randomized Study.

Novel Risk Loci Associated With Genetic Risk for Bipolar Disorder Among Han Chinese Individuals: A Genome-Wide Association Study and Meta-analysis.

Importance: The genetic basis of bipolar disorder (BD) in Han Chinese individuals is not fully understood. Objective: To explore the genetic basis of BD in the Han Chinese population. Design, Setting, and Participants: A genome-wide association study (GWAS), followed by independent replication, was conducted to identify BD risk loci in Han Chinese individuals. Individuals with BD were diagnosed based on DSM-IV criteria and had no history of schizophrenia, mental retardation, or substance dependence; individuals without any personal or family history of mental illnesses, including BD, were included as control participants. In total, discovery samples from 1822 patients and 4650 control participants passed quality control for the GWAS analysis. Replication analyses of samples from 958 patients and 2050 control participants were conducted. Summary statistics from the European Psychiatric Genomics Consortium 2 (PGC2) BD GWAS (20 352 cases and 31 358 controls) were used for the trans-ancestry genetic correlation analysis, polygenetic risk score analysis, and meta-analysis to compare BD genetic risk between Han Chinese and European individuals. The study was performed in February 2020. Main Outcomes and Measures: Single-nucleotide variations with P < 5.00 × 10-8 were considered to show genome-wide significance of statistical association. Results: The Han Chinese discovery GWAS sample included 1822 cases (mean [SD] age, 35.43 [14.12] years; 838 [46%] male) and 4650 controls (mean [SD] age, 27.48 [5.97] years; 2465 [53%] male), and the replication sample included 958 cases (mean [SD] age, 37.82 [15.54] years; 412 [43%] male) and 2050 controls (mean [SD] age, 27.50 [6.00] years; 1189 [58%] male). A novel BD risk locus in Han Chinese individuals was found near the gene encoding transmembrane protein 108 (TMEM108, rs9863544; P = 2.49 × 10-8; odds ratio [OR], 0.650; 95% CI, 0.559-0.756), which is required for dendritic spine development and glutamatergic transmission in the dentate gyrus. Trans-ancestry genetic correlation estimation (ρge = 0.652, SE = 0.106; P = 7.30 × 10-10) and polygenetic risk score analyses (maximum liability-scaled Nagelkerke pseudo R2 = 1.27%; P = 1.30 × 10-19) showed evidence of shared BD genetic risk between Han Chinese and European populations, and meta-analysis identified 2 new GWAS risk loci near VRK2 (rs41335055; P = 4.98 × 10-9; OR, 0.849; 95% CI, 0.804-0.897) and RHEBL1 (rs7969091; P = 3.12 × 10-8; OR, 0.932; 95% CI, 0.909-0.956). Conclusions and Relevance: This GWAS study identified several loci and genes involved in the heritable risk of BD, providing insights into its genetic architecture and biological basis.

Treatment of Chronic Anterior Shoulder Dislocation by Coracoid Osteotomy with or without Bristow-Latarjet Procedure.

OBJECTIVE: To investigate the clinical efficacy and outcomes of the coracoid osteotomy with or without Bristow-Latarjet procedures in the treatment of chronic anterior shoulder dislocation (CASD). METHODS: Between January 2013 and January 2019, 20 shoulders of 18 patients who were diagnosed with chronic anterior dislocation and underwent open reduction in our trauma center were retrospectively studied. Open coracoid osteotomy with Bristow-Latarjet procedures were performed on 16 shoulders and open coracoid osteotomy without Bristow-Latarjet procedures were performed on four shoulders. Open coracoid osteotomy with or without Bristow-Latarjet procedures were chosen on the basis of the stability of the shoulder after reduction. Outcomes were assessed preoperatively and postoperatively with the visual analog scale (VAS) for pain, the American Shoulder and Elbow Surgeons (ASES) score, the University of California Los Angeles (UCLA) shoulder rating scale, and the range of motion (ROM) for shoulder activity. RESULTS: There were three males and 15 females with an average age of 60.94 ± 2.69 years. The time between dislocation and treatment ranged from 21 to 240 days with an average of 73.3 ± 14.4 days. All patients were available for a mean follow-up of 15.2 ± 4.3 months. No procedure-related death or incision-related superficial or deep tissue infection was identified in all cases. No iatrogenic neurovascular injuries or fractures were found in this study. At the time of 12 months follow-up, the range of motion and the shoulder functional evaluation (VAS [P < 0.001], ASES [P < 0.001], and UCLA score [P < 0.001]) in patients who underwent Bristow-Latarjet procedures were significantly improved. Subluxation after surgical procedure was found and confirmed in one patient and this patient refused to undergo revision surgery. According to the Samilson and Prieto classification system, 16 shoulders were assessed as grade 0, three shoulders were grade 1, one shoulder was grade 2. CONCLUSIONS: Coracoid osteotomy with or without Bristow-Latarjet procedure yielded an acceptable clinical result in this study. This method has the advantages of enlarging the exposure of surgical field, assisting reduction of shoulder, and convenient conversion to Bristow-Latarjet procedure. It is an efficient and reliable method for treatment of chronic anterior shoulder dislocation. A 69-year-old woman diagnosed with right chronic anterior shoulder dislocation with large Hill-Sachs lesion. The latarjet procedure with remplissage technique was applied for this patient.

Surgical Treatment and Rehabilitation for Hoffa Fracture Nonunion: Two Case Reports and a Literature Review.

BACKGROUND: A coronal fracture of the distal femoral condyle, known as a Hoffa fracture, seldom occurs and is easy to misdiagnose. Surgery treatment, including open anatomic reduction and internal fixation, is the primary method of treatment. However, cases involving nonunion are extremely rare. CASE PRESENTATION: We reported two cases in a 56-year-old female who visited our outpatient clinic with complaints of locking sensation, swelling, and pain, and a 64-year-old male patient who need additional care after having undergone surgery for a distal femur fracture. They presented with nonunion ofa Hoffa fracture (Letenneur type II), and these cases of nonunion were resolved surgically with debridement, two cannulated lag screws, a lateral extra-articular buttress plate, and the liberal use of autologous bone grafts. After surgery, the two patients were allowed to bear partial weight and perform exercises. They were allowed to walk with full weight-bearing after 3 months. No early complications, such as infection and loss of reduction, were noted after the revision surgery. At the one-year follow-up, both patients had excellent function and reported minimal pain, with a Lysholm score of 94. CONCLUSIONS: Our case reports highlight the importance of the liberal use of autologous bone grafts, which allow stable reconstruction of the affected femoral condyle, thereby restoring joint congruence. A lateral extra-articular buttress plate in combination with two cannulated lag screws is recommended for nonunion in Hoffa fracture patients, and they need to be closely followed up to detect complications promptly, especially those related to nonunion.

Identification of a functional human-unique 351-bp Alu insertion polymorphism associated with major depressive disorder in the 1p31.1 GWAS risk loci.

Genome-wide association studies (GWAS) have reported substantial single-nucleotide polymorphisms (SNPs) associated with major depressive disorder (MDD), but the underlying functional variations in the GWAS risk loci are unclear. Here we show that the European MDD genome-wide risk-associated allele of rs12129573 at 1p31.1 is associated with MDD in Han Chinese, and this SNP is in strong linkage disequilibrium (LD) with a human-unique Alu insertion polymorphism (rs70959274) in the 5' flanking region of a long non-coding RNA (lncRNA) LINC01360 (Long Intergenic Non-Protein Coding RNA 1360), which is preferably expressed in human testis in the currently available expression datasets. The risk allele at rs12129573 is almost completely linked with the absence of this Alu insertion. The Alu insertion polymorphism (rs70959274) is significantly associated with a lower RNA level of LINC01360 and acts as a transcription silencer likely through modulating the methylation of its internal CpG sites. Luciferase assays confirm that the presence of Alu insertion at rs70959274 suppresses transcriptional activities in human cells, and deletion of the Alu insertion through CRISPR/Cas9-directed genome editing increases RNA expression of LINC01360. Deletion of the Alu insertion in human cells also leads to dysregulation of gene expression, biological processes and pathways relevant to MDD, such as the alterations of mRNA levels of DRD2 and FLOT1, transcription of genes involved in synaptic transmission, neurogenesis, learning or memory, and the PI3K-Akt signaling pathway. In summary, we identify a human-unique DNA repetitive polymorphism in robust LD with the MDD risk-associated SNP at the prominent 1p31.1 GWAS loci, and offer insights into the molecular basis of the illness.