Th1-Th2 and M1-M2 interplay sculpt Aeromonas hydrophila pathogenesis in zebrafish (Danio rerio).

Aeromonas hydrophila is an important aquatic zoonotic pathogen that causes septicemia, necrotizing fasciitis and gastroenteritis in various aquatic and non-aquatic animals. However, the pathogenesis of A. hydrophila is not fully understood. Here, we examined the pathogenicity and histopathology of A. hydrophila in the zebrafish (Danio rerio) model system. We found that the intensity of symptoms and mortality is dose-dependent. Bacterial colonization studies demonstrated that A. hydrophila never cleared out from the fish body but stayed in a state of inactivity till it enters a fresh host. Reinfection studies showed that exposure to A. hydrophila provides immunity against future infection and hence improves fish survival. Gene expression studies revealed the crosstalk between T-helper cell and macrophage responses in fish immune system in response to A. hydrophila and infection memory. Histopathological studies showed that symptoms of tissue damage and inflammation lasted for less duration with less intensity in immunized fish when compared to non-immunized fish. Together, our results suggest that the zebrafish model is a useful system in studying the interplay between A. hydrophila pathogenesis, persistence and immunity.

Proficient exclusion of pesticide using humic acid-modified magnetite nanoparticles from aqueous solution.

Extensive dispersal of the pesticides to shield the different types of vegetation from pests has increased the production but at the same it has resulted in an increase in environmental pollution. Consequently, it is necessary to eliminate these undesired pollutants from the environment. The current investigation offers the synthesis of humic acid-coated magnetite nanoparticles towards effective removal of the most common insecticide, imidacloprid, from aqueous solution using a batch adsorption method. These synthesized nanoparticles were characterized with the help of several analytical and spectroscopic techniques. To acquire the maximum conceivable adsorption, effects of different influencing parameters like pH of the solution, time of contact, concentration of pesticide solution, amount of adsorbent and temperature were also examined. Moreover, the kinetic studies were found to be in good agreement with a pseudo-second-order kinetic model supporting the occurrence of chemisorption phenomenon. Additionally, isotherm modeling proved that the adsorption process was in accordance with the Langmuir model of isotherm. Thermodynamic parameters depicted the endothermic and spontaneous behavior of the adsorption process. Desorption studies were also carried out to examine the reusability of these nano-adsorbents. These verdicts confirmed that the surface modified magnetite nanoparticles may be treated as proficient material for exclusion of imidacloprid from the aqueous solution.

Uncommon Manifestation: Thrombotic Thrombocytopenic Purpura Presenting Solely as Petechial Rash.

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder typically presenting with a classic pentad of symptoms: thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal dysfunction, and fever. This report explores an unusual presentation of TTP in a 47-year-old female with a medical history of hypertension, hyperlipidemia, and chronic TTP, who exhibited only petechial rashes, generalized weakness, and headache. Notably, the petechial rash, a less common manifestation of TTP, became a pivotal clue for the diagnosis, underscoring the necessity for vigilance even when classic symptoms are absent. This case reinforces the imperative of a high suspicion index for TTP, especially in patients with thrombocytopenia and hemolytic anemia, irrespective of other traditional signs. Plasmapheresis remains the treatment cornerstone, removing autoantibodies and replenishing ADAMTS13, as evidenced by the patient's initial response. The administration of rituximab, targeting B cells to mitigate autoantibody production against ADAMTS13, featured prominently in her management, aligning with its recognized role in refractory or relapsing TTP cases. Despite an encouraging response to rituximab, a subsequent decline in platelet count indicated the unpredictable nature of TTP and the necessity for multi-pronged therapeutic strategies. The patient's medical background and persistently low ADAMTS13 levels hinted at a chronic relapsing trajectory associated with increased morbidity and mortality. This necessitates ongoing vigilance and treatment flexibility. Highlighting this atypical TTP presentation, the report calls for immediate, robust intervention, serving as a critical reminder of the heterogeneity of TTP manifestations and the complexities in its management, thereby contributing to broader clinical awareness and improved patient prognoses.

Acute Calcific Tendinitis of the Longus Colli: A Case Report and Review of the Literature.

Acute calcific tendinitis of the longus colli (ACTLC) is a rare, self-resolving condition caused by calcium hydroxyapatite crystal deposition in the longus colli muscle tendons. We present a case of a 46-year-old female with a history of hypertension who presented with right-sided neck pain, worsening abdominal pain, nausea, bloody emesis, and generalized body aches in the context of recent alcohol use. Physical examination revealed neck pain with limited range of motion, induration, and tenderness in the right and posterior neck areas. Laboratory findings showed elevated white cell count, inflammatory markers, and metabolic acidosis with an elevated anion gap and lactic acid level. Computed tomography (CT) of the neck with contrast demonstrated amorphous calcification in the longus colli tendons and retropharyngeal effusion, consistent with the diagnosis of ACTLC. The patient was treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and supportive care, leading to symptom resolution. This case highlights the importance of considering ACTLC in the differential diagnosis of acute neck pain and the role of CT imaging in establishing the diagnosis. Prompt recognition and appropriate management of ACTLC can prevent unnecessary interventions and lead to improved patient outcomes.

Mitochondrial electron transport chain in macrophage reprogramming: Potential role in antibacterial immune response.

Macrophages restrain microbial infection and reinstate tissue homeostasis. The mitochondria govern macrophage metabolism and serve as pivot in innate immunity, thus acting as immunometabolic regulon. Metabolic pathways produce electron flows that end up in mitochondrial electron transport chain (mtETC), made of super-complexes regulating multitude of molecular and biochemical processes. Cell-intrinsic and extrinsic factors influence mtETC structure and function, impacting several aspects of macrophage immunity. These factors provide the macrophages with alternate fuel sources and metabolites, critical to gain functional competence and overcoming pathogenic stress. Mitochondrial reactive oxygen species (mtROS) and oxidative phosphorylation (OXPHOS) generated through the mtETC are important innate immune attributes, which help macrophages in mounting antibacterial responses. Recent studies have demonstrated the role of mtETC in governing mitochondrial dynamics and macrophage polarization (M1/M2). M1 macrophages are important for containing bacterial pathogens and M2 macrophages promote tissue repair and wound healing. Thus, mitochondrial bioenergetics and metabolism are intimately coupled with innate immunity. In this review, we have addressed mtETC function as innate rheostats that regulate macrophage reprogramming and innate immune responses. Advancement in this field encourages further exploration and provides potential novel macrophage-based therapeutic targets to control unsolicited inflammation.

Efficacy of SGLT2 inhibitors for anthracycline-induced cardiotoxicity: a meta-analysis in cancer patients.

Aim: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower anthracycline-induced cardiotoxicity. Methods: PubMed and Google Scholar were searched until September 2023 for studies regarding SGLT2i for treating anthracycline-induced cardiotoxicity. Overall mortality and cardiovascular events were considered. Using a random-effects model, data pooled RR and HR at a 95% confidence interval (CI). Results: 3 cohort studies were identified, analyzing 2817 patients. Results display a significant reduction in overall mortality [RR = 0.52 (0.33-0.82); p = 0.005; I2= 32%], HF hospitalization [RR = 0.20 (0.04-1.02); p = 0.05; I2= 0%] and no significant reduction in HF incidence [RR = 0.50 (0.20-1.16); p = 0.11, I2= 0%]. Conclusion: SGLT2i mitigates mortality and hospitalization due to heart failure, improving cancer patient's chances of survival by undergoing anthracycline treatment.

What is this article about? This article explores the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) as a solution for reducing anthracycline-induced cardiotoxicity. Anthracycline is an established subclass of chemotherapeutic drugs which has been known to cause harm to the heart. The study, conducted a systematic search of PubMed and Google Scholar up until September 2023, assessing the effects of SGLT2i on overall mortality and cardiovascular events in cancer patients, regardless of the presence or absence of diabetes mellitus and the effectiveness of SGLT2i as a cardiotoxic therapy in cancer patients.What were the results? The analysis of studies involving 2817 patients showed findings indicating that giving SGLT2i could lower the chances of anthracycline-induced heart problems in cancer patients undergoing treatment. The findings showed a striking decrease in hospitalization due to heart failure and overall mortality whereas the findings for the effect of SGLT2i on incidence of heart failure were insignificant. The encouraging outcomes offer valuable insights that could help enhance the outlook and chances of survival for individuals with cancer.What do the results of the study mean? These findings indicate that SGLT2i notably reduces the risk of death and cardiovascular issues, like being hospitalized due to heart failure, in cancer patients undergoing anthracycline treatment. This has significant implications for how doctors might treat cancer patients in practice. Including SGLT2i in the treatment plan could improve the survival prospects of these patients, offering a promising advancement in handling anthracycline-induced heart issues with side effects that can be managed.

Cardiovascular outcomes post bariatric surgery in patients with metabolic dysfunction-associated steatotic liver disease - A systematic review and meta-analysis.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is linked with an increased risk of adverse cardiovascular events. Studies have suggested an association between the reduction of incident cardiovascular events in patients with MASLD after bariatric surgery. This systematic review and meta-analysis were performed to assess the influence of bariatric surgery on cardiovascular outcomes in patients with diagnosed MASLD by identifying all available cohort studies and pooling their data. METHODS: PubMed and Google Scholar databases were searched till July 2023 for published studies that assessed the effect of bariatric surgery on cardiovascular outcomes in MASLD patients. Using a random effects model, hazard ratios (HRs) with 95 % confidence intervals (CIs) were pooled. RESULTS: The systematic review identified three cohort studies. The analysis of 240,516 MASLD patients found a significantly reduced incidence of cardiovascular events. (HR 0.51; 95 % CI 0.48 to 0.54, P value <0.00001). CONCLUSION: Bariatric surgery in MASLD patients significantly reduced the incidence of cardiovascular events, suggesting that bariatric surgery is an effective therapeutic tool among MASLD patients compared to non-surgical interventions.

Ultralong Stability of Ti3 C2 Tx -MXene Dispersion Through Synergistic Regulation of Storage Environment and Defect Capping with Tris-HCl Buffering.

Aqueous MXene dispersion suffers from a bottleneck issue of oxidation, leading to its gradual deterioration and ultimately compromised physicochemical characteristics. Herein, Tris-HCl buffer is employed to stabilize the diluted Ti3 C2 Tx -MXene dispersion (0.05 mg mL-1 ) through the synergy of its potent pH-regulation capability and capping effect toward oxidation-susceptible defects/edges. Tris-HCl functionalized Ti3 C2 Tx maintained its original morphology, structure, and favorable dispersity even after 150 days of aging under naturally aerated conditions. The pH-regulation nature of Tris-HCl is elucidated through solution monitoring of Ti3 C2 Tx dispersion, while the adsorption of Tris-HCl onto defects/edges is revealed by spectral analysis and multi-scale simulations. Tris-HCl at the neutral pH can bind to the negatively charged basal plane of Ti3 C2 Tx via + HTris moiety, while the other moiety (Tris) interacts with the exposed edge-based Ti atoms and/or intrinsic defects, forming a Ti─N bond that prevents MXene from attack by H2 O and O2 . Besides, Tris-HCl stabilized Ti3 C2 Tx exhibited nearly identical capacitive characteristics to its freshly-etched counterpart, indicating the minimal impact of Tris-HCl on electrochemical performance of Ti3 C2 Tx during long-term storage. This study provides practical guidance for stabilizing MXene in their native aqueous dispersion without compromising the inherent properties.

Long-term clinical outcomes of intravascular imaging-guided percutaneous coronary intervention versus angiography-guided percutaneous coronary intervention in complex coronary lesions: a systematic review and meta-analysis.

Background: In this study, we aim to discuss the long-term clinical outcomes of intravascular ultrasound imaging-guided percutaneous intervention (IVUS-PCI) versus angiography-guided percutaneous coronary intervention (PCI) in complex coronary lesions over a mean period of 2 years. Methods: A systematic search and meta-analysis were conducted to assess the efficacy of using intravascular ultrasound or optical coherence tomography guidance in coronary artery stenting compared to angiography. Results: A total of 11 randomized controlled trials with 6740 patients were included. For the primary outcome, a pooled analysis (3.2 vs 5.6%). For secondary outcomes, the risk was significantly low in image-guided percutaneous intervention compared with angiography. Conclusion: Intravascular imaging-guided PCI is significantly more effective than angiography-guided PCI in reducing the risk of target lesion revascularization, target vessel revascularization, cardiac death, major adverse cardiovascular events and stent thrombosis.

A meta-analysis was conducted to compare intravascular ultrasound guidance/optical coherence tomography percutaneous coronary intervention with angiography percutaneous coronary intervention with target lesion revascularization as the primary outcome and target vessel revascularization, stent thrombosis, myocardial infarction, major adverse cardiovascular events, all cause death and cardiac death as the secondary outcomes.

Safety of procedural sedation in emergency department settings among the adult population: a systematic review and meta-analysis of randomized controlled trials.

Procedural sedation and analgesia (PSA) are a common practice in emergency departments (EDs), aiming to alleviate pain, anxiety, and discomfort during various medical procedures. We have undertaken a systematic review and meta-analysis with the aim of assessing the incidence of adverse events associated with PSA, including those related to individual drugs and various drug combinations. The study adhered to PRISMA guidelines for a systematic review and meta-analysis of adverse events in ED sedation. A comprehensive search strategy was employed across ten databases, supplemented by searches on clinicaltrials.gov and manual reviews of reference lists. Data extraction focused on medication administration and adverse events. The study considered four types of adverse events: cardiac, respiratory, gastrointestinal, and neurological. Only randomized controlled trials (RCTs) focusing on PSA administered to adult patients within the ED setting were included. The statistical analysis employed OpenMeta Analyst to conduct a one-arm meta-analysis, with findings presented alongside their corresponding 95% Confidence Intervals. Forest plots were constructed to combine and evaluate results, and sensitivity analyses were performed to identify sources of heterogeneity. From a literature search of 4246 records, 32 RCTs were deemed suitable for this meta-analysis. The analysis included 6377 procedural sedations. The most common adverse event was hypoxia, with an incidence rate of 78.5 per 1000 sedations (95% CI = 77.5-133.5). This was followed by apnea and hypotension, with incidence rates of 31 (95% CI = 19.5-41.8) and 28.1 (95% CI = 17.4-38.9) per 1,000 sedations, respectively. Agitation and vomiting each occurred in 15.6 per 1,000 sedations (95% CI = 8.7-22.6). Severe adverse events were rare, with bradycardia observed in 16.7 per 1,000 sedations, laryngospasm in 2.9 per 1,000 sedations (95% CI = - 0.1 to 6), intubation in 10.8 per 1,000 sedations (95% CI = 4-17), and aspiration in 2.7 per 1,000 sedations (95% CI = - 0.3 to 5.7). Ketamine is found to be the safest option in terms of respiratory adverse events, with the lowest rates of apnea and hypoxia, making it the least respiratory depressant among the evaluated drugs. Etomidate has the least occurrence of hypotension when used alone. Propofol has the highest incidence of hypotension when used alone and ranks second in hypoxia-related adverse events after midazolam. Using combinations of sedating agents, such as propofol and ketamine, has been found to offer several advantages over single drugs, especially in reducing adverse events like vomiting, intubation difficulty, hypotension, bradycardia, and laryngospasm. The combination significantly reduces the incidence of hypotension compared to using propofol or ketamine individually. Despite the regular use of procedural sedation, it can sometimes lead to serious adverse events. Respiratory issues like apnea and hypoxia, while not common, do occur more often than cardiovascular problems such as hypotension. However, the least frequent respiratory complications, which can also pose a threat to life, include laryngospasm, aspiration, and intubation. These incidents are extremely rare.

Influence of sustainable environmental exercises in the green restaurant industry.

The restaurant business is gaining popularity for its capacity to alleviate numerous adverse environmental influences to achieve a competitive edge. Green restaurants can employ a distinctive brand strategy. Nevertheless, additional research is necessary to better understand customer behavior in this subject. This study explores the relationship between brand awareness and brand image, and brand performance from the consumer's perspective. However, it is unknown how this connection is affected by the attitude of green restaurant brands. This research aims to address the research gaps by determining the structure and function of brand attitudes. This study handles the quantitative data analysis to fit the study problem. The data was collected through a questionnaire form, and the questionnaire was collected from the customers from twelve restaurants in Karachi city of Pakistan by utilizing random sampling. In sum, 290 samples were obtained and interpreted with SPSS (Statistical Package for the Social Sciences) and PLS (Partial Least Squares) to come up with the results of the study. According to the findings, restaurant customers' observed brand awareness and brand image positively impact brand attitude. The results of the structural equation analysis revealed that brand awareness and brand image have a substantial impact on brand performance, whereas brand attitude has a profound effect on meditation. The adaptation of brand attitude to brand management has sparked a lot of interest in the incredibly competitive restaurant business. There is a good likelihood that green restaurants will ultimately find value in using the measuring tools and suggestions offered in this research to analyze and lead their marketing efforts. In practice, it is recommended that green restaurant management cultivate familiar brand awareness and preserve the brand image to create brand attitude and performance.

ß-Catenin Elicits Drp1-Mediated Mitochondrial Fission Activating the Pro-Apoptotic Caspase-1/IL-1ß Signalosome in Aeromonas hydrophila-Infected Zebrafish Macrophages.

Canonical Wnt signaling plays a major role in regulating microbial pathogenesis. However, to date, its involvement in A. hydrophila infection is not well known. Using zebrafish (Danio rerio) kidney macrophages (ZKM), we report that A. hydrophila infection upregulates wnt2, wnt3a, fzd5, lrp6, and ß-catenin (ctnnb1) expression, coinciding with the decreased expression of gsk3b and axin. Additionally, increased nuclear ß-catenin protein accumulation was observed in infected ZKM, thereby suggesting the activation of canonical Wnt signaling in A. hydrophila infection. Our studies with the ß-catenin specific inhibitor JW67 demonstrated ß-catenin to be pro-apoptotic, which initiates the apoptosis of A. hydrophila-infected ZKM. ß-catenin induces NADPH oxidase (NOX)-mediated ROS production, which orchestrates sustained mitochondrial ROS (mtROS) generation in the infected ZKM. Elevated mtROS favors the dissipation of the mitochondrial membrane potential (ΔΨm) and downstream Drp1-mediated mitochondrial fission, leading to cytochrome c release. We also report that ß-catenin-induced mitochondrial fission is an upstream regulator of the caspase-1/IL-1ß signalosome, which triggers the caspase-3 mediated apoptosis of the ZKM as well as A. hydrophila clearance. This is the first study suggesting a host-centric role of canonical Wnt signaling pathway in A. hydrophila pathogenesis wherein ß-catenin plays a primal role in activating the mitochondrial fission machinery, which actively promotes ZKM apoptosis and helps in containing the bacteria.

Natural oxidation of Ti3C2Tx to construct efficient TiO2/Ti3C2Tx photoactive heterojunctions for advanced photoelectrochemical biosensing of folate-expressing cancer cells.

The rapid-charge carrier recombination and low conductivity are critical in devising an efficient photoelectrochemical (PEC) sensor. Herein, we propose partial oxidation of few-layered MXene (Ti3C2Tx) to construct a photo-active TiO2/Ti3C2Tx platform that could be configured for PEC sensing of folate receptors (FR), particularly, FR-expressing breast cancer cells (MDA-MB-231). MXene-Ti3C2Tx dispersion was oxidized in natural-open air conditions, where continuous exposure for six (06) days allowed for homogeneous in-situ growth of TiO2 over MXenes nanosheets (MX-06). This exposure enabled partial oxidation of MXene-sheets with a balanced TiO2 to MXene content that could exhibit improved photoresponsive characteristics owing to the synergism of redox-active TiO2 and highly conductive underlying Ti3C2Tx. The photoelectrode was then adapted for biorecognition by conjugating chitosan and folic acid (FA) networks, which permitted selective detection of FR-expressed cells with significant antifouling capabilities against common proteins such as bovine serum album (BSA), hemoglobin, and immunoglobulin G. (Ig G). The detection mechanism relies on FA's strong affinity for cancer cell folate receptors, which proportionally inhibited the photoelectrodes PEC oxidation response to ascorbic acid (AA)(mediator). The proposed inhibition strategy enabled sensitive detection of FR-expressed MDA-MB-231 cells in the concentration range of 1 × 102 to 2 × 107 cells/mL with a detection limit of 1.01 cells/mL (S/N = 3).

Hierarchical NiMn-LDH Hollow Spheres as a Promising Pseudocapacitive Electrode for Supercapacitor Application.

Layered double hydroxides (LDH) are regarded as attractive pseudocapacitive materials due to their impressive capacitive qualities that may be adjustable to their morphological features. However, the layered structure of LDH renders them susceptible to structural aggregation, which inhibits effective electrolyte transport and limits their practical applicability after limited exposure to active areas. Herein, we propose a simple template-free strategy to synthesize hierarchical hollow sphere NiMn-LDH material with high surface area and exposed active as anode material for supercapacitor application. The template-free approach enables the natural nucleation of Ni-Mn ions resulting in thin sheets that self-assemble into a hollow sphere, offering expended interlayer spaces and abundant redox-active active sites. The optimal NiMn-LDH-12 achieved a specific capacitance of 1010.4 F g-1 at a current density of 0.2 A g-1 with capacitance retention of 70% at 5 A g-1 after 5000 cycles with lower charge transfer impedance. When configured into an asymmetric supercapacitors (ASC) device as NiMn-LDH//AC, the material realized a specific capacitance of 192.4 F g-1 at a current density of 0.2 A g-1 with a good energy density of 47.9 Wh kg-1 and a power density of 196.8 W kg-1. The proposed morphological-tuning route is promising for designing template-free NiMn-LDHs spheres with practical pseudocapacitive characteristics.

The study of etiological and demographic characteristics of neonatal mortality and morbidity - a consecutive case series study from Pakistan.

BACKGROUND: To determine the etiology, management, bacteriological spectrum and outcome of neonatal patients admitted in Civil Hospital Karachi (CHK) and to examine the factors associated with it. METHODS: This hospital based descriptive study of 1463 patients from both sexes who were admitted to Paediatric department, CHK from 1st January 2008 till 31st December 2010 with an established cause according to modified Wigglesworth classification and fulfilling other inclusion criteria were included in the study. Data regarding their demographic profile and potential risk factors was collected on a well structured proforma. Cases were followed until discharge or expiry. Data was analyzed using descriptive statistics. RESULTS: The male to female ratio in our study was 1.12:1. Seven hundred and thirty-four patients were delivered at home (50.2%) and 1010 were less than 7 days old (69%). Out of the total cohort of expired subjects, 89 participants (74.8%) were < 7 days of life. Mortality was more in neonates born at home in rural areas to illiterate mother; 74 patients (62.2%). Most of the deaths; 57 were in neonates suffering from specific infections (47.9%) followed by 38 deaths in immaturity group (31.9%) and 19 related to asphyxial conditions (15.9%). The most common isolates were Staphylococcus aureus (28.7%) followed by Klebsiella (24.8%) and Pseudomonas aeruginosa (16.6 ). One hundred and nineteen (8.13%) of the neonates died in our study group. CONCLUSIONS: These results suggest that neonates with illiterate mothers with high parity and below average socioeconomic level were more susceptible to mortality in the early neonatal period. Most of the cases of mortality were due to specific infections.

Cross border project in China-Pakistan economic corridor and its influence on women empowerment perspectives.

The China-Pakistan Economic Corridor (CPEC) is a significant and inaugural project of the "Belt and Road" initiative which is considered as structure and manifesto for panoramic and fundamental collaboration between China and Pakistan. The CPEC project was initiated to develop economic growth and facilitate free trade between both countries. However, it has generated immense employment opportunities, education facilities, and improved quality of life for local citizens, specifically women, as well as international overreach. This study investigates and examines the benefits of CPEC project and its influence on women empowerment. Based on the background of the CPEC, this study has been carried out by applying a mixture of qualitative and quantitative methods to fill the gap. Data was aggregated with the help of a survey questionnaire and interviews from the residents of the Thar region of Pakistan, which comes under CPEC route. In total, 306 samples were acquired and analysed using different statistical tools such as SPSS (Statistical package for social sciences) and PLS (Partial least squares) to formulate the study results. The findings revealed that the development of CPEC has remarkably improved the quality of life for women by providing enormous employment opportunities, education facilities, skills enhancement programs, and training facilities. The analyzed results will guide government policymakers and officials to promote operational activities in the region, develop new educational institutions, and create employment opportunities for the local community and women to obtain further development of CPEC projects.

TLR22-Induced Pro-Apoptotic mtROS Abets UPRmt-Mediated Mitochondrial Fission in Aeromonas hydrophila-Infected Headkidney Macrophages of Clarias gariepinus.

Toll-like receptors (TLRs) are epitomized as the first line of defense against pathogens. Amongst TLRs, TLR22 is expressed in non-mammalian aquatic vertebrates, including fish. Using headkidney macrophages (HKM) of Clarias gariepinus, we reported the pro-apoptotic and microbicidal role of TLR22 in Aeromonas hydrophila infection. Mitochondria act as a central scaffold in the innate immune system. However, the precise molecular mechanisms underlying TLR22 signaling and mitochondrial involvement in A. hydrophila-pathogenesis remain unexplored in fish. The aim of the present study was to investigate the nexus between TLR22 and mitochondria in pro-apoptotic immune signaling circuitry in A. hydrophila-infected HKM. We report that TLR22-induced mitochondrial-Ca2+ [Ca2+]mt surge is imperative for mtROS production in A. hydrophila-infected HKM. Mitigating mtROS production enhanced intracellular bacterial replication implicating its anti-microbial role in A. hydrophila-pathogenesis. Enhanced mtROS triggers hif1a expression leading to prolonged chop expression. CHOP prompts mitochondrial unfolded protein response (UPRmt) leading to the enhanced expression of mitochondrial fission marker dnml1, implicating mitochondrial fission in A. hydrophila pathogenesis. Inhibition of mitochondrial fission reduced HKM apoptosis and increased the bacterial burden. Additionally, TLR22-mediated alterations in mitochondrial architecture impair mitochondrial function (ΔΨm loss and cytosolic accumulation of cyt c), which in turn activates caspase-9/caspase-3 axis in A. hydrophila-infected HKM. Based on these findings we conclude that TLR22 prompts mtROS generation, which activates the HIF-1α/CHOP signalosome triggering UPRmt-induced mitochondrial fragmentation culminating in caspase-9/-3-mediated HKM apoptosis and bacterial clearance.

IL-27 Modulates the Cytokine Secretion in the T Cell-Osteoclast Crosstalk During HIV Infection.

In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown. In the present study, we determined the impact of OCs in T cell secretion of cytokines and whether IL-27 can regulate this function. We found that the presence of OCs in the T cell cultures significantly enhanced secretion of IFNγ, TNFα, IL-17, RANKL, and IL-10 in both PWH and healthy controls. In PWH, IL-27 inhibited IL-17 secretion and downregulated surface expression of RANKL in CD4 T cells. All together these results suggest that in the context of HIV infection IL-27 may favor IFNγ and TNFα secretion at the sites of bone remodeling.

IL-27 induces IFN/STAT1-dependent genes and enhances function of TIGIT+ HIVGag-specific T cells.

HIV-specific T cells have diminished effector function and fail to control/eliminate the virus. IL-27, a member of the IL-6/IL-12 cytokine superfamily has been shown to inhibit HIV replication. However, whether or not IL-27 can enhance HIV-specific T cell function is largely unknown. In the present manuscript, we investigated the role of IL-27 signaling in human T cells by evaluating the global transcriptional changes related to the function of HIV-specific T cells. We found that T cells from people living with HIV (PLWH), expressed higher levels of STAT1 leading to enhanced STAT1 activation upon IL-27 stimulation. Observed IL-27 induced transcriptional changes were associated with IFN/STAT1-dependent pathways in CD4 and CD8 T cells. Importantly, IL-27 dependent modulation of T-bet expression promoted IFNγ secretion by TIGIT+HIVGag-specific T cells. This new immunomodulatory effect of IL-27 on HIV-specific T cell function suggests its potential therapeutic use in cure strategies.