Gender Differences in Operative Autonomy Using the Surgical Autonomy Program: A Multicenter Study.

Background The proportion of women surgeons is increasing, but studies show that women in surgical residency are granted less autonomy than men. Objective We utilized the Surgical Autonomy Program (SAP), an educational framework, to evaluate gender differences in self-reported autonomy, attending-reported autonomy, and operative feedback among US neurosurgical residents. Methods The SAP tracks resident progression and guides teaching in neurosurgery. Surgeries are divided into zones of proximal development (opening, exposure, critical portion, and closure). Postoperatively, resident autonomy is rated on a 4-point scale by the resident and the attending for each part of the case, or zone. We utilized data from July 2017 to February 2024 from 8 institutions. Ordinal regression was used to evaluate the odds of self- and attending-evaluated autonomy, accounting for gender, training year, case difficulty, and institution. Differences between attending assessment and self-assessment were calculated across time. Chi-square analyses were used to measure any differences in feedback given to men and women. Results From 128 residents (32 women, 25%), 11894 cases were included. Women were granted less autonomy (OR 0.81; 95% CI 0.74-0.89; P<.001) and self-evaluated as having less autonomy (OR 0.73; 95% CI 0.67-0.80; P<.001). The odds of women operating at higher autonomy were similar to the odds of operating on a hard case compared to average difficulty (OR 0.77; 95% CI 0.71-0.84; P<.001). Men's and women's self-assessment became closer to attending assessment over time, with women improving more quickly for the critical portions of surgeries. Women residents received meaningful postoperative feedback on fewer cases (women: 74.2%, men: 80.5%; X2=31.929; P<.001). Conclusions Women operated with lower autonomy by both attending and self-assessment, but the assessment gap between genders decreased over time. Women also received less feedback from their attendings.

CYP303A1 regulates molting and metamorphosis through 20E signaling in Nilaparvata lugens Stål (Hemiptera: Delphacidae).

Cytochrome P450s play a crucial role in the breakdown of external substances and perform important activities in the hormone system of insects. It has been understood that P450s were essential in the metabolism of ecdysteroids. CYP303A1 is a highly conserved CYP in most insects, but its specific physiological functions remain poorly understood in Nilaparvata lugens Stål. In this study, NlCYP303A1 was identified and highly expressed in the pre-molt stages, predominantly in the cuticle-producing tissues. Silencing of NlCYP303A1 caused a lethal phenotype with a molting defect. Moreover, the 20E titers, the expression levels of Halloween genes, and critical genes associated with the 20E signaling pathway in N. lugens nymphs were significantly decreased with the silencing NlCYP303A1. We further performed additional backfilling of 20E to rescue the RNAi effects on NlCYP303A1. The gene expression levels that were previously reduced caused by silencing NlCYP303A1 were significantly elevated. However, the molting defects of nymphs were not effectively improved. The results demonstrated NlCYP303A1 plays a crucial role in the molting and metamorphosis of N. lugens by regulating the 20E signaling pathway and cuticular formation, enhances the understanding of the functional role of CYP 2 clans, and identifies candidate gene for RNAi-based control of N. lugens.

Neural Circuit Mechanisms of Sinisan formula for the Treatment of adolescent Depression: prefrontal cortex to dorsal raphe nucleus.

ETHNOPHARMACOLOGICAL RELEVANCE: Sinisan formula (SNSF), documented in the classic books Shanghan Lun, is known for its ability to regulate liver-qi and treat depression. However, its underlying mechanism, particularly its effects on dynamic real-time neuron activity and circuits remains to be fully elucidated. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect of SNSF and its central nervous system mechanism on depression-like behaviors, focusing on the prefrontal cortex (PFC) to dorsal raphe nucleus (DRN) neural circuit in a stress-induced adolescent animal model. MATERIALS AND METHODS: SNSF comprised four herbs, the root of Bupleurum chinense DC., the root of Paeonia lactiflora Pall., the fruit of Citrus aurantium L., the rhizome of Glycyrrhiza uralensis Fisch., in equal propotions. The adolescent depression animal model was induced by maternal separation (MS) and chronic restraint stress (CRS). In-vivo multichannel physiological electrodes were implanted into the PFC on PND 28 and animals were recorded 5 times during PND 35-46. From PND 47, the behavioral tests were performed to evaluate the antidepressant efficacy of SNSF. Subsequently, brain tissue was collected for Western blot and immunofluorescence staining analysis. Retro virus was injected into the DRN to explore sources of projections received by serotonergic (5-HTergic) neurons. And the PFC-to-DRN circuit was activated or inhibited through chemogenetic techniques to investigate the effects of SNSF on depression-like behaviors. RESULTS: Administration of SNSF for 18 days effectively alleviated depression-like behaviors in MS&CRS adolescent mice. The PFC emerged as the primary glutamatergic projection source of the DRN5-HT neurons. Following SNSF administration for 13/15/18 days, there was an increase in the firing rate of excitatory neurons and excitatory/inhibitory (E/I) ratio in the PFC. MS&CRS stress let to a reduction in the density of 5-HT+ and CaMKII + neurons in the DRN, accompanied by an increase in the density of GAD + neurons in the DRN, while SNSF administration reversed the alterations. Chemogenetic activation of the PFC-to-DRN circuit rescued the depression-like behaviors induced by MS&CRS, whereas suppression of this circuit attenuated the antidepressant effect of SNSF. CONCLUSIONS: SNSF significantly mitigated depression-like behaviors in MS&CRS mice. SNSF exerts its antidepressant effects by increasing the E/I ratio in the PFC and enhancing glutamatergic projections from the PFC to the DRN.

Causal relationship between renal function and risk of esophageal cancer: insights from Mendelian randomization.

Background: Previous studies have indicated a potential correlation between renal function and risk of cancer. However, establishing a causal relationship is challenging. To address this, we employed Mendelian randomization (MR), a novel method that utilizes genotype data to simulate randomized trial groups, to investigate whether there is a causal correlation between renal function and the esophageal cancer (EC) risk. Methods: MR analysis was conducted with the individual-level data on EC from the UK Biobank published dataset. Genetic instruments were derived from single nucleotide polymorphisms (SNPs) extracted from publicly available genome-wide association studies. Furthermore, leave-one-out sensitivity analysis was performed to assess the impact of individual SNPs. Results: In our MR analysis, we examined 39,475,182 SNPs associated with various renal functional indexes from public databases. Based on the primary causal effects model using MR analyses with the inverse variance weighted method, the genetically predicted cystatin C [odds ratio (OR) =1.0005, 95% confidence interval (CI): 1.0000-1.0009; P=0.05] and creatinine (OR =1.0016, 95% CI: 1.0002-1.0031; P=0.02) demonstrated a significant association with higher risk of EC. However, we found no evidence of an association between urinary albumin and glomerular filtration rate with the risk of EC. Conclusions: Our research provides strong evidence for the association of decreased renal function to a potential risk of EC. However, it is crucial to recognize the necessity for additional large-scale prospective studies to validate this discovery and establish a comprehensive understanding of the causal relationships between renal function and EC. Keywords: Esophageal cancer (EC); renal function; Mendelian randomization (MR); causal association.

The feasibility, appropriateness, and usability of mobile neuro clinics in addressing the neurosurgical and neurological demand in Uganda.

INTRODUCTION: Uganda has a high demand for neurosurgical and neurological care. 78% of the over 50 million population reside in rural and remote communities where access to neurosurgical and neurological services is lacking. This study aimed to determine the feasibility, appropriateness, and usability of mobile neuro clinics (MNCs) in providing neurological care to rural and remote Ugandan populations. METHODS: Neurosurgery, neurology, and mobile health clinic providers participated in an education and interview session to assess the feasibility, appropriateness, and usability of the MNC intervention. A qualitative analysis of the interview responses using the constructs in the updated Consolidated Framework for Implementation Research was performed. Providers' opinions were weighted using average sentiment scores on a novel sentiment-weighted scale adapted from the CFIR. A stakeholder analysis was also performed to assess the power and interest of the actors described by the participants. RESULTS: Twenty-one healthcare providers completed the study. Participants discussed the potential benefits and concerns of MNCs as well as potential barriers and critical incidents that could jeopardize the intervention. Of the five CFIR domains evaluated, variables in the implementation process domain showed the highest average sentiment scores, followed by the implementation climate constructs, inner setting, innovation, and outer setting domains. Furthermore, many interested stakeholders were identified with diverse roles and responsibilities for implementing MNCs. These findings demonstrate that MNC innovation is feasible, appropriate, and usable. CONCLUSION: The findings of this study support the feasibility, appropriateness, and usability of MNCs in Uganda. However, integration of this innovation requires careful planning and stakeholder engagement at all levels to ensure the best possible outcomes.

The emerging roles and therapeutic implications of immunosenescence-mediated inflammaging in age-related hearing loss.

Age-related hearing loss (ARHL) represents one of the most prevalent chronic sensory deficits experienced by the elderly, significantly diminishing their quality of life and correlating with various medical and psychological morbidities. This condition arises from the cumulative effects of aging on the auditory system, implicating intricate interactions between genetic predispositions and environmental factors. Aging entails a progressive decline in immune system functionality, termed immunosenescence, leading to a chronic low-grade inflammation known as inflammaging. This phenomenon potentially serves as a common mechanism underlying ARHL and other age-related pathologies. Recent research suggests that rejuvenating immunosenescence could mitigate inflammaging and ameliorate age-related functional declines, offering promising insights into anti-aging therapies. Consequently, this review endeavors to elucidate the role of immunosenescence-mediated inflammaging in ARHL progression and discuss its therapeutic implications.

Exploring the feasibility of pupillometry training and perceptions of potential use for intracranial pressure monitoring in Uganda: A mixed methods study.

INTRODUCTION: Traumatic brain injury (TBI) accounts for the majority of Uganda's neurosurgical disease burden; however, invasive intracranial pressure (ICP) monitoring is infrequently used. Noninvasive monitoring could change the care of patients in such a setting through quick detection of elevated ICP. PURPOSE: Given the novelty of pupillometry in Uganda, this mixed methods study assessed the feasibility of pupillometry for noninvasive ICP monitoring for patients with TBI. METHODS: Twenty-two healthcare workers in Kampala, Uganda received education on pupillometry, practiced using the device on healthy volunteers, and completed interviews discussing pupillometry and its implementation. Interviews were assessed with qualitative analysis, while quantitative analysis evaluated learning time, measurement time, and accuracy of measurements by participants compared to a trainer's measurements. RESULTS: Most participants (79%) reported a positive perception of pupillometry. Participants described the value of pupillometry in the care of patients during examination, monitoring, and intervention delivery. Commonly discussed concerns included pupillometry's cost, understanding, and maintenance needs. Perceived implementation challenges included device availability and contraindications for use. Participants suggested offering continued education and engaging hospital leadership as implementation strategies. During training, the average learning time was 13.5 minutes (IQR 3.5), and the measurement time was 50.6 seconds (IQR 11.8). Paired t-tests to evaluate accuracy showed no statistically significant difference in comparison measurements. CONCLUSION: Pupillometry was considered acceptable for noninvasive ICP monitoring of patients with TBI, and pupillometer use was shown to be feasible during training. However, key concerns would need to be addressed during implementation to aid device utilization.

Women in Nigerian Neurosurgery: A Cross-Sectional Survey.

BACKGROUND: Although women have made remarkable strides in several medical specialties in Sub-Saharan Africa, their presence and contribution to the development of neurosurgery remain limited. We sought to study the gender differences within Nigerian neurosurgery, identify challenges resulting from these differences, and recommend how African female neurosurgeons can maximize their effects in neurosurgery. METHODS: A structured online survey captured data on neurosurgical infrastructural capacity, workforce, and training from neurosurgical consultants and residents in neurosurgical centers in Nigeria. All the collected data were coded and analyzed. RESULTS: Altogether, 82 neurosurgical consultants and 67 neurosurgical residents from 50 primary medical institutions in Nigeria completed the online survey. Only 8 of the respondents (5.4%) were women, comprising 3 consultants, 2 senior residents, and 3 junior residents. Although 40.2% of the respondents did not believe that being female affected the decision of whether to specialize in neurosurgery, 46.3% believed that being female was a disadvantage. Most did not believe that being female affected admission (57.8%), completion of a neurosurgery residency (58.5%), or life working as a neurosurgeon after graduation (63.4%). The most common challenges women face while navigating through neurosurgery training and practice are erosion of family and social life, lack of female mentors, and lack of a work-life balance. CONCLUSIONS: There is a deficit of both female consultants and trainees among Nigerian neurosurgeons. Identifying female medical students with a strong interest in neurosurgery and providing early mentorship might increase the number of female neurosurgeons.

A Geospatial Analysis of the Availability, Distribution, and Accessibility of Neurosurgical Facilities, Workforce, and Infrastructure in Nigeria; and Projection Towards 2050.

OBJECTIVE: There has been a modest but progressive increase in the neurosurgical workforce, training, and service delivery in Nigeria in the last 2 decades. However, these resources are unevenly distributed. This study aimed to quantitatively assess the availability and distribution of neurosurgical resources in Nigeria while projecting the needed workforce capacity up to 2050. METHODS: An online survey of Nigerian neurosurgeons and residents assessed the country's neurosurgical infrastructure, workforce, and resources. The results were analyzed descriptively, and geospatial analysis was used to map their distribution. A projection model was fitted to predict workforce targets for 2022-2050. RESULTS: Out of 86 neurosurgery-capable health facilities, 65.1% were public hospitals, with only 17.4% accredited for residency training. Dedicated hospital beds and operating rooms for neurosurgery make up only 4.0% and 15.4% of the total, respectively. The population disease burden is estimated at 50.2 per 100,000, while the operative coverage was 153.2 cases per neurosurgeon. There are currently 132 neurosurgeons and 114 neurosurgery residents for a population of 218 million (ratio 1:1.65 million). There is an annual growth rate of 8.3%, resulting in a projected deficit of 1113 neurosurgeons by 2030 and 1104 by 2050. Timely access to neurosurgical care ranges from 21.6% to 86.7% of the population within different timeframes. CONCLUSIONS: Collaborative interventions are needed to address gaps in Nigeria's neurosurgical capacity. Investments in training, infrastructure, and funding are necessary for sustainable development and optimized outcomes.

Assessing the Neurosurgical Capacity in Nigeria Using the Modified Neuro-PIPES Tool.

BACKGROUND: Like many low- and-middle-income countries in Africa, documented assessment of the neurosurgical workforce, equipment, infrastructure, and scope of service delivery in Nigeria is lacking. This study aimed to assess the capacity for the delivery of neurosurgical services in Nigeria. METHODS: An 83-question survey was disseminated to neurosurgeons and residents in Nigeria. We report the findings from the capacity assessment section of the survey, which used the modified neurological-PIPES (personnel, infrastructure, procedures, equipment, and supplies) (MN-PIPES) tool to evaluate the availability of neurosurgical personnel, infrastructure, procedures, equipment, and supplies. A comparative analysis was done using the domain and total MN-PIPES scores and MN-PIPES index. RESULTS: The national average MN-PIPES score and index were 176.4 and 9.8, respectively. Overall, the southwest and northwest regions had the highest scores and frequently had high subscores. The survey respondents reported that the main challenges impeding neurosurgery service delivery were a lack of adjunctive supplies (75.2%), a dearth of diagnostic and interventional equipment (72.4%), and an absence of a dedicated intensive care unit (72.4%). CONCLUSIONS: The availability of workforce, infrastructure, equipment, and supplies needed to provide optimal neurosurgical care is uneven in many institutions in Nigeria. Although major strides have been made in recent years, targeted collaborative interventions at local, national, regional, and international levels will further improve neurosurgical service delivery in Nigeria and will have positive ripple effects on the rest of the healthcare system.

Salvia miltiorrhiza inhibited lung cancer through aerobic glycolysis suppression.

Lung cancer causes the most cancer deaths and needs new treatment strategies urgently. Salvia miltiorrhiza is a classical Chinese herb and a strong candidate for tumor treatment. The study found that the aqueous extract of Salvia miltiorrhiza (DSAE), ethanol extract of Salvia miltiorrhiza (DSEE), and its active components danshensu (DSS) and dihydrotanshinone I (DHI), exhibited antineoplastic effects in vivo and in vitro. Meanwhile, DSAE, DSEE, DSS, and DHI reduced glycolysis metabolites (ATP, lactate, and pyruvate contents) production, decreased aerobic glycolysis enzymes, and inhibited Seahorse indexes (OCR and ECAR) in Lewis lung cancer cells (LLC). Data suggests that aerobic glycolysis could be inhibited by Salvia miltiorrhiza and its components. The administration of DSS and DHI further reduced the level of HKII in lung cancer cell lines that had been inhibited with HK-II antagonists (2-deoxyglucose, 2-DG; 3-bromo-pyruvate, 3-BP) or knocked down with siRNA, thereby exerting an anti-lung cancer effect. Although DSS and DHI decreased the level of HKII in HKII-Knock-In lung cancer cell line, their anti-lung cancer efficacy remained limited due to the persistent overexpression of HKII in these cells. Reiterating the main points, we have discovered that the anti-lung cancer effects of Salvia miltiorrhiza may be attributed to its ability to regulate HKII expression levels, thereby inhibiting aerobic glycolysis. This study not only provides a new research paradigm for the treatment of cancer by Salvia miltiorrhiza, but also highlights the important link between glucose metabolism and the effect of Salvia Miltiorrhiza.

The Epidemiology of Spinal Neurosurgery in Nigeria: A Systematic Review and Patient-Level Analysis.

OBJECTIVE: Spinal pathologies are prevalent in Nigeria, though epidemiological data remains sparse. This systematic review used pooled patient-level data from across the country to generate a standardized epidemiological reference. METHODS: Four research databases and gray literature sources were searched. Risk of bias assessment was conducted using Risk of Bias in Non-Randomised Studies - of Interventions and Cochrane's risk of bias tool. We descriptively analyzed all article metrics and statistically analyzed relevant data variables via paired t-test and χ2 independence tests (α = 0.05). RESULTS: One hundred twenty-seven articles, comprising a patient cohort of 8425 patients, were analyzed. Most were retrospective cohort studies (46.5%) and case reports/series (31.5%), with an overall moderate-high risk of bias. Most studies were published in the last 20 years. Most patients were male (∼2.5 males per female), with an average age of 43.2 years (±16.4). Clinical diagnoses spanned the breadth of spinal neurosurgery. Approximately 45.0% of patients had complete spinal impairment. Pain (41.7%) was the most reported presenting feature. X-ray (45.1%) was the most common investigation used. Intervertebral disc herniation (18.9%) was the most prevalent imaging finding on MRI. Most patients were managed nonoperatively (57.8%), with a favorable outcome in 27.4% of patients. Posttreatment complications included pressure sores, infection, and motor deficits. CONCLUSIONS: This systematic review and pooled analysis provide an epidemiological overview of spinal neurosurgery in Nigeria over the last 60 years and serves as a useful reference to direct future global research in this arena.

The Epidemiological Burden of Neurovascular Pathology in Nigeria: A Systematic Review and Pooled Patient-Level Analysis.

OBJECTIVE: Vascular neurosurgery has developed significantly in Nigeria, but its burden and challenges remain unclear. This study systematically reviewed vascular neurosurgical literature from Nigeria. METHODS: Four research databases and gray literature sources were searched from 1962-2021. ROBINS-I tool was used to assess risk of bias. Descriptive, narrative, and statistical analyses were conducted on all variables. Where appropriate, paired t-tests and Chi-squared independence tests were used (α = 0.05). RESULTS: 56 articles were included and 3203 patients pooled for analysis. Risk of bias was moderate-high. Most articles were published over the last 20 years with retrospective cohort studies and case reports being the most common study designs. The cohort had a relatively even gender split and an average age of 49 years (±22). Cerebrovascular accidents accounted for over 85% of diagnoses, with most etiologies being traumatic. Headache and motor deficit were the most prevalent clinical features. X-ray and carotid angiography were the most commonly reported imaging modalities, closely followed by computed tomography (CT) and CT angiography. The top two radiological diagnoses were ischemic cerebrovascular disease and intracerebral hematoma. Aneurysmal clipping and hematoma evacuation were the most commonly reported treatment modalities. Outcome at last follow-up was favorable in 48%. The mortality rate was 6%. Post-treatment complications included chest infection and rebleeding. CONCLUSIONS: This study illustrates the epidemiological burden of neurovascular pathology (based on the available data in published literature) in Nigeria, and raises awareness amongst service providers and researchers of the attendant challenges and epochal trends seen within vascular neurosurgery in Nigeria.

Epidemiological Burden of Neurotrauma in Nigeria: A Systematic Review and Pooled Analysis of 45,763 Patients.

OBJECTIVE: Neurotrauma is a significant cause of morbidity and mortality in Nigeria. We conducted this systematic review to generate nationally generalizable reference data for the country. METHODS: Four research databases and gray literature sources were electronically searched. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions and Cochrane's risk of bias tools. Descriptive analysis, narrative synthesis, and statistical analysis (via paired t-tests and χ2 independence tests) were performed on relevant article metrics (α = 0.05). RESULTS: We identified a cohort of 45,763 patients from 254 articles. The overall risk of bias was moderate to high. Most articles employed retrospective cohort study designs (37.4%) and were published during the last 2 decades (81.89%). The cohort's average age was 32.5 years (standard deviation, 20.2) with a gender split of ∼3 males per female. Almost 90% of subjects were diagnosed with traumatic brain injury, with road traffic accidents (68.6%) being the greatest cause. Altered consciousness (48.4%) was the most commonly reported clinical feature. Computed tomography (53.5%) was the most commonly used imaging modality, with skull (25.7%) and vertebral fracture (14.1%) being the most common radiological findings for traumatic brain injury and traumatic spinal injury, respectively. Two-thirds of patients were treated nonoperatively. Outcomes were favorable in 63.7% of traumatic brain injury patients, but in only 20.9% of traumatic spinal injury patients. Pressure sores, infection, and motor deficits were the most commonly reported complications in the latter. CONCLUSIONS: This systematic review and pooled analysis demonstrate the significant burden of neurotrauma across Nigeria.

Prognostic effects of different treatment modalities for hypopharyngeal squamous cell carcinoma: Experience of two tertiary hospitals in Southwestern China.

Background: The prognostic effects of different treatment modalities on patients with hypopharyngeal squamous cell carcinoma (HPSCC) remain unclear. Methods: HPSCC patients diagnosed and treated at either West China Hospital or Sichuan Cancer Hospital between January 1, 2009, and December 31, 2019, were enrolled in this retrospective, real-world study. Survival rates were presented using Kaplan-Meier curves and compared using log-rank tests. Univariable and multivariable Cox proportional hazards regression models were used to identify the predictors of overall survival (OS). Subgroup analyses were conducted for patients with advanced-stage HPSCC (stages III and IV and category T4). Results: A total of 527 patients with HPSCC were included. Patients receiving SRC (surgery, radiotherapy [RT], and chemotherapy) showed the best OS (p < 0.0001). In comparison with RT alone, both surgery alone (all cases: hazard ratio [HR] = 0.39, p = 0.0018; stage IV cases: HR = 0.38, p = 0.0085) and surgery-based multimodality treatment (SBMT; all cases: HR = 0.27, p < 0.0001; stage IV cases: HR = 0.30, p = 0.00025) showed prognostic benefits, while SBMT also showed survival priority over chemoradiotherapy (CRT; all cases: HR = 0.52, p < 0.0001; stage IV cases: HR = 0.59, p = 0.0033). Moreover, patients who underwent surgery alone had comparable OS to those who underwent SBMT (all patients: p = 0.13; stage IV cases: p = 0.34), while CRT yielded similar prognostic outcomes as RT alone (all patients: p = 0.054; stage IV cases: p = 0.11). Conclusions: Surgery alone was comparable to SBMT and superior to RT/CRT in terms of OS in patients with HPSCC. We suggest that surgery should be encouraged for the treatment of HPSCC, even in patients with advanced-stage disease.

Engineering of Unspecific Peroxygenases Using a Superfolder-Green-Fluorescent-Protein-Mediated Secretion System in Escherichia coli.

Unspecific peroxygenases (UPOs), secreted by fungi, demonstrate versatility in catalyzing challenging selective oxyfunctionalizations. However, the number of peroxygenases and corresponding variants with tailored selectivity for a broader substrate scope is still limited due to the lack of efficient engineering strategies. In this study, a new unspecific peroxygenase from Coprinopsis marcescibilis (CmaUPO) is identified and characterized. To enhance or reverse the enantioselectivity of wildtype (WT) CmaUPO catalyzed asymmetric hydroxylation of ethylbenzene, CmaUPO was engineered using an efficient superfolder-green-fluorescent-protein (sfGFP)-mediated secretion system in Escherichia coli. Iterative saturation mutagenesis (ISM) was used to target the residual sites lining the substrate tunnel, resulting in two variants: T125A/A129G and T125A/A129V/A247H/T244A/F243G. The two variants greatly improved the enantioselectivities [21% ee (R) for WT], generating the (R)-1-phenylethanol or (S)-1-phenylethanol as the main product with 99% ee (R) and 84% ee (S), respectively. The sfGFP-mediated secretion system in E. coli demonstrates applicability for different UPOs (AaeUPO, CciUPO, and PabUPO-I). Therefore, this developed system provides a robust platform for heterologous expression and enzyme engineering of UPOs, indicating great potential for their sustainable and efficient applications in various chemical transformations.

Brain-Targeted Black Phosphorus-Based Nanotherapeutic Platform for Enhanced Hypericin Delivery in Depression.

Depression is a significant global health concern that remains inadequately treated due to the limited effectiveness of conventional drug therapies. One potential therapeutic agent, hypericin (HYP), is identified as an effective natural antidepressant. However, its poor water solubility, low bioavailability, and limited ability to penetrate the brain parenchyma have hindered its clinical application. To address these shortcomings and enhance the therapeutic efficacy of HYP, it is loaded onto black phosphorus nanosheets (BP) modified with the neural cell-targeting peptide RVG29 to synthesize a nanoplatform named BP-RVG29@HYP (BRH). This platform served as a nanocarrier for HYP and integrated the advantages of BP with advanced delivery methods and precise targeting strategies. Under the influence of 808 nm near-infrared irradiation (NIR), BRH effectively traversed an in vitro BBB model. In vivo experiments validated these findings, demonstrating that treatment with BRH significantly alleviated depressive-like behaviors and oxidative stress in mice. Importantly, BRH exhibited an excellent safety profile, causing minimal adverse effects, which highlighted its potential as a promising therapeutic agent. In brief, this novel nanocarrier holds great promise in the development of antidepressant drugs and can create new avenues for the treatment of depression.

Xijiao Dihuang decoction combined with Yinqiao powder promotes autophagy-dependent ROS decrease to inhibit ROS/NLRP3/pyroptosis regulation axis in influenza virus infection.

BACKGROUND: Influenza viral pneumonia is a common complication after influenza virus infection. Xijiao Dihuang Decoction combined with Yinqiao Powder (XDY) is effective on improving influenza viral pneumonia. PURPOSE: This study further explores the anti-inflammatory mechanism of XDY in the treatment of influenza viral pneumonia. STUDY DESIGN: The effects of XDY on inflammation, autophagy, NACHT-LRR-PYD-containing protein 3 (NLRP3) inflammasome and pyroptosis were assessed in the mice with influenza viral pneumonia. In addition, the mouse macrophage cell line (J774A.1) infected with influenza virus was adopted to decode the in vitro effects of XDY on autophagy, reactive oxygen species (ROS), NLRP3 inflammasome and pyroptosis. We analyzed the XDY-induced autophagy, especially the mitophagy-related ROS clearance, and the subsequent inhibition of ROS/NLRP3 inflammasome/pyroptosis signaling in the infected macrophages by different assays based on quantitative polymerase chain reaction, western blot, flow cytometry, immunofluorescence and enzyme-linked immunosorbent assay. RESULTS: In vivo, XDY could effectively improve the lung inflammatory response in the mice with influenza virus pneumonia, due to an intact autophagy flux-promoting effect and the inhibiting roles on NLRP3 inflammasome and pyroptosis. Notably, in vitro, compared with the infected macrophages treated by the NLRP3 inflammasome agonist (Monosodium urate) or the mitochondrial-targeted antioxidant agent, the XDY-dependent treating could inhibit pyroptosis by negatively regulating the signaling axis of ROS/NLRP3 inflammasome/pyroptosis in the influenza virus-infected macrophages. More interestingly, XDY could promote an intact autophagy flux, inducing mitophagy eliminating the damaged mitochondria to reduce the intracellular ROS accumulation, and thus decrease the oxidative stress in the infected macrophages. Especially, the inhibitor of autophagy inition, 3-Methyladenine, could reverse the inhibitory effect of XDY on ROS-NLRP3 inflammasome-mediated pyroptosis, indicating an XDY-promoted mitophagy-dependent ROS scavenging. CONCLUSION: XDY can promote an intact autophagy flux to eliminate damaged mitochondria, namely mitophagy, which reduces the intracellular ROS accumulation contributing to NLRP3 inflammasome activation, restricting pyroptosis and eventually alleviating the influenza virus-induced inflammatory lesions. The obtained results provide new insights into the mechanism of action of XDY in alleviating influenza virus pneumonia, especially the roles of XDY in anti-oxidation, anti-inflammation and anti-pyroptosis, with potential therapeutic targets for future application in integrative medicine.