Antimicrobial sesterterpenoids with a unique 5/8/6/5 tetracyclic carbon-ring-system and diepoxide polyketides from a deep sea-sediment-sourced fungus Chaetomium globosum SD-347.

Two new sesterterpenoids, sesterchaetins A and B (1 and 2), and two new diepoxide polyketides, chaetoketoics A and B (3 and 4), were characterized from the culture extract of Chaetomium globosum SD-347, a fungal strain derived from deep sea-sediment. Their structures and absolute configurations were unambiguously determined by detailed NMR, mass spectra, and X-ray crystallographic analysis. Compounds 1 and 2 contained a distinctive 5/8/6/5 tetracyclic carbon-ring-system, which represented a rarely occurring natural product framework. The new isolates 1-4 exhibited selective antimicrobial activities against human and aquatic pathogenic bacteria and plant-pathogenic fungi.

Antifungal Pseuboyenes A-J, Bergamotene-Derived Sesquiterpenoids from a Cold-Seep-Derived Pseudallescheria boydii.

A chemical investigation of a cold-seep-sediment-derived fungus, Pseudallescheria boydii CS-793, resulted in characterization of 10 novel bergamotene-derived sesquiterpenoids, pseuboyenes A-J (1-10). Their structures were elucidated by spectroscopic and X-ray crystallographic analyses as well as using the modified Mosher's method. Compound 1 represents the first example of a ß-bergamotene containing a 6-oxobicyclo[3.2.1]octane nucleus adducted with a methyl lactate unit, while 8-10 involve a skeletal rearrangement from bergamotene. Compounds 2-5 showed significant antifungal activities against Colletotrichum gloeosporioides Penz. and Fusarium oxysporum with MICs ranging from 0.5 to 8 µg/mL. Compound 4 exhibited an in vitro anti-F. proliferatum effect with an EC50 value of 1.0 µg/mL.

Secondary metabolites with fungicide potentials from the deep-sea seamount-derived fungus Talaromyces scorteus AS-242.

Marine natural products play an important role in biopesticides. Seven new secondary metabolites with different structural classes, including two cycloheptapeptides, scortide A (1) and scortide B (2), two 19-nor-diterpenoids, talascortene H (3) and talascortene I (4), two diterpenoid acids, talascortene J (5) and talascortene K (6), and one triterpenoid, talascortene L (7) were isolated and identified from the sea-anemone-derived endozoic fungus Talaromyces scorteus AS-242. Their structures were comprehensively assigned by spectroscopic data analysis, single-crystal X-ray diffraction, tandem mass spectrometry, and electronic circular dichroism (ECD) calculations. The result of the antimicrobial assay demonstrated that compounds 1 - 6 have inhibitory activity against several human, aquatic, and plant pathogens with minimum inhibitory concentration (MIC) values ranging from 1 to 64 µg/mL. Specially, compounds 2 and 4 showed significant activities against the pathogenic fungus Curvularia spicifera with the MIC value of 1 µg/mL, providing an experimental basis of 2 and 4 with the potential as lead compounds to be developed into biopesticides.

Comparison of sex differences on outcomes after aneurysmal subarachnoid hemorrhage: a propensity score-matched analysis.

OBJECTIVE: Sex differences in outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH) remain controversial. Therefore, the aim of this study was to investigate the sex differences in the prognosis of patients with aSAH. METHODS: This study retrospectively analyzed the clinical data of aSAH patients admitted to the Department of Neurosurgery of General Hospital of Northern Theater Command, from April 2020 to January 2022. The modified Rankin Scale (mRS) was used to evaluate outcomes at 3-month post-discharge. Baseline characteristics, in-hospital complications and outcomes were compared after 1:1 propensity score matching (PSM). RESULTS: A total of 665 patients were included and the majority (63.8%) were female. Female patients were significantly older than male patients (59.3 ± 10.9 years vs. 55.1 ± 10.9 years, P < 0.001). After PSM, 141 male and 141 female patients were compared. Comparing postoperative complications and mRS scores, the incidence of delayed cerebral ischemia (DCI) and hydrocephalus and mRS ≥ 2 at 3-month were significantly higher in female patients than in male patients. After adjustment, the analysis of risk factors for unfavorable prognosis at 3-month showed that age, sex, smoking, high Hunt Hess grade, high mFisher score, DCI, and hydrocephalus were independent risk factors. CONCLUSION: Female patients with aSAH have a worse prognosis than male patients, and this difference may be because females are more vulnerable to DCI and hydrocephalus.

Discovery of (±)-Penindolenes Reveals an Unusual Indole Ring Cleavage Pathway Catalyzed by P450 Monooxygenase.

(±)-Penindolenes A-D (1-4), the first representatives of indole terpenoids featuring a γ-lactam skeleton, were isolated from the mangrove-derived endophytic fungus Penicillium brocae MA-231. Our bioactivity tests revealed their potent antimicrobial and acetylcholinesterase inhibitory activities. The biosynthetic reactions by the five enzymes PbaABCDE leading to γ-lactam ring formation were identified with heterologous expression and in vitro enzymatic assays. Remarkably, the cytochrome P450 monooxygenase PbaB and its homolog in Aspergillus oryzae  catalyzed the 2,3-cleavage of the indole ring to generate two keto groups in 1, in different manners from well-known tryptophan dioxygenases. This is the first example of the oxidative cleavage of indole by a P450 monooxygenase. In addition, rare secondary amide bond formation by the glutamine synthetase-like enzyme PbaD was reported. These findings will contribute to the engineered biosynthesis of unnatural, bioactive indole terpenoids.

Low-Cost Recruitment Approach: Utilizing Facebook Groups to Recruit COVID-19 Long-Haulers.

Introduction: The accessibility of social media (e.g., Facebook groups) presents long-haulers with the ability to connect with others with similar experiences and symptomology that are likely outside of their physical social networks. Social media sites may serve as promising platforms for research recruitment, public health campaigns, or interventions. The present study aims to assess, and comprehensively present, the effectiveness of a low-cost approach to recruitment through groups on Facebook within the context of a broader study of COVID-19 long-haulers. Methods: Facebook groups were searched using a variety of COVID-related terminology and included if they were in English, COVID-19 specific, public, and have or were approaching 1,000 or more members. Group administrators were either contacted for permission to post recruitment materials or posts were made and left pending administrator approval, depending on group settings. Group members were able to follow a link to the online survey platform (i.e., RedCap) where they provided informed consent and completed an online assessment of their COVID-19 experiences and psychosocial wellbeing. Upon survey completion participants were able to opt-in to a raffle-based incentive. The characteristics of the Facebook groups and demographic background of participants were assessed. Findings: Contacting administrators and posts made between January and March of 2022 within 17 COVID-19 specific groups yielded a sample size of 460 long-haulers. The groups relied upon for recruitment had a mean size of 21,022 (SD=45,645.3), most had three or more administrators (43%), and a majority were state specific (60%). The long-hauler participants enrolled from the posts had an average age of 32 years (SD=6.19), approximately split between men (48.91%) and women (50.22%), a majority white (70%), having earned a bachelor's or postgraduate degree (63.48%), and reporting an annual income between $50,000 and $100,000 (56.09%). Discussion: The present study presents strengths and recommendations for survey recruitment through Facebook groups as a low-cost recruitment strategy that is easily targeted to populations with a specific health condition and allows users to complete online psycho-behavioral assessments off-site on a HIPPA compliant survey platform.

Identification of metabolism-related key genes as potential biomarkers for pathogenesis of immune thrombocytopenia.

Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278 ). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples.

Dynamic encoding of temperature in the central circadian circuit coordinates physiological activities.

The circadian clock regulates animal physiological activities. How temperature reorganizes circadian-dependent physiological activities remains elusive. Here, using in-vivo two-photon imaging with the temperature control device, we investigated the response of the Drosophila central circadian circuit to temperature variation and identified that DN1as serves as the most sensitive temperature-sensing neurons. The circadian clock gate DN1a's diurnal temperature response. Trans-synaptic tracing, connectome analysis, and functional imaging data reveal that DN1as bidirectionally targets two circadian neuronal subsets: activity-related E cells and sleep-promoting DN3s. Specifically, behavioral data demonstrate that the DN1a-E cell circuit modulates the evening locomotion peak in response to cold temperature, while the DN1a-DN3 circuit controls the warm temperature-induced nocturnal sleep reduction. Our findings systematically and comprehensively illustrate how the central circadian circuit dynamically integrates temperature and light signals to effectively coordinate wakefulness and sleep at different times of the day, shedding light on the conserved neural mechanisms underlying temperature-regulated circadian physiology in animals.

The dynamic risk factors of cardiovascular disease among people living with HIV: a real-world data study.

BACKGROUND: This study aims to investigate the incidence and dynamic risk factors for cardiovascular diseases (CVD) among people living with HIV (PLWH). METHODS: In this population-based statewide cohort study, we utilized integrated electronic health records data to identify adult (age ≥ 18) who were diagnosed with HIV between 2006 and 2019 and were CVD event-free at the HIV diagnosis in South Carolina. The associations of HIV-related factors and traditional risk factors with the CVD incidence were investigated during the overall study period, and by different follow-up periods (i.e., 0-5yrs, 6-10yrs 11-15yrs) using multivariable logistic regression models. RESULTS: Among 9,082 eligible participants, the incidence of CVD was 18.64 cases per 1000 person-years. Overall, conventional risk factors, such as tobacco use, hypertension, obesity, chronic kidney disease (CKD), were persistently associated with the outcome across all three groups. While HIV-related factors, such as recent CD4 count (e.g., > 350 vs. <200 cells/mm3: adjusted odds ratio [aOR] range: 0.18-0.25), and percent of years in retention (e.g., 31-75% vs. 0-30%: aOR range: 0.24-0.57) were associated with lower odds of CVD incidence regardless of different follow up periods. The impact of the percent of days with viral suppression gradually diminished as the follow-up period increased. CONCLUSIONS: Maintaining an optimal viral suppression might prevent CVD incidence in the short term, whereas restoring immune recovery may be beneficial for reducing CVD risk regardless of the duration of HIV diagnosis. Our findings suggest the necessity of conducting more targeted interventions during different periods of HIV infection.

Teachers' Perceptions of the Impact of the COVID-19 Pandemic and Their Implementation of an Evidence-based HIV Prevention Program in the Bahamas.

Information on how school-based programs is implemented and sustained during crises is limited. In this study, we assessed the impact of the COVID-19 pandemic on the implementation of a HIV prevention intervention in The Bahamas. Data were collected from 139 Grade 6 teachers in 2021-2022. Teachers attended virtual training and received implementation monitoring from coordinators. On average, teachers taught 26.4 (SD = 9.2) of the 35 core activities, and 7.4 (SD = 2.4) out of 9 sessions. More than half (58.3%) of teachers completed 28 or more core activities; 69.1% covered eight or all nine sessions, which is equivalent to 80% of the HIV intervention curriculum. Almost half of the teachers (43%) reported that the pandemic negatively impacted their ability to teach the program; 72% of teachers maintained that the program remained "very important" during times of crisis. Greater self-efficacy and supports increased implementation fidelity.

Consolidated guidance for behavioral intervention pilot and feasibility studies.

BACKGROUND: In the behavioral sciences, conducting pilot and/or feasibility studies (PFS) is a key step that provides essential information used to inform the design, conduct, and implementation of a larger-scale trial. There are more than 160 published guidelines, reporting checklists, frameworks, and recommendations related to PFS. All of these publications offer some form of guidance on PFS, but many focus on one or a few topics. This makes it difficult for researchers wanting to gain a broader understanding of all the relevant and important aspects of PFS and requires them to seek out multiple sources of information, which increases the risk of missing key considerations to incorporate into their PFS. The purpose of this study was to develop a consolidated set of considerations for the design, conduct, implementation, and reporting of PFS for interventions conducted in the behavioral sciences. METHODS: To develop this consolidation, we undertook a review of the published guidance on PFS in combination with expert consensus (via a Delphi study) from the authors who wrote such guidance to inform the identified considerations. A total of 161 PFS-related guidelines, checklists, frameworks, and recommendations were identified via a review of recently published behavioral intervention PFS and backward/forward citation tracking of a well-known PFS literature (e.g., CONSORT Ext. for PFS). Authors of all 161 PFS publications were invited to complete a three-round Delphi survey, which was used to guide the creation of a consolidated list of considerations to guide the design, conduct, and reporting of PFS conducted by researchers in the behavioral sciences. RESULTS: A total of 496 authors were invited to take part in the three-round Delphi survey (round 1, N = 46; round 2, N = 24; round 3, N = 22). A set of twenty considerations, broadly categorized into six themes (intervention design, study design, conduct of trial, implementation of intervention, statistical analysis, and reporting) were generated from a review of the 161 PFS-related publications as well as a synthesis of feedback from the three-round Delphi process. These 20 considerations are presented alongside a supporting narrative for each consideration as well as a crosswalk of all 161 publications aligned with each consideration for further reading. CONCLUSION: We leveraged expert opinion from researchers who have published PFS-related guidelines, checklists, frameworks, and recommendations on a wide range of topics and distilled this knowledge into a valuable and universal resource for researchers conducting PFS. Researchers may use these considerations alongside the previously published literature to guide decisions about all aspects of PFS, with the hope of creating and disseminating interventions with broad public health impact.

Preparation of PLCL/ECM nerve conduits by electrostatic spinning technique and evaluationin vitroandin vivo.

Objective. Artificial nerve scaffolds composed of polymers have attracted great attention as an alternative for autologous nerve grafts recently. Due to their poor bioactivity, satisfactory nerve repair could not be achieved. To solve this problem, we introduced extracellular matrix (ECM) to optimize the materials.Approach.In this study, the ECM extracted from porcine nerves was mixed with Poly(L-Lactide-co-ϵ-caprolactone) (PLCL), and the innovative PLCL/ECM nerve repair conduits were prepared by electrostatic spinning technology. The novel conduits were characterized by scanning electron microscopy (SEM), tensile properties, and suture retention strength test for micromorphology and mechanical strength. The biosafety and biocompatibility of PLCL/ECM nerve conduits were evaluated by cytotoxicity assay with Mouse fibroblast cells and cell adhesion assay with RSC 96 cells, and the effects of PLCL/ECM nerve conduits on the gene expression in Schwann cells was analyzed by real-time polymerase chain reaction (RT-PCR). Moreover, a 10 mm rat (Male Wistar rat) sciatic defect was bridged with a PLCL/ECM nerve conduit, and nerve regeneration was evaluated by walking track, mid-shank circumference, electrophysiology, and histomorphology analyses.Main results.The results showed that PLCL/ECM conduits have similar microstructure and mechanical strength compared with PLCL conduits. The cytotoxicity assay demonstrates better biosafety and biocompatibility of PLCL/ECM nerve conduits. And the cell adhesion assay further verifies that the addition of ECM is more beneficial to cell adhesion and proliferation. RT-PCR showed that the PLCL/ECM nerve conduit was more favorable to the gene expression of functional proteins of Schwann cells. Thein vivoresults indicated that PLCL/ECM nerve conduits possess excellent biocompatibility and exhibit a superior capacity to promote peripheral nerve repair.Significance.The addition of ECM significantly improved the biocompatibility and bioactivity of PLCL, while the PLCL/ECM nerve conduit gained the appropriate mechanical strength from PLCL, which has great potential for clinical repair of peripheral nerve injuries.

Efforts to promote osteogenesis-angiogenesis coupling for bone tissue engineering.

Repair of bone defects exceeding a critical size has been always a big challenge in clinical practice. Tissue engineering has exhibited great potential to effectively repair the defects with less adverse effect than traditional bone grafts, during which how to induce vascularized bone formation has been recognized as a critical issue. Therefore, recently many studies have been launched to attempt to promote osteogenesis-angiogenesis coupling. This review summarized comprehensively and explored in depth current efforts to ameliorate the coupling of osteogenesis and angiogenesis from four aspects, namely the optimization of scaffold components, modification of scaffold structures, loading strategies for bioactive substances, and employment tricks for appropriate cells. Especially, the advantages and the possible reasons for every strategy, as well as the challenges, were elaborated. Furthermore, some promising research directions were proposed based on an in-depth analysis of the current research. This paper will hopefully spark new ideas and approaches for more efficiently boosting new vascularized bone formations.

Diagnostic and prognostic value of angiography-derived index of microvascular resistance: a systematic review and meta-analysis.

Background: The angiography-derived index of microvascular resistance (A-IMR) is a novel tool for diagnosing coronary microvascular dysfunction (CMD) addressing limitation of unavailability. However, the clinical value of A-IMR remains controversial. Methods: A systematic review and meta-analysis was conducted. PubMed, EMBASE, Cochrane Library and Web of Science were searched for relevant studies. Studies that reported estimates of A-IMR's diagnostic accuracy (with thermodilution-based IMR as the reference test) and/or predictions of adverse cardiovascular events were selected. Pooled sensitivity, specificity, area under the summary receiver operating characteristic curve (sROC) were calculated to measure diagnostic performance; pooled hazard/risk ratio (HR/RR) and 95% confidence interval (95% CI) of major adverse cardiovascular events (MACE) or other independent adverse events were calculated to measure prognostic effect. This study was registered with PROSPERO (CRD42023451884). Results: A total of 12 diagnostic studies pooling 1,642 vessels and 12 prognostic studies pooling 2,790 individuals were included. A-IMR yielded an area under sROC of 0.93 (95% CI: 0.91, 0.95), a pooled sensitivity of 0.85 (95% CI: 0.79, 0.89) and a pooled specificity of 0.89 (95% CI: 0.83, 0.93) for the diagnosis of CMD. CMD diagnosed using A-IMR was associated with higher risks of MACE (HR, 2.73, 95% CI: 2.16, 3.45), CV death (RR, 2.39, 95% CI: 1.49, 3.82) and heart failure hospitalization (HR, 2.30, 95% CI: 1.53, 3.45). Conclusion: A-IMR demonstrated high diagnostic accuracy for CMD and showed a strong prognostic capability in predicting the risk of adverse CV outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023451884, PROSPERO (CRD42023451884).

Control of defensive behavior by the nucleus of Darkschewitsch GABAergic neurons.

The nucleus of Darkschewitsch (ND), mainly composed of GABAergic neurons, is widely recognized as a component of the eye-movement controlling system. However, the functional contribution of ND GABAergic neurons (NDGABA) in animal behavior is largely unknown. Here, we show that NDGABA neurons were selectively activated by different types of fear stimuli, such as predator odor and foot shock. Optogenetic and chemogenetic manipulations revealed that NDGABA neurons mediate freezing behavior. Moreover, using circuit-based optogenetic and neuroanatomical tracing methods, we identified an excitatory pathway from the lateral periaqueductal gray (lPAG) to the ND that induces freezing by exciting ND inhibitory outputs to the motor-related gigantocellular reticular nucleus, ventral part (GiV). Together, these findings indicate the NDGABA population as a novel hub for controlling defensive response by relaying fearful information from the lPAG to GiV, a mechanism critical for understanding how the freezing behavior is encoded in the mammalian brain.

Leakage and Thermal Reliability Optimization of Stacked Nanosheet Field-Effect Transistors with SiC Layers.

In this work, we propose a SiC-NSFET structure that uses a PTS scheme only under the gate, with SiC layers under the source and drain, to improve the leakage current and thermal reliability. Punch-through stopper (PTS) doping is widely used to suppress the leakage current, but aggressively high PTS doping will cause additional band-to-band (BTBT) current. Therefore, the bottom oxide isolation nanosheet field-effect transistor (BOX-NSFET) can further reduce the leakage current and become an alternative to conventional structures with PTS. However, thermal reliability issues, like bias temperature instability (BTI), hot carrier injection (HCI), and time-dependent dielectric breakdown (TDDB), induced by the self-heating effect (SHE) of BOX-NSFET, become more profound due to the lower thermal conductivity of SiO2 than silicon. Moreover, the bottom oxide will reduce the stress along the channel due to the challenges associated with growing high-quality SiGe material on SiO2. Therefore, this method faces difficulties in enhancing the mobility of p-type devices. The comprehensive TCAD simulation results show that SiC-NSFET significantly suppresses the substrate leakage current compared to the conventional structure with PTS. In addition, compared to the BOX-NSFET, the stress reduction caused by the bottom oxide is avoided, and the SHE is mitigated. This work provides significant design guidelines for leakage and thermal reliability optimization of next-generation advanced nodes.

Relationship between syncopal symptoms and head-up tilt test modes.

OBJECTIVE: Head-up tilt test (HUTT) is an important tool in the diagnosis of pediatric vasovagal syncope. This research will explore the relationship between syncopal symptoms and HUTT modes in pediatric vasovagal syncope. METHODS: A retrospective analysis was performed on the clinical data of 2513 children aged 3-18 years, who were diagnosed with vasovagal syncope, from Jan. 2001 to Dec. 2021 due to unexplained syncope or pre-syncope. The average age was 11.76 ± 2.83 years, including 1124 males and 1389 females. The patients were divided into the basic head-up tilt test (BHUT) group (596 patients) and the sublingual nitroglycerine head-up tilt test (SNHUT) group (1917 patients) according to the mode of positive HUTT at the time of confirmed pediatric vasovagal syncope. RESULTS: (1) Baseline characteristics: Age, height, weight, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and composition ratio of syncope at baseline status were higher in the BHUT group than in the SNHUT group (all P < 0.05). (2) Univariate analysis: Age, height, weight, HR, SBP, DBP, and syncope were potential risk factors for BHUT positive (all P < 0.05). (3) Multivariate analysis: syncope was an independent risk factor for BHUT positive, with a probability increase of 121% compared to pre-syncope (P<0.001). CONCLUSION: The probability of BHUT positivity was significantly higher than SNHUT in pediatric vasovagal syncope with previous syncopal episodes.

C3aR in the medial prefrontal cortex modulates the susceptibility to LPS-induced depressive-like behaviors through glutamatergic neuronal excitability.

Complement activation and prefrontal cortical dysfunction both contribute to the pathogenesis of major depressive disorder (MDD), but their interplay in MDD is unclear. We here studied the role of complement C3a receptor (C3aR) in the medial prefrontal cortex (mPFC) and its influence on depressive-like behaviors induced by systematic lipopolysaccharides (LPS) administration. C3aR knockout (KO) or intra-mPFC C3aR antagonism confers resilience, whereas C3aR expression in mPFC neurons makes KO mice susceptible to LPS-induced depressive-like behaviors. Importantly, the excitation and inhibition of mPFC neurons have opposing effects on depressive-like behaviors, aligning with increased and decreased excitability by C3aR deletion and activation in cortical neurons. In particular, inhibiting mPFC glutamatergic (mPFCGlu) neurons, the main neuronal subpopulation expresses C3aR, induces depressive-like behaviors in saline-treated WT and KO mice, but not in LPS-treated KO mice. Compared to hypoexcitable mPFCGlu neurons in LPS-treated WT mice, C3aR-null mPFCGlu neurons display hyperexcitability upon LPS treatment, and enhanced excitation of mPFCGlu neurons is anti-depressant, suggesting a protective role of C3aR deficiency in these circumstances. In conclusion, C3aR modulates susceptibility to LPS-induced depressive-like behaviors through mPFCGlu neuronal excitability. This study identifies C3aR as a pivotal intersection of complement activation, mPFC dysfunction, and depression and a promising therapeutic target for MDD.