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With the rapid development of seed research, understanding the external structure and characteristics of plants has become essential. Seed coat thickness plays a key role in assessing seed quality in seed reproduction, storage, processing, and research. However, traditional manual measurement methods are labor-intensive, subjective bias, and measurement errors. To solve this problem , we propose an efficient and universal deep learning method, FSUNet. Base on the UNet model, FSUNet introduces a new Full-Scale Information Fusion module (FSIF), adopting 7 × 7 depth-wise separable convolutions and point convolutions to capture remote information, and designs the MConv module. The FSUNet model has 5.109 M parameters, only 14.79% of the UNet model. This research validated the method with a self-constructed corn seed coat segmentation dataset. FSUNet achieved segmentation results of 69.37%, 67.80%, 83.85%, and 85.40% on the self-constructed dataset and the three public datasets, respectively, which are 0.24%, 1.95%, 1.51%, and 0.73% higher than those of the UNet model. Compared to other recent lightweight models like CMUNext, FSUNet shows significant advantages. In addition, we also provide a seed coat thickness measurement algorithm that can obtain stable and accurate measurement results. Through our method, the measurement efficiency and accuracy of seed coat thickness can be significantly improved, providing strong tools and technical support for plant seed research.

Ethephon (ETH) is a plant growth regulator extensively utilized in agriculture, but its overuse is associated with several health issues. However, detecting ETH sensitively and easily in the field is challenging due to the complexity and time-consuming operation of current approaches. In this study, we synthesized aluminum-based metal-organic frameworks (CAU-1) as fluorescent probes for the detection of ETH in fruit. ETH exposure enhanced and shifted the light green fluorescence of CAU-1 to blue through high absorption of phosphate by electrostatic attraction. We observed a linear correlation between fluorescent intensity and ETH concentration ranging from 2 mg/L to 400 mg/L, with the lowest detection limit at 1 mg/L. This fluorescent analysis exhibited good selectivity towards ETH. To facilitate easy identification of samples in the field, we designed a fluorescent paper-based platform with a logic gate operation, allowing visual distinction of samples containing ETH. We applied this platform to monitor ETH in various fruits, including apples, pears, and tomatoes, through fluorescent spectrum, and visual detection. The platform offered simplicity, speed, ease of use and sensitivity, providing a promising future for ETH detection in agriculture.

The fragmentation of vessel tracks represents a significant challenge in the context of high-frequency surface wave radar (HFSWR) tracking. This paper proposes a new track segment association (TSA) algorithm that integrates optimal tracklet assignment, iterative discrimination, and multi-stage association. This paper reformulates the optimal tracklet assignment task as an optimal state search problem for modeling and solution purposes. To determine whether competing old and new tracklets can be associated, we assume the existence of a public state that represents the correlation between the tracklets. However, due to track fragmentation, this public state remains unknown. We need to search for the optimal public state of all candidate tracklet pairs within a feasible parameter space, using a fitness function value as the evaluation criterion. The old and new tracklets pairs that match the optimal public state are considered optimally associated. Since the solution process involves searching for the optimal state across multiple dimensions, it constitutes a high-dimensional optimization problem. To accomplish this task, the catch fish optimization algorithm (CFOA) is employed for its ability to escape local optima and handle high-dimensional optimization, enhancing the reliability of tracklet assignment. Furthermore, we achieve precise one-to-one associations by assigning new tracklet to old tracklet through the optimal tracklet assignment method we proposed, a process we abbreviate as AN2O, and its inverse process, which assigns old tracklet to new tracklet, abbreviated as AO2N. This dual approach is further complemented by an iterative discrimination mechanism that evaluates unselected tracklets to identify potential associations that may exist. The algorithm effectiveness of the proposed is validated using field experiment data from HFSWR in the Bohai Sea region, demonstrating its capability to accurately process complex tracklet data.

This paper investigates the attitude control problem of unmanned aerial vehicles (UAVs), especially in the presence of uncertainties and external disturbances. To address this challenge, a fractional-order reaching law sliding mode with active disturbance rejection controller (FOSM-ADRC) is proposed. The controller combines a fractional-order calculus operator and active disturbance rejection controller (ADRC) techniques to enhance the dynamic performance and robustness of the system. Through the inner and outer loop design, the jitter of the sliding mode controller (SMC) is effectively suppressed, and fast response and strong anti-jamming ability are achieved, which, in turn, improves the control accuracy. Firstly, the dynamic model of the UAV is established, and its nonlinear dynamic characteristics are analyzed in detail. On this basis, a fractional-order reaching law sliding mode controller (FO-SMC) is designed as the outer loop to achieve fast response. ADRC is employed in the inner loop to compensate for the internal and external disturbances of the system. The results show that the FOSM-ADRC can effectively suppress the jitter phenomenon and maintain good control performance.

ABSTRACT Hypermucoviscosity (HMV) is a phenotype that is commonly associated with hypervirulence in Klebsiella pneumoniae. The factors that contribute to the emergence of HMV subpopulations remain unclear. In this study, eight K. pneumoniae strains were recovered from an inpatient who had been hospitalized for 20 days. Three of the isolates exhibited a non-HMV phenotype, which was concomitant with higher biofilm formation than the other five HMV isolates. All eight isolates were highly susceptible to serum killing, albeit HMV strains were remarkably more infective than non-HMV counterparts in a mouse model of infection. Whole genome sequencing (WGS) showed that the eight isolates belonged to the K57-ST412 lineage. Average nucleotide identity (FastANIb) analysis indicated that eight isolates share 99.96% to 99.99% similarity and were confirmed to be the same clone. Through comparative genomics analysis, 12 non-synonymous mutations were found among these isolates, eight of which in the non-HMV variants, including rmpA (c.285delG) and wbaP (c.1305T > A), which are assumed to be associated with the non-HMV phenotype. Mutations in manB (c.1318G > A), dmsB (c.577C > T) and tkt (c.1928C > A) occurred in HMV isolates only. RNA-Seq revealed transcripts of genes involved in energy metabolism, carbohydrate metabolism and membrane transport, including cysP, cydA, narK, tktA, pduQ, aceB, metN, and lsrA, to be significantly dysregulated in the non-HMV strains, suggesting a contribution to HMV phenotype development. This study suggests that co-occurrence of HMV and non-HMV phenotypes in the same clonal population may be mediated by mutational mechanisms as well as by certain genes involved in membrane transport and central metabolism.IMPORTANCEK. pneumoniae with a hypermucoviscosity (HMV) phenotype is a community-acquired pathogen that is associated with increased invasiveness and pathogenicity, and underlying diseases are the most common comorbid risk factors inducing metastatic complications. HMV was earlier attributed to the overproduction of capsular polysaccharide, and more data point to the possibility of several causes contributing to this bacterial phenotype. Here, we describe a unique event in which the same clonal population showed both HMV and non-HMV characteristics. Studies have demonstrated that this process is influenced by mutational processes and genes related to transport and central metabolism. These findings provide fresh insight into the mechanisms behind co-occurrence of HMV and non-HMV phenotypes in monoclonal populations as well as potentially being critical in developing strategies to control the further spread of HMV K. pneumoniae.

The widespread use and subsequent accumulation of florfenicol (FFC), a common antibiotic, through the food chain poses significant risks to aquatic ecosystems and human health, necessitating effective strategies for its removal from water bodies. To solve the challenge, herein, we developed a novel aluminum-based metal–organic framework CAU-1, engineered for the efficient adsorption of FFC. CAU-1 contains the plentiful –NH2 and μ-OH groups with the positively charged on the surface. In the adsorption process, CAU-1 perform hydrogen bonding interactions with FFC’s functional groups (−F, –OH, −Cl, –NH–, and −SO2–). Furthermore, the positively charged surface of CAU-1 enhances FFC adsorption via electrostatic attraction together. FFC adsorption equilibrium on CAU-1 is attained within 180 min with a monolayer adsorption capacity of 386 mg/g at 303 K, surpassing most of the reported adsorbents. The exothermic FFC adsorption process on CAU-1 remains largely unaffected by coexisting ions. Additionally, CAU-1 can be efficiently regenerated using a mixed solution of 0.1 M HCl and ethanol–water as an eluent. This work highlights CAU-1’s potential as an effective adsorbent for FFC removal, emphasizing the importance of tuning or designing surface functional groups on adsorbents to boost their adsorption capabilities.

The approach to calculating density significantly impacts the clustering efficacy of the Density Peak Clustering (DPC) method, with various density calculation methods tailored for different datasets. To address this, this study introduces a Self-Representation Weighted Density Peak Clustering (SR-DPC) method. Unlike traditional DPC, SR-DPC not only utilizes the local data point information but also amplifies the impact of different data points on the data center by implementing a weighting strategy, enhancing the precision with which data centers are identified. Moreover, SR-DPC adaptively reflects the influence of diverse data points on the data centers via feature representation and employs a weighted Gaussian kernel distance instead of the Euclidean distance to boost its clustering capabilities. Experimental evaluations on both synthetic and real datasets demonstrate the effectiveness and practicality of the SR-DPC method.

ABSTRACT: Objectives: The aim of this study was to characterize the blaKPC-33 in a ST15-K19 ceftazidime-avibactam (CAZ-AVI)-resistant Klebsiella pneumoniae strain after the antibiotic CAZ-AVI was approved for use in Wuxi No. 2 People's Hospital, China. Methods: Antimicrobial susceptibility testing was performed by the microdilution broth method. Whole genome sequencing (WGS) was performed using PacBio II and MiSeq sequencers. High-quality reads were assembled using the SOAPdenovo and GapCloser v1.12, and genome annotation was performed using the NCBI Prokaryotic Genome Annotation Pipeline (PGAP). Genomic characteristics were analysed by using bioinformatics methods. Results: K. pneumoniae strain KPHRJ showed resistance to CAZ-AVI. WGS analysis showed that strain KPHRJ had one 5 536 506 bp chromosome (57.25% G+C content) and one plasmid (133 451 bp, G+C 54.29%). KPHRJ was classified as ST15 and K19 serotype. Resistome analysis showed that KPHRJ carries seven antimicrobial resistance genes (ARGs). WGS analysis and conjugation experiments demonstrated that the blaKPC-33 gene was carried by plasmid pKPHRJ, flanked by two copies of IS26 mobile elements (IS26-ISKpn27-blaKPC-33-ISKpn6-korC-TnAs1-tetR-tetA-Tn3-IS26). Besides these acquired resistance genes, mutations in porin protein-coding genes, such as OmpK36 and OmpK37, which may reduce susceptibility to the CAZ-AVI, were also identified from the genome. Conclusion: Here, we present the WGS of a CAZ-AVI resistant K. pneumoniae isolate, strain KPHRJ, with capsular serotype K19 and belonging to ST15. CAZ-AVI resistance is likely conferred by a KPC-2 variant, blaKPC-33 and mutations in porin-coding genes. We speculate that the approval of the CAZ-AVI in hospital could contribute to the emergence of these genomic features by providing a selective pressure leading to the emergence of CAZ-AVI resistant bacteria.

Abstract Oncolytic viruses (OVs) for cancer treatment are in a rapid stage of development, and the direct tumor lysis and activation of a comprehensive host immune response are irreplaceable advantages of cancer immunotherapy. However, excessive antiviral immune responses also restrict the spread of OVs in vivo and the infection of tumor cells. Macrophages are functionally diverse innate immune cells that phagocytose tumor cells and present antigens to activate the immune response, while also limiting the delivery of OVs to tumors. Studies have shown that the functional propensity of macrophages between OVs and tumor cells affects the overall therapeutic effect of oncolytic virotherapy. How to effectively avoid the restrictive effect of macrophages on OVs and reshape the function of tumor-associated macrophages in oncolytic virotherapy is an important challenge we are now facing. Here, we review and summarize the complex dual role of macrophages in oncolytic virotherapy, highlighting how the functional characteristics of macrophage plasticity can be utilized to cooperate with OVs to enhance anti-tumor effects, as well as highlighting the importance of designing and optimizing delivery modalities for OVs in the future.

Abstract Heavy metal ions pose a threat to both ecological balance and human health owing to the non-biodegradable and poisonous characteristics. A simple, convenient and rapid metal ion monitoring plays a significant role for eliminating metal ions pollution. In this work, we prepared 4-mercaptobenzoic acids (4-MBA)-functionalized silver-coated gold nanoparticles (Au@Ag NPs) as colorimetric probes to construct colorimetric Chromium III (Cr3+) ions detection platform. The results showed that 4-MBA-Au@Ag NPs could effectively coordinate with the low-concentration Cr3+ ions with the group of -COOH, generating the obviously colorimetric reaction. To detection system, the optimal concentration of 4-MBA and pH was 5 μM and 9, respectively. Signal response was found to be proportional to Cr3+ ions concentration in the range from 10 to 500 μM with a correlation coefficient of 0.993, with UV–Vis and colorimetric detection limits determined as 9 μM and 10 μM, respectively. In addition, the recovery of the system was estimated to be from 88.2 to 112.1%, which was satisfactory for practical analysis of samples. The platform would have great potential applications in many areas.

Autophagy is a lysosomal self-degradation pathway that plays an important protective role in maintaining intracellular environment. Deregulation of autophagy is related to several diseases, including cancer, infection, neurodegeneration, aging, and heart disease. In this review, we will summarize recent advances in autophagy-mediated nanomaterials for tumor therapy. Firstly, the autophagy signaling pathway for tumor therapy will be reviewed, including oxidative stress, mammalian target of rapamycin (mTOR) signaling and autophagy-associated genes pathway. Based on that, many autophagy-mediated nanomaterials have been developed and applied in tumor therapy. According to the different structure of nanomaterials, we will review and evaluate these autophagy-mediated nanomaterials’ therapeutic efficacy and potential clinical application.

The sustainable management of wastewater through recycling and utilization stands as a pressing concern in the trajectory of societal advancement. Prioritizing the elimination of diverse organic contaminants is paramount in wastewater treatment, garnering significant attention from researchers worldwide. Emerging metal-organic framework materials (MOFs), bridging organic and inorganic attributes, have surfaced as novel adsorbents, showcasing pivotal potential in wastewater remediation. Nevertheless, challenges like limited water stability, elevated dissolution rates, and inadequate hydrophobicity persist in the context of wastewater treatment. To enhance the performance of MOFs, they can be modified through chemical or physical methods, and combined with membrane materials as additives to create membrane composite materials. These membrane composites, derived from MOFs, exhibit remarkable characteristics including enhanced porosity, adjustable pore dimensions, superior permeability, optimal conductivity, and robust water stability. Their ability to effectively sequester organic compounds has spurred significant research in this field. This paper introduces methods for enhancing the performance of MOFs and explores their potential applications in water treatment. It delves into the detailed design, synthesis strategies, and fabrication of composite membranes using MOFs. Furthermore, it focuses on the application prospects, challenges, and opportunities associated with MOF composite membranes in water treatment.

Abstract Background To establish the normal reference ranges for parameters related to the fetal posterior fossa in the first trimester (11 ~ 13+6 weeks of gestation) and to analyze the relationship between them and crown-rump length (CRL) among the Chinese population. Methods Singleton pregnancies of 11 ~ 13+6 weeks (CRL:45 ~ 84 mm) with both parents from China were randomly selected from January 2021 to November 2021. The related parameters of the posterior fossa including cisterna magna (CM), intracranial translucency (IT), brain stem (BS), brain stem to the occipital bone (BSOB), and brain stem/brain stem to occipital bone (BS/BSOB) were evaluated and measured in nuchal translucency (NT) mid-sagittal section clearly by an experienced sonographer (operator 1). To assess the reproducibility of the measurements, we randomly selected 50 pregnant women. According to the blind method, operators 1 and 2 respectively screened and measured relevant parameters. In addition, operator 1 examined and measured relevant parameters again 2 h after the first. Results This study included 1663 fetuses. All fetuses can clearly show the three spaces of the fetal posterior fossa. The ICCs (95% CI) of intra-operator reproducibility of CM, IT, BS, BSOB, BS/BSOB were 0.981 (0.952 ~ 0.991, P

ABSTRACT Mycoplasma pneumoniae (MP) is an important respiratory pathogen, the prevalence of macrolide-resistant MP (mainly containing A2063G mutation in 23S rRNA) increased in recent years. Epidemiological studies suggest a higher prevalence of type I resistant (IR) strains than corresponding sensitive (IS/IIS) strains, but not type II resistant (IIR) strains. Here, we aimed to analyze the factors underlying the altered prevalence of IR strains. First, proteomic analyses exhibit the protein compositions were type specific, while more differential proteins were detected between IS and IR (227) than IIS and IIR strains (81). mRNA level detection suggested posttranscriptional regulation of these differential proteins. Differential protein-related phenotypic changes were also detected: (i) P1 abundance was different between genotypes (I < II, IR < IS), the adhesion of MPs showed accordance to P1 abundance within IS and IIS strains; (ii) type I, especially IR, strains had a higher proliferation rate, which is potentially associated with differential proteins participating in glycolysis and one carbon pool metabolisms; (iii) A549 cells infected with IR strains had lower activity of caspase-3 and higher levels IL-8, but the differences were not significant between groups (P > 0.05). Correlations of P1 abundance to caspase-3 activity and proliferation rate to the level of IL-8 were obtained. These results suggest changes in protein composition influenced the pathogenicity of MP, especially in IR strains, which may impact the prevalence of MP strains of different genotypes. IMPORTANCE The prevalence of macrolide-resistant MPs increased the difficulty in treatment of MP infections and posed potential threats to children's health. Epidemiological studies showed a high prevalence of IR-resistant strains (mainly A2063G in 23S rRNA) in these years. However, the trigger mechanisms for this phenomenon are not clear. In this paper, proteomic and phenotypic studies suggest that IR strains have reduced levels of multiple adhesion proteins and increased proliferation rate, which may lead to higher transmission rate of IR strains in the population. This suggests that we should pay attention to the prevalence of IR strains.

Abstract Background People live a long time in pre-diabetes/early diabetes without a formal diagnosis or management. Heterogeneity of progression coupled with deficiencies in electronic health records related to incomplete data, discrete events, and irregular event intervals make identification of pre-diabetes and critical points of diabetes progression challenging. Methods We utilized longitudinal electronic health records of 9298 patients with type 2 diabetes or prediabetes from 2005 to 2016 from a large regional healthcare delivery network in China. We optimized a generative Markov-Bayesian-based model to generate 5000 synthetic illness trajectories. The synthetic data were manually reviewed by endocrinologists. Results We build an optimized generative progression model for type 2 diabetes using anchor information to reduce the number of parameters learning in the third layer of the model from $$O\left(N\times W\right)$$ O N × W to $$O\left((N-C)\times W\right)$$ O ( N - C ) × W , where $$N$$ N is the number of clinical findings, $$W$$ W is the number of complications, $$C$$ C is the number of anchors. Based on this model, we infer the relationships between progression stages, the onset of complication categories, and the associated diagnoses during the whole progression of type 2 diabetes using electronic health records. Discussion Our findings indicate that 55.3% of single complications and 31.8% of complication patterns could be predicted early and managed appropriately to potentially delay (as it is a progressive disease) or prevented (by lifestyle modifications that keep patient from developing/triggering diabetes in the first place). Conclusions The full type 2 diabetes patient trajectories generated by the chronic disease progression model can counter a lack of real-world evidence of desired longitudinal timeframe while facilitating population health management.

Abstract Background Bacterial infection in wounds has become a major threat to human life and health. With the growth use of synthetic antibiotics and the elevated evolution of drug resistant bacteria in human body cells requires the development of novel wound curing strategies. Herein, a novel pH-responsive hydrogel (RPC/PB) was fabricated using poly(vinyl alcohol)-borax (PB) and natural antibiotic resveratrol grafted cellulose nanofibrils (RPC) for bacterial-infected wound management. Results In this hydrogel matrix, RPC conjugate was interpenetrated in the PB network to form a semi-interpenetrating network that exhibited robust mechanical properties (fracture strength of 149.6 kPa), high self-healing efficiency (> 90%), and excellent adhesion performance (tissue shear stress of 54.2 kPa). Interestingly, the induced RPC/PB hydrogel showed pH-responsive drug release behavior, the cumulative release amount of resveratrol in pH 5.4 was 2.33 times than that of pH 7.4, which was adapted well to the acidic wound microenvironment. Additionally, this RPC/PB hydrogel exhibited excellent biocompatibility and antioxidant effect. Moreover, in vitro and in vivo results revealed that such RPC/PB hydrogel had excellent antibacterial, skin tissue regeneration and wound closure capabilities. Conclusion Therefore, the generated RPC/PB hydrogel could be an excellent wound dressing for bacteria-infected wound healing.

Hepatocellular carcinoma (HCC) is a common malignant tumor with poor prognosis and high mortality. In this study, we demonstrated a novel vaccine targeting HCC and tumor neovascular endothelial cells by fusing recombinant MHCC97H cells expressing porcine α-1,3-galactose epitopes (αGal) and endorphin extracellular domains (END) with dendritic cells (DCs) from healthy volunteers. END+/Gal+-MHCC97H/DC fusion cells induced cytotoxic T lymphocytes (CTLs) and secretion of interferon-gamma (IFN-γ). CTLs targeted cells expressing αGal and END and tumor angiogenesis. The fused cell vaccine can effectively inhibit tumor growth and prolong the survival time of human hepatoma mice, indicating the high clinical potential of this new cell based vaccine.

Abstract Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.

Abstract Non-human primates (NHPs) represent the most valuable animals for drug discovery. However, the current main challenge remains that the NHP has not yet been used to develop an efficient translational medicine platform simulating human diseases, such as cancer. This study generated an in situ gene-editing approach to induce efficient loss-of-function mutations of Pten and p53 genes for rapid modeling primary and metastatic liver tumors using the CRISPR/Cas9 in the adult cynomolgus monkey. Under ultrasound guidance, the CRISPR/Cas9 was injected into the cynomolgus monkey liver through the intrahepatic portal vein. The results showed that the ultrasound-guided CRISPR/Cas9 resulted in indels of the Pten and p53 genes in seven out of eight monkeys. The best mutation efficiencies for Pten and p53 were up to 74.71% and 74.68%, respectively. Furthermore, the morbidity of primary and extensively metastatic (lung, spleen, lymph nodes) hepatoma in CRISPR-treated monkeys was 87.5%. The ultrasound-guided CRISPR system could have great potential to successfully pursue the desired target genes, thereby reducing possible side effects associated with hitting non-specific off-target genes, and significantly increasing more efficiency as well as higher specificity of in situ gene editing in vivo, which holds promise as a powerful, yet feasible tool, to edit disease genes to build corresponding human disease models in adult NHPs and to greatly accelerate the discovery of new drugs and save economic costs.

The heat flow density is constantly increasing due to the growing demand for the integration and compaction of electronic devices. A sintered thin flat heat pipe (TFHP) is a typical device for managing the heat flux of highly integrated electronic circuits. Four different structures of the vapor–liquid flow channel architecture are designed in this work. Heat transfer performance tests of different TFHPs are carried out for different thermal powers. The surface temperature distribution and thermal resistance of the TFHP under different operating conditions are investigated. The experimental results show that the design of the vapor–liquid flow channel significantly impacts the TFHP’s heat transfer performance and that the wedge-shaped wick is better suited to the flow channel. The wedge-shaped wick has the lowest thermal resistance of 0.28 °C/W and the most elevated maximum thermal power of 22 W. The heat dispatch performance of the sintered wick TFHP is improved.

Due to its wide use in agriculture, a convenient and sensitive detection method for triazophos is urgent need. In this study, a terbium-based metal-organic framework (Tb-MOF) is mildly prepared as a fluorescent probe for triazophos detection. The fluorescence of Tb-MOF can be quenched by triazophos through the inner filter effect (IFE) and static quenching effect (SQE). The fluorescence analysis exhibits high sensitivity and limit of detection of 0.12 ng·mL−1 with a linear range of 3–800 ng·mL−1 to triazophos. The fluorescence analysis displays good selectivity towards triazophos. In addition, this method has been successfully applied to the detection of triazophos in tap water and strawberry with good recovery rates. More importantly, a fluorescent paper-based sensor and a logic gate operation for the detection of triazophos based on the Tb-MOF are designed. This strategy was simple, free of modification and complicated operation, and easy to operate, which has good prospects for future applications of triazophos detection.

Mycoplasma pneumoniae (MP) is an important human pathogen that mainly affects children causing general and severe Mycoplasma pneumoniae pneumonia (G/SMPP). In the present study, a comprehensive immune response data (33 cytokines) was obtained in school-age children (3–9 years old) during MPP, aiming to analyze the immune response patterns during MPP. At acute phase, changes of cytokines were both detected in GMPP (24/33) and SMPP (23/33) groups compared to the healthy group (p < 0.05), with 20 identical cytokines. Between MPP groups, the levels of 13 cytokines (IL-2, IL-10, IL-11, IL-12, IL-20, IL-28A, IL-32, IL-35, IFN-α2, IFN-γ, IFN-β, BAFF, and TSLP) were higher and three cytokines (LIGHT, OPN and CHI3L1) were lower in the SMPP group than in the GMPP group (p < 0.05). Function analysis reveals that macrophage function (sCD163, CHI3L1) are not activated in both MPP groups; difference in regulatory patterns of T cells (IL26, IL27, OPN, LIGHT) and defective activation of B cells (BAFF) were detected in the SMPP group compared to the GMPP group. Besides, the level of osteocalcin; sIL-6Rβ and MMP-2 are both decreased in MPP groups at acute and convalescent phases compared to the healthy group, among which the levels of sIL-6Rβ and MMP-2 showed negative correlations (p < 0.1) to the application of bronchial lavage in SMPP group, indicating their roles in the development of MPP. At the convalescent phase, more cytokines recovered in GMPP (18) than SMPP (11), revealing better controlled immune response during GMPP. These results reveal different immune response patterns during GMPP and SMPP. In addition, the differentiated cytokines may serve as potential indicators of SMPP; early intervention on immune response regulations may be helpful in reducing the severity of SMPP.

Abstract Objective Our goal was to research and develop exploratory analysis tools for clinical notes, which now are underrepresented to limit the diversity of data insights on medically relevant applications. Results We characterize how exploratory analysis can affect representation learning on clinical narratives and present several self-developed tools to explore sepsis. Our experiments focus on patients with sepsis in the MIMIC-III Clinical Database or in our institution’s research patient data repository. We found that global embeddings assist in learning local representations of clinical notes. Second, aligning at any specific time facilitates the use of learning models by pooling more available clinical notes to form a training set. Furthermore, reconstruction of the timeline enhances downstream-processing techniques by emphasizing temporal expressions and temporal relationships in clinical documentation. We demonstrate that clustering helps plot various types of clinical notes against a scale, which conveys a sense of the range or spread of the data and is useful for understanding data correlations. Appropriate exploratory analysis tools provide keen insights into preprocessing clinical notes, thereby further enhancing downstream analysis capabilities, making data driven medicine possible. Our examples can help generate better data representation of clinical documentation for models with improved performance and interpretability.

Herein, a colorimetric copper (Ⅱ) ion (Cu2+) detection system based on the oxidization reaction of 3′3′5′5′-tetramethylbenzidine (TMB) and Ag(S2O3)23− (in aqueous solution) was designed. The detection system comprised TMB, silver nanoparticles (AgNPs) and thiosulfate (S2O32−). It was observed that AgNPs were unable to oxidize TMB to a blue color. While, Cu2+ ions could effectively catalyze the S2O32--leaching system, thereby converting AgNPs to Ag(S2O3)23−. Similar to Ag (I), Ag(S2O3)23− catalyzed the color reaction of TMB. The colorimetric copper (Ⅱ) ion (Cu2+) detection system was fabricated. Results showed that the optimal amounts of TMB and Na2S2O3 were 800 and 400 μM, respectively, and the reaction time and temperature were 40 min and 25 °C, respectively. The range of curvature tendency was 1–100 μM, with a limit of detection of 100 nM. The detection system exhibited a high selectiveness for copper ions in an aqueous solution. Furthermore, this system shows remarkable promise for monitoring the aqueous quality.

Polygon shape is an important factor affecting the efficiency of vector polygon overlay analysis. Aiming at the problems that polygon shape is difficult to accurately measure and different algorithms have different sensitivities to the same polygon in vector polygon overlay analysis, 27 shape variables are selected from literature to establish the shape complexity models for Vatti, Greiner-Hormann and Martinez algorithms by multiple linear regression analysis in this paper. These three algorithms are suitable for arbitrary polygon clipping and include intersection, union, difference and symmetric difference operators. The experimental results show that the calculated performances of the intersection, union, difference and symmetric difference operators belonging to the same algorithm are similar to their sensitivity to the same polygon shape. The fitting correlation coefficient R2 of the shape complexity model based on the Greiner-Hormann algorithm is the highest among the three algorithms, which can explain 99% of the performance of this algorithm.

Abstract Herein, we report the construction of a colorimetric probe used to detecting Cr3+ ions in aqueous solution based on functionalized gold nanoparticles. We investigated 4-mercaptobenzoic acid, 4-nitrobenzenethiol, and a mixture of 4-mercaptobenzoic acid and 4-nitrobenzenethiol as ligands for Cr3+ ions to functionalize the gold nanoparticles, respectively. The results showed that the three probes were all aggregated in the presence of Cr3+ ions, which induces a color change from ruby to violet. Moreover, gold nanoparticles modified with 4-mercaptobenzoic acid exhibit a higher response toward Cr3+ than the two other probes, which can be detected by the naked eye and UV-vis absorption spectroscopy. The detection time was rapid (within 25 min). A linear relationship was obtained from 20 to 25 μM between the ratio of the absorbance observed at 635 nm and 520 nm (A635 nm/A520 nm) with the limit of detection was 5 × 10−6 M. This method exhibited excellent selectivity for Cr3+ ions over other tested heavy metal ions, anions, and organic molecules in the absence of another shielding reagent of metal ion. The system was successfully utilized to detect Cr3+ ions in simulated samples.

Tumor markers are important substances for assessing cancer development. In recent years, RNA tumor markers have attracted significant attention, and studies have shown that their abnormal expression of post-transcriptional regulatory genes is associated with tumor progression. Therefore, RNA tumor markers are considered as potential targets in clinical diagnosis and prognosis. Many studies show that biosensors have good application prospects in the field of medical diagnosis. The application of biosensors in RNA tumor markers is developing rapidly. These sensors have the advantages of high sensitivity, excellent selectivity, and convenience. However, the detection abundance of RNA tumor markers is low. In order to improve the detection sensitivity, researchers have developed a variety of signal amplification strategies to enhance the detection signal. In this review, after a brief introduction of the sensing principles and designs of different biosensing platforms, we will summarize the latest research progress of electrochemical, photoelectrochemical, and fluorescent biosensors based on signal amplification strategies for detecting RNA tumor markers. This review provides a high sensitivity and good selectivity sensing platform for early-stage cancer research. It provides a new idea for the development of accurate, sensitive, and convenient biological analysis in the future, which can be used for the early diagnosis and monitoring of cancer and contribute to the reduction in the mortality rate.

L-Histidine (L-His) is an essential amino acid, which is used to synthesize proteins and enzymes. The concentration of L-His in the body is controlled to regulate tissue growth and repair of tissues. In this study, a rapid and sensitive method was developed for colorimetric L-his detection using Cu2+ ions to inhibit the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB)–H2O2 system. H2O2 can oxidize TMB to oxTMB in the presence of copper, and the change in color from colorless (TMB) to blue (oxTMB) is similar to that observed in the presence of peroxidase. However, because the imidazole ring and carboxyl group of L-His can coordinate with Cu2+ ions to form stable L-His–Cu2+ complexes, the color of the TMB–H2O2 solution remains unchanged after the addition of L-His. Therefore, because L-His effectively hinders the colorimetric reaction of TMB with H2O2, this assay can be used to quantitatively determine the concentration of L-His in samples. Under optimized conditions, our colorimetric sensor exhibited two linear ranges of 60 nM to 1 μM and 1 μM to 1 mM for L-His detection and a detection limit of 50 nM (S/N = 3); furthermore, the assay can be performed within 20 min. Moreover, the proposed assay was used to determine the concentration of L-His in urine samples, suggesting that this convenient and label-free colorimetric method presents promising applications in bioanalytical chemistry and clinical diagnosis.

Photodynamic therapy (PDT) is a low invasive antitumor therapy with fewer side effects. On the other hand, immunotherapy also has significant clinical applications in the treatment of cancer. Both therapies, on their own, have some limitations and are incapable of meeting the demands of the current cancer treatment. The efficacy of PDT and immunotherapy against tumor metastasis and tumor recurrence may be improved by combination strategies. In this review, we discussed the possibility that PDT could be used to activate immune responses by inducing immunogenic cell death or generating cancer vaccines. Furthermore, we explored the latest advances in PDT antitumor therapy in combination with some immunotherapy such as immune adjuvants, inhibitors of immune suppression, and immune checkpoint blockade.

We summarize the experience of participating in two differential privacycompetitions organized by the National Institute of Standards and Technology (NIST). Inthis paper, we document our experiences in the competition, the approaches we have used,the lessons we have learned, and our call to the research community to further bridge thegap between theory and practice in DP research.

Objectives: The aim of this study was to characterise a high biofilm-forming capacity, hypermucoviscous, blaKPC and blaNDM co-producing Klebsiella pneumoniae strain (KSH203). Methods: Antimicrobial susceptibility, biofilm formation and hypermucoviscous phenotype were determined by the disk diffusion method, crystal violet staining and positive string test, respectively. Whole-genome sequencing was performed using a PacBio RS II Sequencer. High-quality reads were de novo assembled using Celera Assembler v.8.0. Genome annotation was performed using the NCBI Prokaryotic Genome Annotation Pipeline (PGAP), and the genome characteristics were analysed by bioinformatics methods. Results: Klebsiella pneumoniae strain KSH203 was resistant to all antibiotics tested but was only intermediate-resistant to polymyxin B. This strain showed high biofilm-forming ability and a hypermucoviscous phenotype with serotype K25 belonging to the ST11 clone. KSH203 consists of a 5 464 059-bp single chromosome and four plasmids including pKSH203-NDM (53 144 bp), pKSH203-KPC (159 467 bp), pKSH203-CTX-M-3 (156 910 bp) and pKSH203-qnrS (253 705 bp). A total of 44 antimicrobial resistance genes and a large number virulence-associated genes were identified in the genome of strain KSH203. Conclusion: In this study, we illustrate the whole genome sequence of high biofilm-forming capacity, hypermucoviscous K. pneumoniae isolate KSH203 with capsular serotype K25 belonging to ST11 isolated from a patient in China, which carried a large number of antimicrobial resistance genes and virulence-associated genes. Future studies are needed to be aware of dissemination of this type of strain among environmental, animal and human isolates.

Summary: Background: Antipsychotic medications are the common treatment for schizophrenia. However, reliable biomarkers that can predict individual treatment response are still lacking. The present study aimed to examine whether baseline putamen activity can predict individual treatment response in schizophrenia. Methods: Two independent samples of patients with drug-naive, first-episode schizophrenia (32 patients in sample 1 and 44 in sample 2) and matched healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) at baseline. Patients were treated with olanzapine for 8 weeks; symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and week 8. Fractional amplitude of low frequency fluctuation (fALFF) and pattern classification techniques were used to analyze the data. Findings: Univariate analysis shows an elevated pre-treatment fALFF in the left ventromedial putamen in both patient samples compared to healthy controls (p's

A change in the crystallinity of short-carbon-fiber-reinforced polyether ether ketone (CF/PEEK) composites has a significant effect on the shrinkage deformation characteristics and mechanical properties of the components that are fabricated using 3D printing of CF/PEEK composites. In this study, we propose a novel process for controlling the crystallinity of 3D-printed CF/PEEK composites. First, components of a CF/PEEK composite with low crystallinity and warping deformation were 3D printed at a normal ambient temperature (20 °C). Second, the crystallinity and mechanical properties of the composite were quantitatively controlled via a recrystallization process. Finally, the mechanical properties of the CF/PEEK composite (10 wt%) were found to be similar to those of the materials fabricated via the injection molding process. This research work is of positive significance to promote the application of 3D printed PEEK composite materials in the field of aerospace and orthopedic implants.

BackgroundDysfunctions of the thalamus and its projections to cortical cortices have been implicated in patient with somatization disorder (SD). However, changes in the anatomical specificity of thalamo-cortical functional connectivity (FC) in SD remain unclear.MethodsResting-state fMRI scans were collected in 25 first-episode, drug-naive patients with SD, as well as 28 sex-, age-, and education-matched healthy controls. We parcellated the thalamus with seven predefined regions of interest (ROIs) and used them as seeds to map whole-brain FC. Correlation analysis was conducted in the patients.ResultsWe found an increased pattern of thalamic ROI-cortex connectivity in patients with SD. Patients with SD demonstrated enhanced thalamic connectivity to the bilateral anterior/middle cingulum, motor/sensory cortex, visual cortex, and auditory cortex. A significantly negative correlation was found between the right occipital thalamic ROI to the anterior cingulum and EPQ extraversion scores (r=0.404, p=0.045) after the Benjamini-Hochberg correction.ConclusionsThis study demonstrates that anatomical specificity of enhanced thalamo-cortical FCs exists in first-episode, drug-naive patients with SD. These findings further highlight the importance of the thalamic subregions in the pathophysiology of SD.

Excessive intake of beer could increase serum uric acid levels, leading to high risk of gout, which was previously attributed to high purine content in beer. Recent reports that purine-rich vegetables and bean products do not cause higher uric acid levels do not support this theory. Why excessive intake of beer could increase a high risk of gout has been unclear. Other factors affecting the accumulation of uric acid in the blood have been explored. Beer contains relatively high levels of D-amino acids due to the racemization of l-amino acids induced by food processing. D-amino acid was catalyzed by D-amino acid oxidase to produce H2O2, which is further oxidized in the presence of Fe2+ to produce hydroxyl radicals, resulting in DNA damage and formation of a large amount of purine bases, which are oxidized to uric acid by a series of enzymes. Some food ingredients, such as vitamins and I–, prompt D-amino acids to form uric acid. D-amino acids in beer are one of the key factors responsible for the increase in uric acid levels. The biological response of D-amino acids could explain gout occurrence in beer drinkers.

Background: Lack of normal asymmetry in the brain has been reported in patients with schizophrenia. However, it remains unclear whether disrupted asymmetry originates from inter-hemispheric functional connectivity (FC) and/or intra-hemispheric FC in this patient population. Methods: Forty-four patients with drug-naive, first-episode schizophrenia, 42 unaffected siblings, and 44 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The parameter of asymmetry (PAS) and support vector machine (SVM) were used to analyze the data. Patients were treated with olanzapine for 8 weeks. Findings: Compared with healthy controls, patients showed lower PAS scores in the left middle temporal gyrus (MTG)/inferior temporal gyrus (ITG), left posterior cingulate cortex (PCC)/precuneus and left angular gyrus, and higher PAS scores in the left precentral gyrus/postcentral gyrus. Unaffected siblings also showed lower PAS scores in the left MTG/ITG and left PCC/precuneus relative to healthy controls. Further, SVM analysis showed that a combination of the PAS scores in these two clusters in patients at baseline was able to predict clinical response after 8 weeks of olanzapine treatment with 77.27% sensitivity, 72.73% specificity, and 75.00% accuracy. Interpretation: The present study suggests disrupted asymmetry of inter- and intra-hemispheric FC in drug-naive, first-episode schizophrenia; in addition, a reduced asymmetry of inter-hemispheric FC in the left MTG/ITG and left PCC/precuneus may serve as an endophenotype for schizophrenia, and may have clinical utility to predict response to olanzapine treatment. Fund: The National Key R&D Program of China and the National Natural Science Foundation of China. Keywords: Schizophrenia, Asymmetry, Olanzapine, Functional connectivity, Endophenotype

Abstract D-amino acid oxidases (DAAO) are stereospecific enzymes which are generally almost inactive towards L-enantiomer in neutral solution when L-, D-amino acids are supplied as substrates. In this paper, the D-amino acid oxidase can catalytic oxidize L-amino acids by modulating pH of aqueous solution. With L-Pro as substrate, the catalytic rate (k cat) and the affinity (K m) of DAAO were 6.71 s−1 and 33 mM at pH 8.0, respectively, suggesting that optimal pH condition enhanced the activity of DAAO towards L-Pro. Similar results were obtained when L-Ala (pH 9.8), L-Arg (pH 6.5), L-Phe (pH 9.0), L-Thr (pH 9.4), and L-Val (pH 8.5) were catalyzed by DAAO at various pH values. The racemization of the L-amino acids was not found by capillary electrophoresis analysis during oxidation, and quantification analysis of L-amino acids before and after catalytic reaction was performed, which confirmed that the modulation of enantioselectivity of DAAO resulted from the oxidation of L-amino acids rather than D-amino acids by changing pH. A mechanistic model was proposed to explain enhanced activity of DAAO towards L-amino acids under optimal pH condition.

The nucleus accumbens (NAc) plays an important role in the reward circuit, and abnormal regional activities of the reward circuit have been reported in various psychiatric disorders including somatization disorder (SD). However, few researches are designed to analyze the NAc connectivity in SD. This study was designed to explore the NAc connectivity in first-episode, drug-naive patients with SD using the bilateral NAc as seeds. Twenty-five first-episode, drug-naive patients with SD and 28 healthy controls were recruited. Functional connectivity (FC) was designed to analyze the images. LIBSVM (a library for support vector machines) was used to identify whether abnormal FC could be utilized to discriminate the patients from the controls. The patients showed significantly increased FC between the left NAc and the right gyrus rectus and left medial prefrontal cortex/anterior cingulate cortex (MPFC/ACC), and between the right NAc and the left gyrus rectus and left MPFC/ACC compared with the controls. The patients could be separated from the controls through increased FC between the left NAc and the right gyrus rectus with a sensitivity of 88.00% and a specificity of 82.14%. The findings reveal that patients with SD have increased NAc connectivity with the frontal regions of the reward circuit. Increased left NAc-right gyrus rectus connectivity can be used as a potential marker to discriminate patients with SD from healthy controls. The study thus highlights the importance of the reward circuit in the neuropathology of SD.

Ultraclean and damage-free transfer of graphene over large areas is crucial for the future development of flexible electronics and optoelectronics. Using a rosin-assisted method, the authors transfer graphene with an ultraclean surface and uniform small sheet resistance—a 4-inch monolithic organic light-emitting diode is demonstrated.

The notion of dysconnectivity in schizophrenia has been put forward for many years and results in substantial attempts to explore altered functional connectivity (FC) within different networks with inconsistent results. Clinical, demographical, and methodological heterogeneity may contribute to the inconsistency. Forty-four patients with first-episode, drug-naive schizophrenia, 42 unaffected siblings of schizophrenia patients and 44 healthy controls took part in this study. Global-brain FC (GFC) was employed to analyze the imaging data. Compared with healthy controls, patients with schizophrenia and unaffected siblings shared enhanced GFC in the left superior frontal gyrus (SFG). In addition, patients had increased GFC mainly in the thalamo-cortical network, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC)/precuneus, left superior medial prefrontal cortex (MPFC), right angular gyrus, and right SFG/middle frontal gyrus and decreased GFC in the left ITG/cerebellum Crus I. No other altered GFC values were observed in the siblings group relative to the control group. Further ROC analysis showed that increased GFC in the left SFG could separate the patients or the siblings from the controls with acceptable sensitivities. Our findings suggest that increased GFC in the left SFG may serve as a potential endophenotype for schizophrenia.

Background: Anatomical and functional deficits in the cortico-limbic-cerebellar circuit are involved in the neurobiology of somatization disorder (SD). The present study was performed to examine causal connectivity of the cortico-limbic-cerebellar circuit related to structural deficits in first-episode, drug-naive patients with SD at rest.Methods: A total of 25 first-episode, drug-naive patients with SD and 28 healthy controls underwent structural and resting-state functional magnetic resonance imaging. Voxel-based morphometry and Granger causality analysis (GCA) were used to analyze the data.Results: Results showed that patients with SD exhibited decreased gray matter volume (GMV) in the right cerebellum Crus I, and increased GMV in the left anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), and left angular gyrus. Causal connectivity of the cortico-limbic-cerebellar circuit was partly affected by structural alterations in the patients. Patients with SD showed bidirectional cortico-limbic connectivity abnormalities and bidirectional cortico-cerebellar and limbic-cerebellar connectivity abnormalities. The mean GMV of the right MFG was negatively correlated with the scores of the somatization subscale of the symptom checklist-90 and persistent error response of the Wisconsin Card Sorting Test (WCST) in the patients. A negative correlation was observed between increased driving connectivity from the right MFG to the right fusiform gyrus/cerebellum IV, V and the scores of the Eysenck Personality Questionnaire extraversion subscale. The mean GMV of the left ACC was negatively correlated with the WCST number of errors and persistent error response. Negative correlation was found between the causal effect from the left ACC to the right middle temporal gyrus and the scores of WCST number of categories achieved.Conclusions: Our findings show the partial effects of structural alterations on the cortico-limbic-cerebellar circuit in first-episode, drug-naive patients with SD. Correlations are observed between anatomical alterations or causal effects and clinical variables in patients with SD, and bear clinical significance. The present study emphasizes the importance of the cortico-limbic-cerebellar circuit in the neurobiology of SD.

Carbapenem-resistant Enterobacteriaceae have been a global public health issue in recent years. Here, a carbapenem-resistant Kluyvera cryocrescens strain SCW13 was isolated from hospital sewage, and was then subjected to whole-genome sequencing (WGS). Based on WGS data, antimicrobial resistance genes were identified. Resistance plasmids were completely circularized and further bioinformatics analyses of plasmids were performed. A conjugation assay was performed to identify a self-transmissible plasmid mediating carbapenem resistance. A phylogenetic tree was constructed based on the core genome of publicly available Kluyvera strains. The isolate SCW13 exhibited resistance to cephalosporin and carbapenem. blaNDM-1 was found to be located on a ~53-kb self-transmissible IncX3 plasmid, which exhibited high similarity to the previously reported pNDM-HN380, which is an epidemic blaNDM-1-carrying IncX3 plasmid. Further, we found that SCW13 contained a chromosomal blaKLUC-2 gene, which was the probable origin of the plasmid-born blaKLUC-2 found in Enterobacter cloacae. Phylogenetic analysis showed that K. cryocrescens SCW13 exhibited a close relationship with K. cryocrescens NCTC10483. These findings highlight the further dissemination of blaNDM through clonal IncX3 plasmids related to pNDM-HN380 among uncommon Enterobacteriaceae strains, including Kluyvera in this case.

BACKGROUND: Patients with somatization disorder (SD) have altered neural activity in the brain regions of the default mode network (DMN). However, the regional alteration of the DMN in SD remains unknown. The present study was designed to investigate the regional alterations of the DMN in patients with SD at rest. METHODS: Twenty-five first-episode, medication-naive patients with SD and 28 age-, sex-, education- matched healthy controls underwent a resting-state functional magnetic resonance imaging (fMRI) scan. The fractional amplitude of low-frequency fluctuations (fALFF) was applied to analyze the data. RESULTS: Patients with SD showed a dissociation pattern of resting-state fALFF in the DMN, with increased fALFF in the bilateral superior medial prefrontal cortex (MPFC, BA8, 9) and decreased fALFF in the left precuneus (PCu, BA7). Furthermore, significantly positive correlation was observed between the z values of the voxels within the bilateral superior MPFC and somatization subscale scores of the Symptom Check List (SCL-90) in patients with SD. CONCLUSIONS: Our findings indicate that there is a dissociation pattern of the anterior and posterior DMN in first-episode, treatment-naive patients with SD. The results provide new insight for the importance of the DMN in the pathophysiology of SD.

BACKGROUND: Default mode network (DMN) is one of the most commonly recognized resting-state networks in major depressive disorder (MDD). However, the homogeneity of this network in MDD is poorly understood. As such, this study was conducted to determine whether or not an abnormal network homogeneity (NH) of DMN is observed in patients with first-episode and drug-naive MDD. METHODS: Twenty-four first-episode drug-naive patients with MDD and twenty-four healthy control subjects participated in the study. NH and independent component analysis (ICA) methods were used to analyze data. RESULTS: Depressed patients exhibited a significantly increased NH in the left dorsal medial prefrontal cortex (MPFC) and decreased NH in the right inferior temporal gyrus (ITG) compared with the healthy control subjects. Receiver operating characteristic curves (ROC) were analyzed and results revealed that the NH values of MPFC and ITG could be applied as candidate markers with relatively high sensitivity and specificity to distinguish patients from healthy control subjects. No correlation was observed between the NH values of the two regions and clinical variables. CONCLUSIONS: Our findings suggested that an abnormal DMN homogeneity could be observed in MDD, which highlight the importance of the DMN in the pathophysiology of MDD.