The digestion and dietary carbohydrate pathway contains 100% gene mutations enrichment among 117 patients with major depressive disorder.

Introduction: Major depressive disorder (MDD) is partially inheritable while its mechanism is still uncertain. Methods: This cross-sectional study focused on gene pathways as a whole rather than polymorphisms of single genes. Deep sequencing and gene enrichment analysis based on pathways in Reactome database were obtained to reveal gene mutations. Results: A total of 117 patients with MDD and 78 healthy controls were enrolled. The Digestion and Dietary Carbohydrate pathway (Carbohydrate pathway) was determined to contain 100% mutations in patients with MDD and 0 mutation in matched healthy controls. Discussion: Findings revealed in the current study enable a better understanding of gene pathways mutations status in MDD patients, indicating a possible genetic mechanism of MDD development and a potential diagnostic or therapeutic target.

Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. Synaptic dysfunction has appeared in the early stage of AD and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here we found upregulated Maf1 transcription factor in AD, and Maf1 conditional knockout in AD transgenic mice restored learning and memory function. Downregulation of Maf1 reduced intraneuronal Ca2+ concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodeling in neurons. Therefore, our results clarified the important role and mechanism of the Maf1-NMDAR1 signaling pathway in the stability of the synaptic structure, neuronal function, and behavior during the pathogenesis of AD, serving as a potential diagnostic and therapeutic target for the early onset of AD.

Impaired visual-motor functional connectivity in first-episode medication-naïve patients with major depressive disorder.

The perceptual dysfunctions have been fundamental causes of cognitive and emotional problems in patients with major depressive disorder. However, visual system impairment in depression has been underexplored. Here, we explored functional connectivity in a large cohort of first-episode medication-naïve patients with major depressive disorder (n = 190) and compared it with age- and sex-matched healthy controls (n = 190). A recently developed individual-oriented approach was applied to parcellate the cerebral cortex into 92 regions of interest using resting-state functional magnetic resonance imaging data. Significant reductions in functional connectivities were observed between the right lateral occipitotemporal junction within the visual network and 2 regions of interest within the sensorimotor network in patients. The volume of right lateral occipitotemporal junction was also significantly reduced in major depressive disorder patients, indicating that this visual region is anatomically and functionally impaired. Behavioral correlation analysis showed that the reduced functional connectivities were significantly associated with inhibition control in visual-motor processing in patients. Taken together, our data suggest that functional connectivity between visual network and sensorimotor network already shows a significant reduction in the first episode of major depressive disorder, which may interfere with the inhibition control in visual-motor processing. The lateral occipitotemporal junction may be a hub of disconnection and may play a role in the pathophysiology of major depressive disorder.

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder.

Background: The retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD. Methods: A total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein-protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway. Results: Our analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress. Conclusion: These results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

Memory and processing speed impairments in first-episode drug-naïve patients with major depressive disorder.

BACKGROUND: Cognitive impairment, an intrinsic feature of major depressive disorder (MDD), affects daily and social functioning in depression patients. However, the cognitive impairment profile in MDD remains ambiguous because of the high heterogeneity of previous studies. METHODS: Four cognitive domains, including memory, processing speed, executive function (EF), and attention, were assessed in 184 first-episode drug-naïve (FEDN) MDD patients and matched 71 healthy controls (HCs). The effects of demographic and depressive factors on cognitive performance were analyzed using various statistical methods, including multi-factor analysis of variance, Mann-Whitney U test, and Spearman's rank correlation. In addition, the impact of depression severity on cognitive function was further assessed using subgroup analyses and partial correlation analyses. RESULTS: Age and education significantly impacted most cognitive performances, and depression severity appeared to influence processing speed. Moreover, cognitive scores in memory and processing speed, rather than in EF and attention, were significantly different between FEDN MDD patients and HCs after controlling for sex, age, educational attainment, household income, and body mass index. LIMITATIONS: The number of HCs was relatively small, which may have slightly reduced the study's statistical power. CONCLUSIONS: Age and educational attainment have confirmative confounding effects greater than those of depression in most cognitive functions. More importantly, memory and processing speed were impaired in MDD after strictly controlling for confounders. These findings provide new information for understanding the pattern of cognitive impairment and offer clues for further exploring the pathogenesis of cognitive abnormalities in MDD.

Individualized functional connectome identified generalizable biomarkers for psychiatric symptoms in transdiagnostic patients.

Substantial clinical heterogeneity and comorbidity inherent amongst mental disorders limit the identification of neuroimaging biomarkers that can reliably track clinical symptoms. Strategies that enable generation of meaningful and replicable neurobiological markers at the individual level will push the field of neuropsychiatry forward in developing efficacious personalized treatment. The current study included 142 adult patients with a primary diagnosis of schizophrenia (SCZ), bipolar (BP), or attention deficit/hyperactivity disorder (ADHD), and 67 patient ratings across four behavioral measures. Using functional connectivity derived from a personalized fMRI approach, we identified several candidate imaging markers related to dimensional phenotypes across disorders, assessed the internal and external generalizability of these markers, and compared the probability of replicating findings across datasets using individual and group-averaged defined functional regions. We identified subject-specific connections related to three different clinical domains (attention deficit, appetite-energy, psychosis-positive) in a discovery dataset. Importantly, these connectivity biomarkers were robust and were reproduced in an independent validation dataset. For markers related to neurovegetative symptoms (attention deficit, appetite-energy symptoms), the brain connections involved showed similar connectivity patterns across the different diagnoses. However, psychosis-positive symptoms were associated with connections of varying strength across disorders. Finally, we found that markers for symptom domains were replicable for individually-specified connections, but not for group template-derived connections. Our personalized strategies allowed us to identify meaningful and generalizable imaging markers for symptom domains in patients who exhibit high levels of heterogeneity. These biomarkers may shed new light on the connectivity underpinnings of psychiatric symptoms and lead to personalized interventions.

Discovery of mobocertinib, a potent, oral inhibitor of EGFR exon 20 insertion mutations in non-small cell lung cancer.

In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy.

Individualized Functional Connectome Identified Replicable Biomarkers for Dysphoric Symptoms in First-Episode Medication-Naïve Patients With Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous syndrome and can be conceptualized as a mixture of dimensional abnormalities across several specific brain circuits. The neural underpinnings of different symptom dimensions in MDD are not well understood. We aimed to identify robust, generalizable, functional connectivity (FC)-based biomarkers for different symptom dimensions in MDD using individualized functional connectomes. METHODS: Patterns of FC associated with symptom severity were identified using a novel, individualized, functional network parcellation analysis in conjunction with hierarchical clustering. Dimension-specific prediction models were trained to estimate symptom severity in first-episode medication-naïve patients (discovery dataset, n = 95) and replicated in an independent validation dataset (n = 94). The correlation between FC changes and symptom changes was further explored in a treatment dataset (n = 55). RESULTS: Two distinct symptom clusters previously identified in patients with MDD, namely dysphoric and anxiosomatic clusters, were robustly replicated in our data. A connectivity biomarker associated with dysphoric symptoms was identified, which mainly involved the default, dorsal attention, and limbic networks. Critically, this brain-symptom association was confirmed in the validation dataset. Moreover, the marker also tracked dysphoric symptom improvement following a 2-week antidepressant treatment. For comparison, we repeated our analyses using a nonindividualized approach and failed to identify replicable brain-symptom biomarkers. Further quantitative analysis indicated that the generalizability of the connectivity-symptom association was hampered when functional regions were not localized in individuals. CONCLUSIONS: This work reveals robust, replicable FC biomarkers for dysphoric symptoms in MDD, demonstrates the advantage of individual-oriented approach, and emphasizes the importance of independent validation in psychiatric neuroimaging analysis.

SIAH2 regulates colorectal cancer tumorigenesis via PI3K/ATK signaling pathway.

Colorectal cancer (CRC) is the third most common cancer and the 4th leading cause of cancer-related deaths, although with a dismal prognosis. The SIAH E3 Ubiquitin Protein Ligase 2 (SIAH2) regulates the expression of multiple proteins via ubiquitination and proteasome. However, the biological role of SIAH2 in colorectal cancer tumorigenesis remains controversial. In this work, we found that SIAH2 is an oncogene in colorectal cancer. Moreover, SIAH2 promoted colorectal cancer cell proliferation, migration, invasion, and colony formation. Mechanistically, SIAH2 promoted the PI3K/AKT signaling pathway both in vivo and in vitro. Besides, we discovered that PTEN loss regulates SIAH2-mediated PI3K/AKT signaling pathway activation. In summary, these findings highlight the role of SIAH2 in colorectal cancer progression and provide novel insights for treatment.

Adult-Onset Neuronal Ceroid Lipofuscinosis With a Novel DNAJC5 Mutation Exhibits Aberrant Protein Palmitoylation.

Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits.

Quantifying the contribution of evaporation from Lake Taihu to precipitation with an isotope-based method.

Moisture recycling plays a crucial role in regional hydrological budgets. The isotopic composition of precipitation has long been considered as a good tracer to investigate moisture recycling. This study quantifies the moisture recycling fractions (fr) in the Lake Taihu region using spatial variations of deuterium excess in precipitation (dP) and surface water vapour flux (dE). Results show that dP at a site downwind of the lake was higher than that at an upwind site, indicating the influence of lake moisture recycling. Spatial variations in dP after sub-cloud evaporation corrections were 2.3, 1.4 and 3.2 ‰, and dE values were 27.4, 32.3 and 31.4 ‰ for the first winter monsoon, the summer monsoon and the second winter monsoon, respectively. Moisture recycling fractions were 0.48 ± 0.13, 0.07 ± 0.03 and 0.38 ± 0.05 for the three monsoon periods, respectively. Both using the lake parameterization kinetic fractionation factors or neglecting sub-cloud evaporation would decrease fr, and the former has a larger influence on the fr calculation. The larger fr in the winter monsoon periods was mainly caused by lower specific humidity of airmasses but comparable moisture uptake along their trajectories compared to the summer monsoon period.

The China Alzheimer Report 2022.

China's population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer's disease (AD) and related dementias (ADRD). AD's incidence rate, morbidity, and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals, families and society. The 'Healthy China Action' plan of 2019-2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD. This report describes related epidemiological trends, evaluates the economic burden of the disease, outlines current clinical diagnosis and treatment status and delineates existing available public health resources. More specifically, it examines the public health impact of ADRD, including prevalence, mortality, costs, usage of care, and the overall effect on caregivers and society. In addition, this special report presents technical guidance and supports for the prevention and treatment of AD, provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation.

Sex-specific alterations of cortical morphometry in treatment-naïve patients with major depressive disorder.

Major depressive disorder (MDD) shows sex differences in terms of incidence and symptoms, but the neurobiological basis underlying these sex differences remains to be clarified. High resolution T1-weighted Magnetic Resonance Imaging (MRI) scans were obtained from 123 non-comorbid treatment-naïve individuals with MDD and 81 age-, sex-, and handedness-matched healthy controls (HCs). MRI data were preprocessed with FreeSurfer software and four cortical measures were extracted: cortical thickness (CT), surface area (SA), cortical volume (CV), and local gyrification index (LGI). We tested for both sex-specific and sex-nonspecific patterns of cortical anatomic alterations. Regardless of sex, individuals with MDD showed significantly higher LGI in posterior cortex relative to HCs. Significant sex-by-group interactions were observed, and subsequent post-hoc analyses revealed that female individuals with MDD showed significantly lower SA in left ventrolateral prefrontal cortex (vlPFC), lower CV in right rostromedial prefrontal cortex (rmPFC), and higher LGI in left visual cortex compared with sex-matched HCs, whereas the opposite patterns of significant effects were seen in male individuals with MDD relative to their sex-matched HCs. Thus, sex-nonspecific and specific morphometric differences from HCs were found in posterior cortex, while in PFC alterations were highly sex-specific early in the illness course. This may involve sex-specific alterations in brain development or processes related to illness onset. These findings highlight the presence and regional distribution of generalized as well as sex-specific alterations of brain neurobiology in MDD.

Nitrous oxide flux observed with tall-tower eddy covariance over a heterogeneous rice cultivation landscape.

Although croplands are known to be strong sources of anthropogenic N2O, large uncertainties still exist regarding their emission factors, that is, the proportion of N in fertilizer application that escapes to the atmosphere as N2O. In this study, we report the results of an experiment on the N2O flux in a landscape dominated by rice cultivation in the Yangtze River Delta, China. The observation was made with a closed-path eddy covariance system on a 70-m tall tower from October 2018 to December 2020 (27 months). Temperature and precipitation explained 78% of the seasonal and interannual variability in the observed N2O flux. The growing season (May to October) mean flux (1.14 nmol m-2 s-1) was much higher than the median flux found in the literature for rice paddies. The mean N2O flux during the observational period was 0.90 ± 0.71 nmol m-2 s-1, and the annual cumulative N2O emission was 7.6 and 9.1 kg N2O-N ha-1 during 2019 and 2020, respectively. The corresponding landscape emission factor was 3.8% and 4.6%, respectively, which were much higher than the IPCC default direct (0.3%) and indirect emission factors (0.75%) for rice paddies.

Clinical manifestations and imaging and pathological features of giant cell angioblastoma: Report of four cases and literature review.

Giant cell angioblastoma is a relatively rare vasogenic tumour. To date, studies on its clinical manifestations, imaging characteristics, pathological features, and prognosis are extremely limited and unknown, with only a few cases recorded. In this study, four cases of giant cell angioblastoma confirmed by pathological examination were reported to improve our understanding and deep exploration of the tumour spectrum. All cases in our study were male, including two adults and two boys. The lesions were located in the lower segment of the femur, medial condyle of the femur, knee joint, and popliteal fossa. Regarding the imaging characteristics, two patients with lesions in bone showed bone destruction, while the other two had lesions that invaded soft tissues, showing irregular, abnormal signal shadows and obvious enhancement. Histopathological analysis revealed that the nodular tumour tissue was mainly composed of oval and spindle cells, with varying numbers of osteoclast-like multinucleated giant cells, and the interstitial tissues were often filled with blood vessels of different sizes. The immunophenotype demonstrates that endothelial cells of small vessels in nodules expressed CD31, SMA, and ERG, while osteoclast-like multinucleated giant cells and histiocytes expressed CD68 and CD163, and the surrounding cells expressed SMA. All four patients were treated with surgical resection. One of them relapsed 1 month after surgery and received a second surgical resection. No distant metastasis or death occurred during the follow-up period. This study indicates that giant cell angioblastoma is a local invasive vascular tumour that can develop both in children and adults with skin, mucous membrane, soft tissue, and bone involvement. Imaging characteristics show bone destruction and irregular, abnormal signal shadows; in addition, obvious pathological morphological features can be observed. Currently, the treatment is mainly surgical resection, and interferons may be used as adjuvant chemotherapy.

Structural covariance network of the hippocampus-amygdala complex in medication-naïve patients with first-episode major depressive disorder.

Background: The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder (MDD). Each of these structures consists of several heterogeneous subfields. We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus-amygdala complex in medication-naïve patients with first-episode MDD. Methods: High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode, medication-naïve, and noncomorbid MDD patients and 81 age-, sex-, and education level-matched healthy control participants (HCs). The structural covariance network (SCN) was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions; the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions, controlled for age, sex, education level, and intracranial volume. The global and nodal graph metrics were calculated and compared between groups. Results: Compared with HCs, the SCN within the hippocampus-amygdala complex in patients with MDD showed a shortened mean characteristic path length, reduced modularity, and reduced small-worldness index. At the nodal level, the left hippocampal tail showed increased measures of centrality, segregation, and integration, while nodes in the left amygdala showed decreased measures of centrality, segregation, and integration in patients with MDD compared with HCs. Conclusion: Our results provide the first evidence of atypical topologic characteristics within the hippocampus-amygdala complex in patients with MDD using structure network analysis. It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.

microRNA-425 loss mediates amyloid plaque microenvironment heterogeneity and promotes neurodegenerative pathologies.

Different cellular and molecular changes underlie the pathogenesis of Alzheimer's disease (AD). Among these, neuron-specific dysregulation is a necessary event for accumulation of classic pathologies including amyloid plaques. Here, we show that AD-associated pathophysiology including neuronal cell death, inflammatory signaling, and endolysosomal dysfunction is spatially colocalized to amyloid plaques in regions with abnormal microRNA-425 (miR-425) levels and this change leads to focal brain microenvironment heterogeneity, that is, an amyloid plaque-associated microenvironment (APAM). APAM consists of multiple specific neurodegenerative signature pathologies associated with senile plaques that contribute to the heterogeneity and complexity of AD. Remarkably, miR-425, a neuronal-specific regulator decreased in AD brain, maintains a normal spatial transcriptome within brain neurons. We tested the hypothesis that miR-425 loss correlates with enhanced levels of mRNA targets downstream, supporting APAM and AD progression. A miR-425-deficient mouse model has enhanced APP amyloidogenic processing, neuroinflammation, neuron loss, and cognitive impairment. In the APP/PS1 mouse model, intervening with miR-425 supplementation ameliorated APAM changes and memory deficits. This study reveals a novel mechanism of dysregulation of spatial transcriptomic changes in AD brain, identifying a probable neuronal-specific microRNA regulator capable of staving off amyloid pathogenesis. Moreover, our findings provide new insights for developing AD treatment strategies with miRNA oligonucleotide(s).

Arginine methyltransferase PRMT3 promote tumorigenesis through regulating c-MYC stabilization in colorectal cancer.

The incidence rates of colorectal cancer have been increasing in the last decades, yet the overall survival rate is still not ideal. There is a need to further investigate detailed mechanism for colorectal cancer tumorigenesis. The biological function of protein arginine methyltransferases 3 (PRMT3) is seldom studied in tumorigenesis. Here, we attempted to elucidate the link between PRMT3 and tumorigenesis in colorectal cancer. Results revealed that PRMT3 was upregulated in colorectal cancer. Besides, PRMT3 overexpression promoted colorectal cancer cell proliferation, migration, and invasion. Regarding mechanism for colorectal cancer tumorigenesis, PRMT3 stabilized C-MYC and the pro-tumorigenesis function of PRMT3 was dependent on C-MYC. Clinically, these findings might provide a novel therapeutical treatment strategy for colorectal cancer.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer.

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.