Post-translational Modifications of Key Machinery in the Control of Mitophagy.

Mitophagy refers to the process of selective removal of damaged or superfluous mitochondria via the autophagy/lysosome pathway. In the past decade the molecular mechanisms underlying mitophagy have been extensively studied. It is now well established that the key mitophagy machinery undergoes extensive post-translational modifications (PTMs) such as phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation that involve an array of enzymes including protein kinases/phosphatases, E3 ligases/deubiquitinases, acetyltransferases/deacetylases. In this review we provide a systematic summary of these key PTMs, and discuss the effectors and the functional implications of such PTMs in mitophagy-related diseases. Understanding PTM of the mitophagy machinery offers a unique window of opportunity for the discovery of novel mitophagy interventional strategies and for the control of mitophagy-related diseases.

Analysis of the differentially expressed genes in the combs and testes of Qingyuan partridge roosters at different developmental stages.

BACKGROUND: The sexual maturity of chickens is an important economic trait, and the breeding of precocious and delayed puberty roosters is an important selection strategy for broilers. The comb serves as an important secondary sexual characteristic of roosters and determines their sexual precocity. Moreover, comb development is closely associated with gonad development in roosters. However, the underlying molecular mechanism regulating the sexual maturity of roosters has not yet been fully explored. RESULTS: In order to identify the genes related to precocious puberty in Qingyuan partridge roosters, and based on the synchrony of testis and combs development, combined with histological observation and RNA-seq method, the developmental status and gene expression profile of combs and testis were obtained. The results showed that during the early growth and development period (77 days of age), the development of combs and testis was significant in the high comb (H) group versus the low comb (L) group (p < 0.05); however, the morphological characteristic of the comb and testicular tissues converged during the late growth and development period (112 days of age) in the H and L groups. Based on these results, RNA-sequencing analysis was performed on the comb and testis tissues of the 77 and 112 days old Qingyuan Partridge roosters with different comb height traits. GO and KEGG analysis enrichment analysis showed that the differentially expressed genes were primarily enriched in MAPK signaling, VEGF signaling, and retinol metabolism pathways. Moreover, weighted correlation network analysis and module co-expression network analysis identified WNT6, AMH, IHH, STT3A, PEX16, KPNA7, CATHL2, ROR2, PAMR1, WISP2, IL17REL, NDRG4, CYP26B1, and CRHBP as the key genes associated with the regulation of precocity and delayed puberty in Qingyuan Partridge roosters. CONCLUSIONS: In summary, we identified the key regulatory genes of sexual precocity in roosters, which provide a theoretical basis for understanding the developmental differences between precocious and delayed puberty in roosters.

Network-based analysis revealed significant interactions between risk genes of severe COVID-19 and host genes interacted with SARS-CoV-2 proteins.

Whether risk genes of severe coronavirus disease 2019 (COVID-19) from genome-wide association study could play their regulatory roles by interacting with host genes that were interacted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins was worthy of exploration. In this study, we implemented a network-based approach by developing a user-friendly software Network Calculator (https://github.com/Haoxiang-Qi/Network-Calculator.git). By using Network Calculator, we identified a network composed of 13 risk genes and 28 SARS-CoV-2 interacted host genes that had the highest network proximity with each other, with a hub gene HNRNPK identified. Among these genes, 14 of them were identified to be differentially expressed in RNA-seq data from severe COVID-19 cases. Besides, by expression enrichment analysis in single-cell RNA-seq data, compared with mild COVID-19, these genes were significantly enriched in macrophage, T cell and epithelial cell for severe COVID-19. Meanwhile, 74 pathways were significantly enriched. Our analysis provided insights for the underlying genetic etiology of severe COVID-19 from the perspective of network biology.

Recent Advances in First-Row Transition Metal-Catalyzed Reductive Coupling Reactions for π-Bond Functionalization and C-Glycosylation.

ConspectusEfficient construction of ubiquitous carbon-carbon bonds between two electrophiles has garnered interest in recent decades, particularly if it is mediated by nonprecious, first-row transition metals. Reductive coupling has advantages over traditional cross-coupling by obviating the need for stoichiometric air- and moisture-sensitive organometallic reagents. By harnessing transition metal-catalyzed reductive coupling as a powerful tool, intricate molecular architectures can be readily assembled through the installation of two C-C bonds across π systems (alkenes/alkynes) via reaction with two appropriate electrophiles. Despite advances in reductive alkene difunctionalization, there remains significant potential for the discovery of novel reaction pathways. In this regard, development of reductive protocols that enable the union of challenging alkyl/alkynyl electrophiles in high regio- and chemoselectivity remains a highly sought-after goal.Apart from π-bond functionalization, reductive coupling has found application in carbohydrate chemistry, particularly in the synthesis of valuable C-glycosyl compounds. In this vein, suitable glycosyl donors can be used to generate reactive glycosyl radical intermediates under reductive conditions. Through elaborately designed reactions, these intermediates can be trapped to furnish pharmaceutically relevant glycoconjugates. Consequently, diversification in C-glycosyl compound synthesis using first-row transition metal catalysis holds strong appeal.In this Account, we summarize our efforts in the development of first-row transition metal-catalyzed reductive coupling reactions for applications in alkene/alkyne functionalization and C-glycosylation. We will first discuss the nickel (Ni)-catalyzed reductive difunctionalization of alkenes, aided by an 8-aminoquinoline (AQ) directing auxiliary. Next, we highlight the Ni-catalyzed hydroalkylation of alkenyl amides tethered with a similar AQ-derived directing auxiliary. Lastly, we discuss an efficient synthesis of 1,3-enynes involving site- and stereoselective reductive coupling of terminal alkynes with alkynyl halides and NHPI esters.Beyond alkene dicarbofunctionalization, we extended the paradigm of transition metal-catalyzed reductive coupling toward the construction of C-glycosidic linkages in carbohydrates. By employing an earth-abundant iron (Fe)-based catalyst, we show that useful glycosyl radicals can be generated from glycosyl chlorides under reductive conditions. These intermediates can be captured in C-C bond formation to furnish valuable C-aryl, C-alkenyl, and C-alkynyl glycosyl compounds with high diastereoselectivity. Our Ni-catalyzed multicomponent union of glycosyl chlorides, aryl/alkyl iodides, and isobutyl chloroformate under reductive conditions led to the stereoselective synthesis of C-acyl glycosides. In addition to Fe and Ni, we discovered a Ti-catalyzed/Mn-promoted synthetic route to access C-alkyl and C-alkenyl glycosyl compounds, through the reaction of glycosyl chlorides with electron-deficient alkenes/alkynes. We further developed an electron donor-acceptor (EDA) photoactivation system leveraging decarboxylative and deaminative strategies for C-glycosylation under Ni catalysis. This approach has been demonstrated to selectively activate carboxyl and amino motifs to furnish glycopeptide conjugates. Finally, through two distinct catalytic transformations of bench-stable heteroaryl glycosyl sulfones, we achieved stereodivergent access to both α- and ß-anomers of C-aryl glycosides, one of which involves a Ni-catalyzed reductive coupling with aryl iodides.The findings presented in this Account are anticipated to have far-reaching implications beyond our research. We foresee that these results will pave the way for new transformations founded on the concept of reductive coupling, leading to the discovery of novel applications in the future.

2,6-diaminopurine (Z)-containing toehold probes improve genotyping sensitivity.

2,6-diaminopurine (Z), a naturally occurring noncanonical nucleotide base found in bacteriophages, enhances DNA hybridization by forming three hydrogen bonds with thymine (T). These distinct biochemical characteristics make it particularly valuable in applications that rely on the thermodynamics of DNA hybridization. However, the practical use of Z-containing oligos is limited by their high production cost and the challenges associated with their synthesis. Here, we developed an efficient and cost-effective approach to synthesize Z-containing oligos of high quality based on an isothermal strand displacement reaction. These newly synthesized Z-oligos are then employed as toehold-blockers in an isothermal genotyping assay designed to detect rare single nucleotide variations (SNV). When compared with their counterparts containing the standard adenine (A) base, the Z-containing blockers significantly enhance the accuracy of identifying SNV. Overall, our innovative methodology in the synthesis of Z-containing oligos, which can also be used to incorporate other unconventional and unnatural bases into oligonucleotides, is anticipated to be adopted for diverse applications, including genotyping, biosensing, and gene therapy.

MI-DenseCFNet: deep learning-based multimodal diagnosis models for Aureus and Aspergillus pneumonia.

OBJECTIVE: To build and merge a diagnostic model called multi-input DenseNet fused with clinical features (MI-DenseCFNet) for discriminating between Staphylococcus aureus pneumonia (SAP) and Aspergillus pneumonia (ASP) and to evaluate the significant correlation of each clinical feature in determining these two types of pneumonia using a random forest dichotomous diagnosis model. This will enhance diagnostic accuracy and efficiency in distinguishing between SAP and ASP. METHODS: In this study, 60 patients with clinically confirmed SAP and ASP, who were admitted to four large tertiary hospitals in Kunming, China, were included. Thoracic high-resolution CT lung windows of all patients were extracted from the picture archiving and communication system, and the corresponding clinical data of each patient were collected. RESULTS: The MI-DenseCFNet diagnosis model demonstrates an internal validation set with an area under the curve (AUC) of 0.92. Its external validation set demonstrates an AUC of 0.83. The model requires only 10.24s to generate a categorical diagnosis and produce results from 20 cases of data. Compared with high-, mid-, and low-ranking radiologists, the model achieves accuracies of 78% vs. 75% vs. 60% vs. 40%. Eleven significant clinical features were screened by the random forest dichotomous diagnosis model. CONCLUSION: The MI-DenseCFNet multimodal diagnosis model can effectively diagnose SAP and ASP, and its diagnostic performance significantly exceeds that of junior radiologists. The 11 important clinical features were screened in the constructed random forest dichotomous diagnostic model, providing a reference for clinicians. CLINICAL RELEVANCE STATEMENT: MI-DenseCFNet could provide diagnostic assistance for primary hospitals that do not have advanced radiologists, enabling patients with suspected infections like Staphylococcus aureus pneumonia or Aspergillus pneumonia to receive a quicker diagnosis and cut down on the abuse of antibiotics. KEY POINTS: • MI-DenseCFNet combines deep learning neural networks with crucial clinical features to discern between Staphylococcus aureus pneumonia and Aspergillus pneumonia. • The comprehensive group had an area under the curve of 0.92, surpassing the proficiency of junior radiologists. • This model can enhance a primary radiologist's diagnostic capacity.

Magnetic-field induced shape memory hydrogels for deformable actuators.

Magnetic hydrogel actuators exhibit promising applications in the fields of soft robotics, bioactuators, and flexible sensors owing to their inherent advantages such as remote control capability, untethered deformation and motion control, as well as easily manipulable behavior. However, it is still a challenge for magnetic hydrogels to achieve adjustable stiffness and shape fixation under magnetic field actuation deformation. Herein, a simple and effective approach is proposed for the design of magnetic shape memory hydrogels to accomplish this objective. The magnetic shape memory hydrogels, consisting of methacrylamide, methacrylic acid, polyvinyl alcohol and Fe3O4 magnetic particles, which crosslinked by hydrogen bonds, are facilely prepared via one-pot polymerization. The dynamic nature of noncovalent bonds offers the magnetic hydrogels with excellent mechanical properties, precisely controlled stiffness, and effective shape fixation. The presence of Fe3O4 particles renders the hydrogels soft when subjected to an alternating current field, facilitating their deformation under the influence of an actuation magnetic field. After the elimination of the alternating current magnetic field, the hydrogels stiffen and attain a fixed actuated shape in the absence of any external magnetic field. Moreover, this remarkable magnetic shape memory hydrogel is effectively employed as an underwater soft gripper for lifting heavy objects. This work provides a novel strategy for fabricating magnetic hydrogels with non-contact reversible actuation deformation, tunable stiffness and shape locking.

Short-term effects of a new resistance exercise approach on physical function during chemotherapy after radical breast cancer surgery: a randomized controlled trial.

BACKGROUND: Approximately 30% of post-operative breast cancer patients develop shoulder joint movement disorders affecting routine upper limb movement. This study discusses the impact of a neuromuscular joint facilitation (NJF) method on the physical function of breast cancer patients experiencing shoulder dysfunction during chemotherapy after radical surgery. METHODS: This study included 162 female patients who have unilateral breast cancer in a cancer hospital in China. They developed shoulder joint mobility disorders during chemotherapy within 1-3 months postoperatively. These patients were divided into three groups: NJF, conventional rehabilitation (conventional group), and control groups. The clinical examination included the maximum passive and active range of motion (ROM) of the shoulder (flexion, extension, abduction, adduction, and external and internal rotation). Other evaluations included a pain score using a visual analog scale (VAS), grip strength, and supraspinatus muscle thickness. All tests were evaluated pre-and post-intervention. RESULTS: The NJF group showed a significant increase in all shoulder ROM angles post-intervention. In the conventional group, all other ROM values increased significantly, except passive external rotation ROM. In the control group, all other ROM values increased significantly, except passive and active external rotation ROM. All three groups had decreased VAS scores, increased grip strength, and supraspinatus muscle thickness post-intervention during active abduction. In the control group, the supraspinatus contraction rate decreased significantly at 60° and 90° abduction post-intervention compared to that at pre-intervention. CONCLUSION: This study revealed that NJF during chemotherapy had positive clinical intervention effects, improving shoulder joint mobility disorders, pain, grip strength, and external rotation following radical breast cancer surgery. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry; https://www.chictr.org.cn/ (ChiCTR2300073170), registered (03/07/2023).

Mid-term clinical effect of resecting posterior longitudinal ligament in anterior approach for cervical spondylosis with sympathetic symptoms: retrospective cohort analysis.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: The purpose of this study is to investigate whether the removal of the posterior longitudinal ligament (PLL) affects the mid-term outcome of anterior cervical fusion for cervical spondylosis with sympathetic symptoms(CSSS). METHODS: From January 2012 to July 2013, 66 patients who were diagnosed with CSSS with ≥ 10-year follow-up at our institution were assessed. All patients were divided into two groups: Group A (36 cases) in which patients underwent anterior cervical fusion with PLL resection and Group B (30 cases) in which patients underwent anterior cervical fusion without PLL resection. The sympathetic symptom 20-point system was used to evaluate the sympathetic symptoms, such as tinnitus, headache and vertigo, etc. And the neurological status was assessed by the Japanese Orthopedic Association (JOA) scores. Clinical and radiologic data were evaluated preoperatively, 9 days, 3 months, 6 months, 12 months, 24 months, 60 months, and 120 months postoperatively. Data collected included all perioperative complications as morbidities that occurred during the period of follow-up. RESULTS: The postoperative JOA scores and 20-point score can be significantly improved compared with preoperative whether the PLL is removed in both groups. However, the postoperative 20-point score of patients in group A was significantly different from that in group B. No loosening and displacement of prosthesis occurred. CONCLUSION: A better clinical effect could be attained when resecting the PLL in the operation. The PLL may play an important role in CSSS. The mid-term outcomes of anterior cervical fusion with PLL resection were satisfied in treating CSSS.

Normal spinopelvic parameters and correlation analysis in 217 asymptomatic children.

BACKGROUND: Understanding spinal sagittal balance is crucial for assessing and treating spinal deformities in pediatric populations. OBJECTIVE: The aim of the present observational study is to examine the parameters of sagittal alignment of the regional spine and spinopelvic region in asymptomatic pediatric populations and the characteristics of these parameters with age and sex. METHODS: We enrolled 217 participants, consisting of 112 males (51.6%) and 105 females (48.4%), aged between 4 and 15 years, with an average age of 12.19 years. Pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, thoracic kyphosis, T1 slope, C7 slope, cervical sagittal vertical axis, and C2-7 Cobb angle were measured. Three spine surgeons conducted radiographic measurements utilizing the PACS software. The measurement reliability was assessed through ICCs. RESULTS: Our results show significant age-related changes in pelvic tilt and cervical sagittal vertical axis, with notable gender differences in pelvic tilt, lumbar lordosis, and thoracic kyphosis. Girls have larger PT, boys have larger cSVA. PI, PT, and cSVA also differ among different age groups. Correlation analysis shows that a series of relationships that align with adult population patterns between pelvic incidence, pelvic tilt, sacral slope, lumbar lordosis, and thoracic kyphosis. CONCLUSION: Significant variations in PT and cSVA across diverse age cohorts highlights notable disparities in the distribution of PT and cSVA values within the pediatric population. Gender-based differences in PT, LL, and TK and correlation in spinopelvic parameter could enhances our understanding of compensatory mechanisms.

Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1.

Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn-induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D1, and E2F1) and enhancing negative ones (p27KIP1 and p57KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn-dependent changes to these proteins and the cell cycle through nuclear receptor-related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus-expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn-induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

N-Heterocyclic carbenes as privileged ligands for nickel-catalysed alkene functionalisation.

Alkene functionalisation is a powerful strategy that has enabled access to a wide array of compounds including valuable pharmaceuticals and agrochemicals. The reactivity of the alkene π-bond has allowed incorporation of a diverse range of atoms and functional groups through a wide variety of reaction pathways. N-Heterocyclic carbenes (NHCs) are a class of persistent carbenes that are widely employed as ancillary ligands due to their ability to act as strong σ-donors compared to widely-applied conventional phosphine-based ligands. NHCs are also unique as their molecular bulk provides steric influence for regio- and stereo-control in many alkene functionalisation reactions, illustrated by the examples covered in this review. A combination of the unique reactivity of NHC ligands and nickel's characteristics has facilitated the design of reaction pathways that show distinct selectivity and reactivity, including the activation of bonds previously considered "inert", such as C-H bonds, the C-O bond of ethers and esters, and the C-N bonds of amides. This review summarises the advancements in Ni(NHC) catalysed alkene functionalisation up to 2022, covering the following major reaction classes: Heck-type reactions, hydrofunctionalisation and dicarbofunctionalisation.

Selective 1,2-Hydroarylation(Alkenylation) of gem-Difluoroalkenes to Access (-CF2 H) Motifs.

An emerging class of C-C coupling transformations that furnish drug-like building blocks involves catalytic hydrocarbonation of alkenes. However, despite notable advances in the field, hydrocarbon addition to gem-difluoroalkenes without additional electronic activation remains largely unsuccessful. This owes partly to poor reactivity and the propensity of difluoroalkenes to undergo defluorinative side reactions. Here, we report a nickel catalytic system that promotes efficient 1,2-selective hydroarylation and hydroalkenylation, suppressing defluorination and providing straightforward access to a diverse assortment of prized organofluorides bearing difluoromethyl-substituted carbon centers. In contrast to radical-based pathways and reactions triggered by hydrometallation via a nickel-hydride complex, our experimental and computational studies support a mechanism in which a catalytically active nickel-bromide species promotes selective carbonickelation with difluoroalkenes followed by alkoxide exchange and hydride transfer, effectively overcoming the difluoroalkene's intrinsic electronic bias.

Knockdown of NR3C1 inhibits the proliferation and migration of clear cell renal cell carcinoma through activating endoplasmic reticulum stress-mitophagy.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1's carcinogenic effects in ccRCC. METHODS: Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways. RESULTS: The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05). CONCLUSIONS: This study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC.

An Arabidopsis Retention and Splicing complex regulates root and embryo development through pre-mRNA splicing.

Pre-mRNA splicing is an important step in the posttranscriptional processing of transcripts and a key regulator of development. The heterotrimeric retention and splicing (RES) complex plays vital roles in the growth and development of yeast, zebrafish, and humans by mediating pre-mRNA splicing of multiple genes. However, whether the RES complex is conserved in plants and what specific functions it has remain unknown. In this study, we identified Arabidopsis (Arabidopsis thaliana) BUD13 (AtBUD13), GROWTH, DEVELOPMENT AND SPLICING 1 (GDS1), and DAWDLE (DDL) as the counterparts of the yeast RES complex subunits Bud site selection protein 13 (Bud13), U2 snRNP component Snu17 (Snu17), and Pre-mRNA leakage protein 1, respectively. Moreover, we showed that RES is an ancient complex evolutionarily conserved in eukaryotes. GDS1 directly interacts with both AtBUD13 and DDL in nuclear speckles. The BUD13 domain of AtBUD13 and the RNA recognition motif domain of GDS1 are necessary and sufficient for AtBUD13-GDS1 interaction. Mutants of AtBUD13, GDS1, and DDL failed to properly splice multiple genes involved in cell proliferation and showed defects in early embryogenesis and root development. In addition, we found that GDS1 and DDL interact, respectively, with the U2 small nuclear ribonucleoproteins auxiliary factor AtU2AF65B and the NineTeen Complex-related splicing factor SKIP, which are essential for early steps of spliceosome assembly and recognition of splice sites. Altogether, our work reveals that the Arabidopsis RES complex is important for root and early embryo development by modulating pre-mRNA splicing.

New "drugs and targets" in the GWAS era of bipolar disorder.

OBJECTIVE: Due to the phenotypic heterogeneity and etiological complexity of bipolar disorder (BD), many patients do not respond well to the current medications, and developing novel effective treatment is necessary. Whether any BD genome-wide association study (GWAS) risk genes were targets of existing drugs or novel drugs that can be repurposed in the clinical treatment of BD is a hot topic in the GWAS era of BD. METHODS: A list of 425 protein-coding BD risk genes was distilled through the BD GWAS, and 4479 protein-coding druggable targets were retrieved from the druggable genome. The overlapped genes/targets were subjected to further analyses in DrugBank, Pharos, and DGIdb datasets in terms of their FDA status, mechanism of action and primary indication, to identify their potential for repurposing. RESULTS: We identified 58 BD GWAS risk genes grouped as the druggable targets, and several genes were given higher priority. These BD risk genes were targets of antipsychotics, antidepressants, antiepileptics, calcium channel antagonists, as well as anxiolytics and analgesics, either existing clinically-approved drugs for BD or the drugs than can be repurposed for treatment of BD in the future. Those genes were also likely relevant to BD pathophysiology, as many of them encode ion channel, ion transporter or neurotransmitter receptor, or the mice manipulating those genes are likely to mimic the phenotypes manifest in BD patients. CONCLUSIONS: This study identifies several targets that may facilitate the discovery of novel treatments in BD, and implies the value of conducting GWAS into clinical translation.

ARID3A plays a key regulatory role in palmitic acid-stimulated milk fat synthesis in mouse mammary epithelial cells.

Palmitic acid (PA) can stimulate milk fat synthesis in mammary gland, but the specific mechanism is still unclear. In our research, we aim to explore the role and corresponding mechanism of AT-rich interaction domain 3A (ARID3A) in milk fat synthesis stimulated by PA. We found that ARID3A protein level in mouse mammary gland tissues during lactation was much higher than that during puberty and involution. ARID3A knockdown and gene activation showed that ARID3A stimulated the synthesis of triglycerides and cholesterol in HC11 cells, secretion of free fatty acids from cells and lipid droplet formation in cells. ARID3A also promoted the expression and maturation of SREBP1 in HC11 cells. PA stimulated ARID3A protein expression and SREBP1 expression and maturation in a dose-dependent manner, and the PI3K specific inhibitor LY294002 blocked the stimulation of PA on ARID3A expression. ARID3A knockdown blocked the stimulation of PA on SREBP1 protein expression and maturation. We further showed that ARID3A was localized in the nucleus and PA stimulated this localization, and ARID3A knockdown blocked the stimulation of PA on the mRNA expression of SREBP1. To sum up, our data reveal that ARID3A is a key mediator for PA to promote SREBP1 mRNA expression and stimulate milk fat synthesis in mammary epithelial cells.

Comparative transcriptomic analysis of mammary gland tissues reveals the critical role of GPR110 in palmitic acid-stimulated milk protein and fat synthesis.

The G protein-coupled receptors (GPCR) sensing nutritional signals (amino acids, fatty acids, glucose, etc.) are not fully understood. In this research, we used transcriptome sequencing to analyse differentially expressed genes (DEG) in mouse mammary gland tissues at puberty, lactation and involution stages, in which eight GPCR were selected out and verified by qRT-PCR assay. It was further identified the role of GPR110-mediating nutrients including palmitic acid (PA) and methionine (Met) to improve milk synthesis using mouse mammary epithelial cell line HC11. PA but not Met affected GPR110 expression in a dose-dependent manner. GPR110 knockdown decreased milk protein and fat synthesis and cell proliferation and blocked the stimulation of PA on mechanistic target of rapamycin (mTOR) phosphorylation and sterol-regulatory element binding protein 1c (SREBP-1c) expression. In summary, these experimental results disclose DEG related to lactation and reveal that GPR110 mediates PA to activate the mTOR and SREBP-1c pathways to promote milk protein and fat synthesis.

Self-Assembly and In Situ Quaternization of Triblock Bottlebrush Block Copolymers via Organized Spontaneous Emulsification for Effective Loading of DNA.

Microspheres bearing large pores are useful in the capture and separation of biomolecules. However, pore size is typically poorly controlled, leading to disordered porous structures with limited performances. Herein, ordered porous spheres with a layer of cations on the internal surface of the nanopores are facilely fabricated in a single step for effective loading of DNA bearing negative charges. Triblock bottlebrush copolymers (BBCPs), (polynorbornene-g-polystyrene)-b-(polynorbornene-g-polyethylene oxide)-b-(polynorbornene-g-bromoethane) (PNPS-b-PNPEO-b-PNBr), are designed and synthesized for fabrication of the positively charged porous spheres through self-assembly and in situ quaternization during an organized spontaneous emulsification (OSE) process. Pore diameter as well as charge density increase with the increase of PNBr content, resulting in a significant increase of loading density from 4.79 to 22.5 ng µg-1 within the spheres. This work provides a general strategy for efficient loading and encapsulation of DNA, which may be extended to a variety of different areas for different real applications.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.