Regiocontrollable B(2/3)-H Alkenylation of nido-Carboranes.

Anionic nido-carboranes, as open-cage analogues of closo-carboranes with strong hydrophilicity and higher potential in the development of biomedicines, have been notably more challenging because of their strong interaction with transition metals. While the exo-cage B-H activation reactions of nido-carboranes have been widely studied, there are few reports on the direct functionalization of B-H bonds located on a closed polyhedral sphere. Here, we report an efficient palladium-catalyzed regioselective B(2/3)-H alkenylation of nido-carboranes with various alkenes and alkyne coupling partners, enabled by 3-methylpyridine directing groups, to achieve a regiocontrollable functionalization of B(2/3)-H vertices over highly reactive exo-cage B11-H vertex in nido-carboranes.

Breaking the Base Barrier: Cu(II)-Mediated C-H Heteroarylation of o-Carboranes with Base-Sensitive Heteroaryl Halides.

While cage C-arylation reactions using strong bases are among the most frequently used transformations in carborane chemistry, there has been no general solution to allow for the use of weak bases in the reaction. Moreover, base-metal-promoted C-H heteroarylation with base-sensitive heteroaryl halides remained elusive. Herein, copper-mediated cage C-H (hetero)arylation has been achieved without the need for strong bases, leading to the facile synthesis of a wide range of C-(hetero)arylated carboranes in good to excellent yields with a broad substrate scope and good functional group compatibility.

The egg ribonuclease SjCP1412 accelerates liver fibrosis caused by Schistosoma japonicum infection involving damage-associated molecular patterns (DAMPs).

Schistosomiasis, a parasite infectious disease caused by Schistosoma japonicum, often leads to egg granuloma and fibrosis due to the inflammatory reaction triggered by egg antigens released in the host liver. This study focuses on the role of the egg antigens CP1412 protein of S. japonicum (SjCP1412) with RNase activity in promoting liver fibrosis. In this study, the recombinant egg ribonuclease SjCP1412, which had RNase activity, was successfully prepared. By analysing the serum of the population, it has been proven that the anti-SjCP1412 IgG in the serum of patients with advanced schistosomiasis was moderately correlated with liver fibrosis, and SjCP1412 may be an important antigen associated with liver fibrosis in schistosomiasis. In vitro, the rSjCP1412 protein induced the human liver cancer cell line Hep G2 and liver sinusoidal endothelial cells apoptosis and necrosis and the release of proinflammatory damage-associated molecular patterns (DAMPs). In mice infected with schistosomes, rSjCP1412 immunization or antibody neutralization of SjCP1412 activity significantly reduced cell apoptosis and necroptosis in liver tissue, thereby reducing inflammation and liver fibrosis. In summary, the SjCP1412 protein plays a crucial role in promoting liver fibrosis during schistosomiasis through mediating the liver cells apoptosis and necroptosis to release DAMPs inducing an inflammatory reaction. Blocking SjCP1412 activity could inhibit its proapoptotic and necrotic effects and alleviate hepatic fibrosis. These findings suggest that SjCP1412 may be served as a promising drug target for managing liver fibrosis in schistosomiasis japonica.

Programmed cell death in hepatic fibrosis: current and perspectives.

The initiation, development and resolution of hepatic fibrosis are influenced by various cytokines, chemokines, damage-associated molecular patterns (DAMPs) and signaling pathways. A significant number of studies in recent years have indicated that the progression of hepatic fibrosis is closely linked to programmed cell death processes such as apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, cuproptosis, and PANoptosis. Inducement of hepatic stellate cells (HSCs) death or preventing death in other liver cells can delay or even reverse hepatic fibrosis. Nevertheless, the roles of programmed cell death in hepatic fibrosis have not been reviewed. Therefore, this review summarizes the characteristics of various of hepatic fibrosis and programmed cell death, focuses on the latest progress of programmed cell death in the promotion and regression of hepatic fibrosis, and highlights the different roles of the programmed cell death of HSCs and other liver cells in hepatic fibrosis. In the end, the possible therapeutic approaches targeting programmed cell death for treating hepatic fibrosis are discussed and prospected.

Cortical circuit dynamics underlying motor skill learning: from rodents to humans.

Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning.

Value of a preoperative prognostic nutritional index for the prognostic evaluation of gastric neuroendocrine carcinoma patients.

Objective: To study the value of Onodera's prognostic nutrition index (PNI) in patients with gastric neuroendocrine cancer (G-NEC). Methods: The clinical data on 148 cases of G-NEC presented between March 2010 and April 2022 were retrospectively analyzed. The relationship between the clinical characteristics of the patients and PNI was analyzed. Optimal PNI cutoff values for G-NEC prognosis prediction were calculated using the X-tile software. The survival curves were created using the Kaplan-Meier method. A Cox proportional hazards model was also established to identify independent prognostic factors that impact the prognosis of patients with G-NEC. Results: The median overall survival (OS) rate was 30 months (range 6-127 months), and the OS rates at 1, 3 and 5 years were 89.2, 71.6 and 68.2%, respectively. The mean PNI of the 148 patients before the operation was 49.5 ± 8.0. The mean PNI of patients with anemia (p < 0.001) and abnormal carcinoembryonic antigen (p = 0.039) was significantly lower than that of patients without such comorbidities. The mean PNI of patients with Stage III tumors (p < 0.001) and postoperative complications was significantly lower (p = 0.005). PNI optimal cutoff values were 50 (p < 0.001). Based on the cut-off value of the PNI, these patients were divided into a PNI-high group (PNI ≥ 50.0, n = 77) and a PNI-low group (PNI < 50.0, n = 71). The PNI-high group had a significantly better 5-years OS rate compared with the PNI-low group (76.6% vs. 59.2%, χ2 = 14.7, p < 0. 001). Multivariate analysis demonstrated that PNI and pathological stage were independent prognostic factors for patients with G-NEC. In the subgroup analysis, OS rates were significantly lower in the PNI-low group than in the PNI-high group among patients with stage I and stage III of the disease. Conclusion: The PNI is a simple and useful marker for predicting long-term outcomes in G-NEC patients regardless of tumor stage. Based on our results, we suggest that PNI should be included in routine assessments of patients with G-NEC.

Ammonium sulfate supplementation enhances erythromycin biosynthesis by augmenting intracellular metabolism and precursor supply in Saccharopolyspora erythraea.

In this study, the cellular metabolic mechanisms regarding ammonium sulfate supplementation on erythromycin production were investigated by employing targeted metabolomics and metabolic flux analysis. The results suggested that the addition of ammonium sulfate stimulates erythromycin biosynthesis. Targeted metabolomics analysis uncovered that the addition of ammonium sulfate during the late stage of fermentation resulted in an augmented intracellular amino acid metabolism pool, guaranteeing an ample supply of precursors for organic acids and coenzyme A-related compounds. Therefore, adequate precursors facilitated cellular maintenance and erythromycin biosynthesis. Subsequently, an optimal supplementation rate of 0.02 g/L/h was determined. The results exhibited that erythromycin titer (1311.1 µg/mL) and specific production rate (0.008 mmol/gDCW/h) were 101.3% and 41.0% higher than those of the process without ammonium sulfate supplementation, respectively. Moreover, the erythromycin A component proportion increased from 83.2% to 99.5%. Metabolic flux analysis revealed increased metabolic fluxes with the supplementation of three ammonium sulfate rates.

The effect of single-cell knockout of Fragile X Messenger Ribonucleoprotein on synaptic structural plasticity.

Fragile X Syndrome (FXS) is the best-known form of inherited intellectual disability caused by the loss-of-function mutation in a single gene. The FMR1 gene mutation abolishes the expression of Fragile X Messenger Ribonucleoprotein (FMRP), which regulates the expression of many synaptic proteins. Cortical pyramidal neurons in postmortem FXS patient brains show abnormally high density and immature morphology of dendritic spines; this phenotype is replicated in the Fmr1 knockout (KO) mouse. While FMRP is well-positioned in the dendrite to regulate synaptic plasticity, intriguing in vitro and in vivo data show that wild type neurons embedded in a network of Fmr1 KO neurons or glia exhibit spine abnormalities just as neurons in Fmr1 global KO mice. This raises the question: does FMRP regulate synaptic morphology and dynamics in a cell-autonomous manner, or do the synaptic phenotypes arise from abnormal pre-synaptic inputs? To address this question, we combined viral and mouse genetic approaches to delete FMRP from a very sparse subset of cortical layer 5 pyramidal neurons (L5 PyrNs) either during early postnatal development or in adulthood. We then followed the structural dynamics of dendritic spines on these Fmr1 KO neurons by in vivo two-photon microscopy. We found that, while L5 PyrNs in adult Fmr1 global KO mice have abnormally high density of thin spines, single-cell Fmr1 KO in adulthood does not affect spine density, morphology, or dynamics. On the contrary, neurons with neonatal FMRP deletion have normal spine density but elevated spine formation at 1 month of age, replicating the phenotype in Fmr1 global KO mice. Interestingly, these neurons exhibit elevated thin spine density, but normal total spine density, by adulthood. Together, our data reveal cell-autonomous FMRP regulation of cortical synaptic dynamics during adolescence, but spine defects in adulthood also implicate non-cell-autonomous factors.

Patient-Derived Organoids from Locally Advanced Gastric Adenocarcinomas Can Predict Resistance to Neoadjuvant Chemotherapy.

BACKGROUND: Patients (pts) with locally advanced gastric adenocarcinoma (LAGA) often receive neoadjuvant chemotherapy. A minority of patients do not respond to chemotherapy and thus may benefit from upfront surgery. Patient-derived organoids (PDOs) are an in vitro model that may mimic the chemotherapy response of the original tumors. METHODS: PDOs were generated from endoscopic biopsies of LAGAs prior to the initiation of chemotherapy and treated with the two chemotherapy regimens: FLOT and FOLFOX. Cell proliferation was assayed after 3-6 days. Following chemotherapy, pts underwent surgical resection, and percent pathological necrosis was determined. RESULTS: Successful PDOs were obtained from 13 of 24 (54%) LAGAs. Failure to generate PDOs were due to contamination (n = 3, 13%), early senescence (n = 3, 13%), and late senescence (n = 5, 21%). By H&E staining, there were significant similarities in tumor morphology and high concordance in immunohistochemical expression of 6 markers between tumors and derived PDOs. Four of 13 pts with successful PDOs did not undergo chemotherapy and surgery. For the remaining 9 pts, percent necrosis in resected tumors was ≤ 50% in 2 pts. The corresponding PDOs from these 2 pts were clearly chemoresistant outliers. The Pearson correlation coefficient between chemosensitivity of PDOs to FOLFOX (n = 2) or FLOT (n = 7) and percent tumor necrosis in resected tumors was 0.87 (p = 0.003). CONCLUSIONS: PDOs from pts with LAGAs in many respects mimic the original tumors from which they are derived and may be used to predict resistance to neoadjuvant chemotherapy. SYNOPSIS: Patient-derived organoids (PDOs) can serve as personalized in vitro models of patient tumors. In this study, PDOs from locally advanced gastric cancers were able to reliably predict resistance to neoadjuvant chemotherapy.

Pd-Catalyzed Oxidative Dehydrogenative Cross Coupling of Cage B-H/B-H Bonds at Room Temperature: Synthesis of Bis(o-carborane)s.

Efficient Pd-catalyzed oxidative dehydrogenative cross coupling of B-H/B-H bonds of two pyridyl o-carboranes has been developed, leading to the preparation of B(3)-B(6') heterocoupled and B(3)-B(6') homocoupled biscarboranes with a broad substrate scope at room temperature.

Reconstruction of the Genome-Scale Metabolic Model of Saccharopolyspora erythraea and Its Application in the Overproduction of Erythromycin.

Saccharopolyspora erythraea is considered to be an effective host for erythromycin. However, little is known about the regulation in terms of its metabolism. To develop an accurate model-driven strategy for the efficient production of erythromycin, a genome-scale metabolic model (iJL1426) was reconstructed for the industrial strain. The final model included 1426 genes, 1858 reactions, and 1687 metabolites. The accurate rates of the growth predictions for the 27 carbon and 31 nitrogen sources available were 92.6% and 100%, respectively. Moreover, the simulation results were consistent with the physiological observation and 13C metabolic flux analysis obtained from the experimental data. Furthermore, by comparing the single knockout targets with earlier published results, four genes coincided within the range of successful knockouts. Finally, iJL1426 was used to guide the optimal addition strategy of n-propanol during industrial erythromycin fermentation to demonstrate its ability. The experimental results showed that the highest erythromycin titer was 1442.8 µg/mL at an n-propanol supplementation rate of 0.05 g/L/h, which was 45.0% higher than that without n-propanol supplementation, and the erythromycin-specific synthesis rate was also increased by 30.3%. Therefore, iJL1426 will lead to a better understanding of the metabolic capabilities and, thus, is helpful in a systematic metabolic engineering approach.

Pd-Catalyzed Selective B(6)-H Phosphorization of nido-Carboranes via Cascade Deboronation/B-H Activation from closo-Carboranes.

Efficient Pd-catalyzed regioselective B(6)-H phosphorization of nido-carboranes via cascade deboronation/B-H activation of readily available C-substituted o-carboranes with various phosphines using 3-methylpyridine or isoquinoline as a directing group in combination with pyridine ligands has been developed, affording unprecedented B(6)-phosphinated nido-carborane derivatives with high selectivity in a simple one-pot process.

N-glycosylation stabilizes MerTK and promotes hepatocellular carcinoma tumor growth.

Despite the evidences of elevated expression of Mer tyrosine kinase (MerTK) in multiple human cancers, mechanisms underlying the oncogenic roles of MerTK in hepatocellular carcinoma (HCC) remains undefined. We explored the functional effects of MerTK and N-Glycosylated MerTK on HCC cell survival and tumor growth. Here, we show that MerTK ablation increases reactive oxygen species (ROS) production and promotes the switching from glycolytic metabolism to oxidative phosphorylation in HCC cells, thus suppressing HCC cell proliferation and tumor growth. MerTK is N-glycosylated in HCC cells at asparagine 294 and 454 that stabilizes MerTK to promote oncogenic transformation. Moreover, we observed that nuclear located non-glycosylated MerTK is indispensable for survival of HCC cells under stress. Pathologically, tissue microarray (TMA) data indicate that MerTK is a pivotal prognostic factor for HCC. Our data strongly support the roles of MerTK N-glycosylation in HCC tumorigenesis and suggesting N-glycosylation inhibition as a potential HCC therapeutic strategy.

Dictyophora Polysaccharide Attenuates As-Mediated PINK1/Parkin Pathway-Induced Mitophagy in L-02 Cell through Scavenging ROS.

Arsenic (As) is common in the human living environment and a certain amount of exposure to As can lead to liver damage; this toxic effect has been proved to be closely related to intracellular PINK1/Parkin pathway-mediated mitophagy. Dictyophora is an edible fungus that extracts polysaccharides with antioxidant and hepatoprotective effects. In the present study, we demonstrated that As induced the onset of mitophagy in hepatocytes by stimulating cellular production of ROS to activate PINK1/Parkin, and the extent of damage increased with increased As-induced toxicity. Dictyophora polysaccharide (DIP) has the ability to scavenge intracellular ROS, which can inhibit oxidative stress injury and inhibit the PINK/Parkin pathway through its receptors or efficacious proteins, thus preventing mitochondrial autophagy and alleviating the hepatotoxicity of As. In conclusion, our results indicate that DIP can reduce As-induced PINK1/Parkin pathway-mediated hepatic mitophagy through scavenging ROS and exert hepatoprotective effects, providing experimental data and theoretical basis for the development of medicinal value of Dictyophora as a dual-use food and medicinal fungus.

Palladium-Catalyzed Regioselective B(3,4)-H Acyloxylation of o-Carboranes.

We disclose herein an efficient regioselective B(3,4)-H activation via a ligand strategy, affording B(3)-monoacyloxylated and B(3,4)-diacyloxylated o-carboranes. The identification of amino acid and phosphoric acid ligands is crucial for the success of B(3)-mono- and B(3,4)-diacyloxylation, respectively. This ligand approach is compatible with a broad range of carboxylic acids. The functionalization of complex drug molecules is demonstrated. Other acyloxyl sources, including sodium benzoate, benzoic anhydride, and iodobenzene diacetate, are also tolerated.

Pharmacogenetic study of methadone treatment for heroin addiction: associations between drug-metabolizing gene polymorphisms and treatment efficacy.

OBJECTIVES: Opioid dependence is currently one of the most serious problems affecting the social norms and public health system. Methadone maintenance therapy (MMT) is being widely used in treating heroin-dependent patients. The mechanism of methadone metabolism and disposition has been shown to involve cytochrome P450 (CYP450) and P-glycoprotein. The aim of this study was to explore the relationships among genetic polymorphisms, BMI and effective dose of methadone used in MMT within a northern Taiwan cohort. METHODS: One hundred heroin-dependent patients were enrolled in the study. The clinical data gathered included methadone dose, sex and BMI. DNA was collected from the oral swab of the participants to analyze the relevant alleles. RESULTS: An effective methadone dose correlated with sex, BMI and the presence of ABCB1 2677GG (rs2032582) and CYP2B6 516GG (rs374527). Furthermore, the CYP2B6 516GG homozygote was related to a higher average dose of methadone (GG: 68.50 ± 32.43; GT: 52.28 ± 25.75; TT: 44.44 ± 29.64; P < 0.02), whereas the ABCB1 2677GG homozygote was related to a lower dose (GG: 51.09 ± 20.83; GT: 69.65 ± 37.51; TT: 62.52 ± 30.44; P < 0.05). We examined the predictive effect of polymorphisms combined with sex and BMI on methadone dose by conducting multiple linear regressions. Our data predicted the average dose of methadone in approximately 30% of heroin-dependent patients. CONCLUSION: The interactions between genetic polymorphisms and clinical features proved useful in identifying the effective dose of MMT for heroin-dependent patients in Taiwan more precisely.

Clinical Inertia and 2-Year Glycaemic Trajectories in Patients with Non-Newly Diagnosed Type 2 Diabetes Mellitus in Primary Care: A Retrospective Cohort Study.

OBJECTIVE: To analyse diabetes treatment, treatment change and self-management behaviours in association with 2-year glycaemic trajectories in patients with non-newly diagnosed type 2 diabetes mellitus in Chinese primary care. METHODS: This was an observational, multi-centre, longitudinal, retrospective cohort study. Clinical data of 4690 subjects were extracted from electronic medical records, including serial glycated haemoglobin A1c (HbA1c) measurements, antidiabetic medication records and compliance to exercise, diet, medications and self-monitoring of blood glucose (SMBG). Patterns of longitudinal HbA1c trajectories were identified using the percentage of HbA1c measurements <7.5% from the second available HbA1c measurement. Clinical relevance of the clusters was assessed through multivariable analysis. RESULTS: Approximately half of the participants demonstrated good glycaemic control; of these, 34.5% demonstrated stable, good control, and 13.7% demonstrated relatively good control. About 16.2% demonstrated moderate control, and 35.6% demonstrated poor control. From the good to poor control groups, the percentage of subjects treated with insulin at baseline and during the follow-up period increased gradually, while the percentage of subjects adhering to exercise, diet, medications and SMBG decreased gradually. Compared with baseline, the adherence to exercise, diet, medications and SMBG improved significantly. Approximately 50% and 26% of subjects in the two poorest control groups, respectively, experienced treatment changes. After multivariable adjustments, baseline HbA1c ≥7.5%, HbA1c change ≥-0.5% from baseline to visit 1, insulin treatment, treatment change, poor adherence to diet, exercise, SMBG during the follow-up period and HbA1c measurements <3 per year were significantly associated with poorer glycaemic control. CONCLUSION: We identified four longitudinal HbA1c trajectories in patients with non-newly diagnosed type 2 diabetes. Even if baseline HbA1c is suboptimal, aggressive treatment changes, good adherence during the follow-up period, ≥3 HbA1c measurements per year and reducing HbA1c levels to a certain extent by the first follow-up visit were important for good, stable, long-term glycaemic control.

Serotonergic Psychedelics in Neural Plasticity.

Psychedelics, compounds that can induce dramatic changes in conscious experience, have been used by humans for centuries. Recent studies have shown that certain psychedelics can induce neural plasticity by promoting neurite growth and synapse formation. In this review, we focus on the role of classical serotonergic psychedelics in neural plasticity and discuss its implication for their therapeutic potentials.

Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex.

The mammalian dorsomedial prefrontal cortex (dmPFC) receives diverse inputs and plays important roles in adaptive behavior and cognitive flexibility. Stress, a major risk factor for many psychiatric disorders, compromises the structure and function of multiple brain regions and circuits. Here we show that 7-day restraint stress impairs reversal learning in the 4-choice odor discrimination test, a decision-making task requiring an intact dmPFC. In vivo two-photon imaging further reveals that stress increases dmPFC dendritic spine elimination, particularly those of the mushroom morphology, without affecting spine formation. In addition, stress alters dmPFC microglial branching complexity and elevates their terminal process dynamics. In stressed mice, dmPFC microglia contact dendrites more frequently, and dendritic spines with microglial contact are prone to elimination. In summary, our work suggests that stress-induced changes in glial-synapse interaction contributes to synaptic loss in dmPFC, resulting in neuronal circuit deficits and impaired cognitive flexibility.

An analog of psychedelics restores functional neural circuits disrupted by unpredictable stress.

Psychological stress affects a wide spectrum of brain functions and poses risks for many mental disorders. However, effective therapeutics to alleviate or revert its deleterious effects are lacking. A recently synthesized psychedelic analog tabernanthalog (TBG) has demonstrated anti-addictive and antidepressant potential. Whether TBG can rescue stress-induced affective, sensory, and cognitive deficits, and how it may achieve such effects by modulating neural circuits, remain unknown. Here we show that in mice exposed to unpredictable mild stress (UMS), administration of a single dose of TBG decreases their anxiety level and rescues deficits in sensory processing as well as in cognitive flexibility. Post-stress TBG treatment promotes the regrowth of excitatory neuron dendritic spines lost during UMS, decreases the baseline neuronal activity, and enhances whisking-modulation of neuronal activity in the somatosensory cortex. Moreover, calcium imaging in head-fixed mice performing a whisker-dependent texture discrimination task shows that novel textures elicit responses from a greater proportion of neurons in the somatosensory cortex than do familiar textures. Such differential response is diminished by UMS and is restored by TBG. Together, our study reveals the effects of UMS on cortical neuronal circuit activity patterns and demonstrate that TBG combats the detrimental effects of stress by modulating basal and stimulus-dependent neural activity in cortical networks.