Spiro- and bridged bicyclic structures are in demand for their sp3-rich frameworks that offer unique physiochemical properties and precisely positioned substituent groups. In order to rapidly access ...such molecules in a cross-coupling fashion we describe olefin amine (OLA) reagents for the transformation of aldehydes and ketones into all three topological types of bicyclic N-heterocycles: bridged, spiro-, and fused rings. The OLA reagents are easily prepared and allow the synthesis of complex molecular frameworks under operationally simple conditions that tolerate a wide array of functional groups. Investigations into the Mn or Fe promoted reaction pathway support a metal hydride hydrogen atom transfer (MH-HAT) to generate a C-centered radical that undergoes addition to an unactivated imine, leading to an N-centered radical. A catalytic cycle featuring regeneration of the metal catalyst by O2 and a second HAT to form the unprotected saturated N-heterocycle appears to be operative.
Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal ...circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the MPOA as key mediators of pup approach and retrieval. Reversible inactivation of MPOAEsr1+ cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOAEsr1+ cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOAEsr1+ cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors.
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•MPOAEsr1+ cells are necessary and sufficient for driving pup approach and retrieval•MPOAEsr1+ cells are naturally and preferentially activated during pup retrieval•MPOA cells decrease baseline firing and increase response to pups during lactation•MPOAEsr1+ provides strong inhibitory inputs to VTA non-DA cells to drive retrieval
Maternal behavior is mediated by a hardwired neural circuit that remains poorly understood. Fang et al. find that medial preoptic Esr1+ cells (MPOAESR1+) are highly active during maternal behaviors. Activation of MPOAESR1+ projection to ventral tegmental area drives immediate pup retrieval.
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote ...tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
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•Cancer cells secrete succinate to promote TAM polarization and cancer metastasis•Cancer-cell-derived secreted succinate is related to reduction of SDH activity•SUCNR1-triggered PI3K-HIF-1α axis mediates TAM polarization and cancer metastasis•Serum succinate is elevated in patients with lung cancer and serves as a biomarker
We have shown that cancer cells secrete succinate into extracellular milieu, which mediates TAM polarization and promotes cancer metastasis. Succinate exerts its effects on TAM polarization and cancer metastasis via a specific membrane receptor, SUCNR1, which transmits signaling through the PI3K/HIF-1α pathway.
Symbiosis between organisms is an important driving force in evolution. Among the diverse relationships described, extensive progress has been made in insect–bacteria symbiosis, which improved our ...understanding of the genome evolution in host-associated bacteria. Particularly, investigations on several obligate mutualists have pushed the limits of what we know about the minimal genomes for sustaining cellular life. To bridge the gap between those obligate symbionts with extremely reduced genomes and their non-host-restricted ancestors, this review focuses on the recent progress in genome characterization of facultative insect symbionts. Notable cases representing various types and stages of host associations, including those from multiple genera in the family Enterobacteriaceae (class Gammaproteobacteria), Wolbachia (Alphaproteobacteria) and Spiroplasma (Mollicutes), are discussed. Although several general patterns of genome reduction associated with the adoption of symbiotic relationships could be identified, extensive variation was found among these facultative symbionts. These findings are incorporated into the established conceptual frameworks to develop a more detailed evolutionary model for the discussion of possible trajectories. In summary, transitions from facultative to obligate symbiosis do not appear to be a universal one-way street; switches between hosts and lifestyles (e.g. commensalism, parasitism or mutualism) occur frequently and could be facilitated by horizontal gene transfer.
This review synthesizes the recent progress in genome characterization of insect-symbiotic bacteria, the emphases include (i) patterns of genome organization, (ii) evolutionary models and trajectories, and (iii) comparisons between facultative and obligate symbionts.
Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the ...hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.
Highly enantioselective Michael‐type addition (MTA) reactions between N‐protected alkenyl benzimidazoles and either pyrazoles or indazoles as nitrogen nucleophiles are accomplished for the first time ...using chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcomes, where the catalyst substituent and the N‐protecting group of benzimidazole contributed to the resulting high enantioselectivity.
Heterocycle squared: Highly enantioselective Michael‐type addition reactions to alkenyl benzimidazoles with pyrazoles and indazoles as nitrogen nucleophiles are accomplished using a chiral phosphoric acid catalyst. Theoretical studies elucidated the reaction pathway and the origin of the stereochemical outcome. The catalyst substituent and the N‐protecting group (PG) of the benzimidazole contribute to the resulting high enantioselectivity.
In some fish species, high or low temperature can switch the sex determination mechanisms and induce fish sex reversal when the gonads are undifferentiated. During this high or low ...temperature-induced sex reversal, the expressions of many genes are altered. However, genome-wide DNA methylation changes in fish gonads after high or low temperature treatment are unclear. Herein, we compared the global DNA methylation changes in the gonads from control females (CF), control males (CM), high temperature-treated females (TF), and high temperature-induced males (IM) from the F8 family of Nile tilapia (Oreochromis niloticus) using methylated DNA immunoprecipitation sequencing. The DNA methylation level in CF was higher than that in CM for various chromosomes. Both females and males showed an increase in methylation levels on various chromosomes after high-temperature induction. We identified 64,438 (CF/CM), 63,437 (TF/IM), 98,675 (TF/CF), 235,270 (IM/CM) and 119,958 (IM/CF) differentially methylated regions (DMRs) in Nile tilapia gonads, representing approximately 0.70% (CF/CM), 0.69% (TF/IM), 1.07% (TF/CF), 2.56% (IM/CM), and 1.30% (IM/CF)of the length of the genome. A total of 89 and 65 genes that exhibited DMRs in their gene bodies and promoters were mapped to the Nile tilapia genome. Furthermore, more than half of the genes with DMRs in the gene body in CF/CM were also included in the IM/CM, TF/CF, TF/IM, and IM/CF groups. Additionally, many important pathways, including neuroactive ligand-receptor interaction, extracellular matrix-receptor interaction, and biosynthesis of unsaturated fatty acids were identified. This study provided an important foundation to investigate the molecular mechanism of high temperature-induced sex reversal in fish species.
Background
Diabetic cognitive dysfunction (DCD) is one of the most insidious complications of type 2 diabetes mellitus, which can seriously affect the ability to self‐monitoring of blood glucose and ...the quality of life in the elderly. Previous pathological studies of cognitive dysfunction have focused on neuronal dysfunction, characterized by extracellular beta‐amyloid deposition and intracellular tau hyperphosphorylation. In recent years, astrocytes have been recognized as a potential therapeutic target for cognitive dysfunction and important participants in the central control of metabolism. The disorder of gut microbiota and their metabolites have been linked to a series of metabolic diseases such as diabetes mellitus. The imbalance of intestinal flora has the effect of promoting the occurrence and deterioration of several diabetes‐related complications. Gut microbes and their metabolites can drive astrocyte activation.
Aims
We reviewed the pathological progress of DCD related to the “gut microbiota‐astrocyte” axis in terms of peripheral and central inflammation, intestinal and blood–brain barrier (BBB) dysfunction, systemic and brain energy metabolism disorders to deepen the pathological research progress of DCD and explore the potential therapeutic targets.
Conclusion
“Gut microbiota‐astrocyte” axis, unique bidirectional crosstalk in the brain‐gut axis, mediates the intermediate pathological process of neurocognitive dysfunction secondary to metabolic disorders in diabetes mellitus.
The “gut microbiota‐astrocyte” axis is coupled to the pathogenesis of cognitive dysfunction secondary to type 2 diabetes mellitus. Gut microbes and astrocytes are critical factors in the gut‐brain axis, leading to diabetic cognitive dysfunction through peripheral and central inflammation, gut and blood–brain barriers (BBB), and systemic and brain energy metabolism. Gut microbiota and its metabolites are upstream drivers of astrocytic activation. The reactive astrocytes' morphology and function changes result in BBB injury, neuroinflammation, and brain energy metabolic disorder.
The present study aims to compare the efficacy and side effects of a platinum-containing combination regimen and platinum single-drug concurrent chemoradiotherapy (CCRT) in patients with advanced ...cervical cancer (CC) and to understand the prognostic factors in patients with CC.OBJECTIVEThe present study aims to compare the efficacy and side effects of a platinum-containing combination regimen and platinum single-drug concurrent chemoradiotherapy (CCRT) in patients with advanced cervical cancer (CC) and to understand the prognostic factors in patients with CC.A total of 108 cases of CC treated in Wenzhou Central Hospital were retrospectively selected. Patients in the monotherapy (single-drug) group received external pelvic radiotherapy (RT) and platinum-based single-drug chemotherapy (CT). Patients in the combined group received external pelvic RT and platinum-containing CT. The efficacy, CCRT time, 3-year survival rate after treatment and side effects were compared between the two groups, and the prognostic factors were analysed.METHODSA total of 108 cases of CC treated in Wenzhou Central Hospital were retrospectively selected. Patients in the monotherapy (single-drug) group received external pelvic radiotherapy (RT) and platinum-based single-drug chemotherapy (CT). Patients in the combined group received external pelvic RT and platinum-containing CT. The efficacy, CCRT time, 3-year survival rate after treatment and side effects were compared between the two groups, and the prognostic factors were analysed.The total effective rate was 74.07% in the monotherapy group and 72.22% in the combined group (p = .828). The incidences of myelosuppression, gastrointestinal reaction and abnormal liver function in the grades III-IV combined group were significantly higher than those in the monotherapy group (p < .001; p = .236; p = .022). Furthermore, the CCRT time was significantly longer in the combined group than in the monotherapy group, and the 3-year overall survival (OS) was 81.48% in the monotherapy group and 79.63% in the combined group (p = .643; p = .808). The older the age was, the higher the serum squamous cell carcinoma antigen (SCC-Ag) value before treatment and the shorter the progression-free survival time. In addition, the older the adenocarcinoma (AC) was, the shorter the OS.RESULTSThe total effective rate was 74.07% in the monotherapy group and 72.22% in the combined group (p = .828). The incidences of myelosuppression, gastrointestinal reaction and abnormal liver function in the grades III-IV combined group were significantly higher than those in the monotherapy group (p < .001; p = .236; p = .022). Furthermore, the CCRT time was significantly longer in the combined group than in the monotherapy group, and the 3-year overall survival (OS) was 81.48% in the monotherapy group and 79.63% in the combined group (p = .643; p = .808). The older the age was, the higher the serum squamous cell carcinoma antigen (SCC-Ag) value before treatment and the shorter the progression-free survival time. In addition, the older the adenocarcinoma (AC) was, the shorter the OS.The efficacy of the two regimens in the treatment of advanced CC was similar. However, the side effects increased significantly during combined treatment.CONCLUSIONThe efficacy of the two regimens in the treatment of advanced CC was similar. However, the side effects increased significantly during combined treatment.A higher patient age, having an AC and stage of IIIa and a high SCC-Ag value before treatment resulted in a relatively low survival rate.PROGNOSTIC FACTORSA higher patient age, having an AC and stage of IIIa and a high SCC-Ag value before treatment resulted in a relatively low survival rate.
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