To develop a prognostic model for neoadjuvant immunochemotherapy efficacy in esophageal squamous cell carcinoma by analyzing the immune microenvironment.

Objective: The choice of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) is controversial. This study aims to provide a basis for clinical treatment selection by establishing a predictive model for the efficacy of neoadjuvant immunochemotherapy (NICT). Methods: A retrospective analysis of 30 patients was conducted, divided into Response and Non-response groups based on whether they achieved major pathological remission (MPR). Differences in genes and immune microenvironment between the two groups were analyzed through next-generation sequencing (NGS) and multiplex immunofluorescence (mIF). Variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves to establish a predictive model. An additional 48 patients were prospectively collected as a validation set to verify the model's effectiveness. Results: NGS suggested seven differential genes (ATM, ATR, BIVM-ERCC5, MAP3K1, PRG, RBM10, and TSHR) between the two groups (P < 0.05). mIF indicated significant differences in the quantity and location of CD3+, PD-L1+, CD3+PD-L1+, CD4+PD-1+, CD4+LAG-3+, CD8+LAG-3+, LAG-3+ between the two groups before treatment (P < 0.05). Dynamic mIF analysis also indicated that CD3+, CD8+, and CD20+ all increased after treatment in both groups, with a more significant increase in CD8+ and CD20+ in the Response group (P < 0.05), and a more significant decrease in PD-L1+ (P < 0.05). The three variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves: Tumor area PD-L1+ (AUC= 0.881), CD3+PD-L1+ (AUC= 0.833), and CD3+ (AUC= 0.826), and a predictive model was established. The model showed high performance in both the training set (AUC= 0.938) and the validation set (AUC= 0.832). Compared to the traditional CPS scoring criteria, the model showed significant improvements in accuracy (83.3% vs 70.8%), sensitivity (0.625 vs 0.312), and specificity (0.937 vs 0.906). Conclusion: NICT treatment may exert anti-tumor effects by enriching immune cells and activating exhausted T cells. Tumor area CD3+, PD-L1+, and CD3+PD-L1+ are closely related to therapeutic efficacy. The model containing these three variables can accurately predict treatment outcomes, providing a reliable basis for the selection of neoadjuvant treatment plans.

Genetic Dissection of BDNF and TrkB Expression in Glial Cells.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL) as well as a lower level of truncated TrkB (TrkB.T). However, there are conflicting reports regarding the expression of BDNF and TrkB in glial cells, particularly microglia. In this study, we employed a sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent reporter mice to label BDNF- or TrkB-expressing cells with soma-localized EGFP. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB-expressing microglia in examined CNS regions, including the somatomotor cortex, hippocampal CA1, and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the hippocampus of adult brains. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF in the hippocampus, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the hippocampus of adult mice. These results not only clarify the expression of BDNF and TrkB in glial cells but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in astrocytes and oligodendrocytes.

Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions.

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.

Association between congenital hypothyroidism and in-hospital adverse outcomes in very low birth weight infants / 中华儿科杂志

Objective: To investigate the association between congenital hypothyroidism (CH) and the adverse outcomes during hospitalization in very low birth weight infants (VLBWI). Methods: This prospective, multicenter observational cohort study was conducted based on the data from the Sino-northern Neonatal Network (SNN). Data of 5 818 VLBWI with birth weight <1 500 g and gestational age between 24-<37 weeks that were admitted to the 37 neonatal intensive care units from January 1st, 2019 to December 31st, 2022 were collected and analyzed. Thyroid function was first screened at 7 to 10 days after birth, followed by weekly tests within the first 4 weeks, and retested at 36 weeks of corrected gestational age or before discharge. The VLBWI were assigned to the CH group or non-CH group. Chi-square test, Fisher exact probability method, Wilcoxon rank sum test, univariate and multivariate Logistic regression were used to analyze the relationship between CH and poor prognosis during hospitalization in VLBWI. Results: A total of 5 818 eligible VLBWI were enrolled, with 2 982 (51.3%) males and the gestational age of 30 (29, 31) weeks. The incidence of CH was 5.5% (319 VLBWI). Among the CH group, only 121 VLBWI (37.9%) were diagnosed at the first screening. Univariate Logistic regression analysis showed that CH was associated with increased incidence of extrauterine growth retardation (EUGR) (OR=1.31(1.04-1.64), P<0.05) and retinopathy of prematurity (ROP) of stage Ⅲ and above (OR=1.74(1.11-2.75), P<0.05). However, multivariate Logistic regression analysis showed no significant correlation between CH and EUGR, moderate to severe bronchopulmonary dysplasia, grade Ⅲ to Ⅳ intraventricular hemorrhage, neonatal necrotizing enterocolitis in stage Ⅱ or above, and ROP in stage Ⅲ or above (OR=1.04 (0.81-1.33), 0.79 (0.54-1.15), 1.15 (0.58-2.26), 1.43 (0.81-2.53), 1.12 (0.70-1.80), all P>0.05). Conclusion: There is no significant correlation between CH and in-hospital adverse outcomes, possibly due to timely diagnosis and active replacement therapy.

Genetic dissection of BDNF and TrkB expression in glial cells.

The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL), and a lower level of truncated TrkB (TrkB.T). With conflicting results, glial cells also have been reported to express BDNF and TrkB. In the current study, we employed a more sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent EGFP reporter mice to label BDNF- or TrkB- expressing cells. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB- expressing microglia in the brain and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the adult brain. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the adult brain. These results not only clarify the expression of BDNF and TrkB in glial cells, but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in glial cells.

Correlation between global burden of small vessel disease on MRI and impaired spatial navigation in patients with cerebral small vessel disease / 国际脑血管病杂志

Objective:To investigate the correlation between global burden of small vessel disease(CSVD) on MRI and impaired spatial navigation in patients with CSVD.Methods:Patients with CSVD admitted to the Department of Neurology, Nanjing Jiangning Hospital from November 2020 to June 2022 were selected as the research subjects. The global burden of CSVD was scored according to the head MRI findings, and was divided into mild group (0-1 points), moderate group (2 points), and severe group (3-4 points). All patients were tested for spatial navigation function. Multivariate linear regression model was used to analyze the correlation between the global burden of CSVD and the spatial navigation function.Results:A total of 101 patients with CSVD were enrolled, including 37 patients in the mild group (36.6%), 28 in the moderate group (27.7%), and 36 in the severe group (35.6%). Age, glycosylated hemoglobin, total cholesterol, low-density lipoprotein cholesterol and creatinine, as well as the proportions of hypertension, diabetes, previous stroke or transient ischemic attack in the moderate group and the severe group were significantly higher than those in the mild group, while the high-density lipoprotein cholesterol was significantly lower than that in the mild group (all P<0.05). The spatial navigation function test showed that the environment + self-navigation, self-navigation and environment navigation functions of the moderate group and the severe group decreased significantly compared with the mild group (all P<0.05). Multivariate linear regression analysis showed that after adjusting for age, sex, hypertension, previous stroke or transient ischemic attack history and years of education, the global burden of CSVD and environment + self-navigation ( β=0.518, P<0.001), self-navigation ( β=0.481, P<0.001) and environmental navigation ( β=0.699, P<0.001) function had significant correlation. Conclusion:The global burden of CSVD is correlated with spatial navigation functions.

Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis.

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis.

Exosomal microRNAs: an emerging player in systemic lupus erythematosus / 生理学报

Exosomes are nanometer-sized membranous extracellular vesicles that can be secreted by almost all types of cells in the body. Exosomes are involved in cell-to-cell communication through autocrine and paracrine forms. Exosomal microRNAs (miRNAs) are stable in plasma, urine and other body fluids, and have various biological functions. They play an irreplaceable role in the occurrence, development, immune regulation of systemic lupus erythematosus (SLE). Recent studies have proposed that exosomal miRNAs have promising application prospects in the pathogenesis, early diagnosis, and treatment of SLE. Therefore, this review aims to introduce the current research progress on exosomal miRNAs in SLE and analyze their potential application value.

TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits.

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVHTrkB) neurons suppresses or increases food intake, respectively. PVHTrkB neurons project to multiple brain regions, including ventromedial hypothalamus (VMH) and lateral parabrachial nucleus (LPBN). We find that PVHTrkB neurons projecting to LPBN are distinct from those to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Additionally, TrkB activation with BDNF increases firing of these PVH neurons. Therefore, TrkB signaling is a key regulator of a previously uncharacterized neuronal population within the PVH that impinges upon multiple circuits to govern appetite.

TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding.

Genetic evidence indicates that brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor plays a critical role in the control of energy balance. Mutations in the BDNF or the TrkB-encoding NTRK2 gene have been found to cause severe obesity in humans and mice. However, it remains unknown which brain neurons express TrkB to control body weight. Here, we report that TrkB-expressing neurons in the dorsomedial hypothalamus (DMH) regulate food intake. We found that the DMH contains both glutamatergic and GABAergic TrkB-expressing neurons, some of which also express the leptin receptor (LepR). As revealed by Fos immunohistochemistry, a significant number of TrkB-expressing DMH (DMHTrkB) neurons were activated upon either overnight fasting or after refeeding. Chemogenetic activation of DMHTrkB neurons strongly suppressed feeding in the dark cycle when mice are physiologically hungry, whereas chemogenetic inhibition of DMHTrkB neurons greatly promoted feeding in the light cycle when mice are physiologically satiated, without affecting feeding in the dark cycle. Neuronal tracing revealed that DMHTrkB neurons do not innervate neurons expressing agouti-related protein in the arcuate nucleus, indicating that DMHTrkB neurons are distinct from previously identified LepR-expressing GABAergic DMH neurons that suppress feeding. Furthermore, selective Ntrk2 deletion in the DMH of adult mice led to hyperphagia, reduced energy expenditure, and obesity. Thus, our data show that DMHTrkB neurons are a population of neurons that are necessary and sufficient to suppress appetite and maintain physiological satiation. Pharmacological activation of these neurons could be a therapeutic intervention for the treatment of obesity.

Activation of Anxiogenic Circuits Instigates Resistance to Diet-Induced Obesity via Increased Energy Expenditure.

Anxiety disorders are associated with body weight changes in humans. However, the mechanisms underlying anxiety-induced weight changes remain poorly understood. Using Emx1Cre/+ mice, we deleted the gene for brain-derived neurotrophic factor (BDNF) in the cortex, hippocampus, and some amygdalar subregions. The resulting mutant mice displayed impaired GABAergic transmission and elevated anxiety. They were leaner when fed either a chow diet or a high-fat diet, owing to higher sympathetic activity, basal metabolic rate, brown adipocyte thermogenesis, and beige adipocyte formation, compared to control mice. BDNF re-expression in the amygdala rescued the anxiety and metabolic phenotypes in mutant mice. Conversely, anxiety induced by amygdala-specific Bdnf deletion or administration of an inverse GABAA receptor agonist increased energy expenditure. These results reveal that increased activities in anxiogenic circuits can reduce body weight by promoting adaptive thermogenesis and basal metabolism via the sympathetic nervous system and suggest that amygdalar GABAergic neurons are a link between anxiety and metabolic dysfunction.

Effect of Acori Tatarinowii Rhizoma on Intestinal Absorption of Ginsenosides in Dingzhi Xiaowan / 中国实验方剂学杂志

Objective: To explore the effect of Acori Tatarinowii Rhizoma on intestinal absorption of ginsenosides in Dingzhi Xiaowan,and reveal the mechanism of Acori Tatarinowii Rhizoma acting as " adjuvant drug" in this formula. Method: The contents of ginsenoside Rg1,Re and Rb1 were measured by UPLC-MS/MS and the absorption of three ginsenosides in different intestine segments was investigated by rat single pass intestinal perfusion in situ,including absorption rate constant(Ka) and apparent permeability coefficient(Papp).Everted intestinal sac model was used to investigate the absorption dosage of three ginsenosides affected by volatile oil from Acori Tatarinowii Rhizoma and verapamil[Ver,a P-glycoprotein(P-gp) inhibitor]. Result:Papp values of three ginsenosides were ≤ 0.191×10-3 cm·min-1 in Dingzhi Xiaowan when lack of Acori Tatarinowii Rhizoma.Compared with lack of Acori Tatarinowii Rhizoma in Dingzhi Xiaowan group,the Ka and Papp values of lack of volatile oil from Acori Tatarinowii Rhizoma in Dingzhi Xiaowan group slightly increased without significant difference in the four intestinal segments,but when the prescription had Acori Tatarinowii Rhizoma,the Ka increased by 3.97-8.35 fold and the Papp increased by 3.99-8.49 fold.The results of everted intestinal sac test showed that volatile oil of Acori Tatarinowii Rhizoma could significantly promote the intestinal absorption of ginsenoside Rg1,Re and Rb1,but there was no dose-dependent. Conclusion:Volatile oil of Acori Tatarinowii Rhizoma can promote the intestinal absorption of three ginsenosides in Dingzhi Xiaowan,and the mechanism may be related to the inhibiting function on P-gp.

A Study on the Effects of Occlusal Function on CTGF Expression in Orthodontics / 昆明医科大学学报

Objective To investigate CTGF changes in the expression of the gum tissue before and after orthodontic treatment, and to preliminarily explore the modification mechanism of gingival tissue and the effectiveness of the intervention measures. Methods 72 male Sprague-Dawley rats of 12-week-old, weight about 250 g-300 g, randomly divided into 6 groups: blank control group (A), healthy teeth orthodontic group (B), low functional group (C), low occlusal function teeth orthodontic group (D), combined intervention group (E), bite orthodontic intervention group (F). The results of the study were compared at 1 w, 2 w, 4 w, 6 w.Results (1) HE staining results showed the atrophy of the gingival tissue, which suggested that occlusal hypofunction SD rats model were successfully established. (2) Fluorescence quantitative results of CTGF in gingival tissue: 6 w: group B was higher than group D and group F (P＜0.05). Conclusion (1) the expression of CTGF in the low occlusion group was lower than that of the normal control group with time, and the gum tissue was vulnerable to atrophy. (2) It remains to be further studied whether the bite force recovery is effective.

Distinct cellular toxicity of two mutant huntingtin mRNA variants due to translation regulation.

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion within exon1 of the HTT gene. The gene generates two mRNA variants that carry either a short or long 3' untranslated region (3'UTR) while encoding the same protein. It remains unknown whether the two mRNA variants play distinct roles in HD pathogenesis. We found that the long HTT 3'UTR was capable of guiding mRNA to neuronal dendrites, suggesting that some long-form HTT mRNA is transported to dendrites for local protein synthesis. To assay roles of two HTT mRNA variants in cell bodies, we expressed mRNA harboring HTT exon1 containing 23x or 145x CAGs with the short or long 3'UTR. We found that mutant mRNA containing the short 3'UTR produced more protein aggregates and caused more apoptosis in both cultured neurons and HEK293 cells, compared with mutant mRNA containing the long 3'UTR. Although the two 3'UTRs did not affect mRNA stability, we detected higher levels of protein synthesis from mRNA containing the short 3'UTR than from mRNA containing the long 3'UTR. These results indicate that the long HTT 3'UTR suppresses translation. Thus, short-form mutant HTT mRNA will be more efficient in producing toxic protein than its long-form counterpart.

Early postnatal application of glucocorticoids for preventing bronchopulmonary dysplasia in preterm infants: a Meta analysis / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the clinical effect and safety of early postnatal application of glucocorticoids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.</p><p><b>METHODS</b>The databases including PubMed, Cochrane Library, Embase, CNKI, Wanfang Data, and VIP were comprehensively searched for articles on early postnatal application of glucocorticoids in the prevention of BPD in preterm infants published up to June 2016. Review Manager 5.3 was used for the Meta analysis of 16 randomized controlled trials (RCTs) that met the inclusion criteria.</p><p><b>RESULTS</b>A total of 2 962 participants were enrolled in the 16 RCTs, with 1 486 patients in the trial group and 1 476 in the control group. The Meta analysis showed that early postnatal application of glucocorticoids reduced the incidence rate of BPD at a corrected gestational age of 36 weeks (OR=0.73, 95%CI: 0.61-0.87, P=0.0004), but there was an increase in the risk of hyperglycemia (OR=1.61, 95%CI: 1.24-2.09, P=0.0003), hypertension (OR=1.63, 95%CI: 1.11-2.38, P=0.01), and intestinal perforation (OR=1.51, 95%CI: 1.12-2.04, P=0.007).</p><p><b>CONCLUSIONS</b>At present, it is not recommended to use glucocorticoids to prevent BPD in preterm infants. Its advantages and disadvantages need further studies, with special focuses on the adverse effects of hyperglycemia, hypertension, and intestinal perforation.</p>

Screening and follow-up for congenital heart disease in children aged 0-3 years in rural areas of Chongqing, China / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To examine the incidence of congenital heart disease (CHD) in children aged 0-3 years in the rural areas of Chongqing, and to determine the suitable "screening-diagnosis-follow-up" system and screening indicators for CHD in these areas.</p><p><b>METHODS</b>Children aged 0-3 years from rural areas of the Fuling Disctrict of Chongqing were selected by cluster sampling. Using the "screening-diagnosis-evaluation system" employed at the levels of village/town, district/county, and province/city, the children were screened for seven indicators, i.e., family history of CHD, dyspnea, cyanosis, unique facial features, other congenital malformations, heart murmurs, and blood oxygen saturation (SpO<95%). Children who were positive for one or more indicators accepted echocardiography (ECG) for the diagnosis of CHD. CHD patients were evaluated for disease progression, given guided treatments, and followed-up by pediatric cardiologists.</p><p><b>RESULTS</b>Screening was performed for 10 005 out of the 10 281 children enrolled in the study (97.32% response rate). Among the 175 children who were positive for the indicators, 166 underwent ECG and 60 (0.6‰) were diagnosed with CHD, including 46 cases of simple CHD (76.65%), 11 cases of combined CHD (18.33%), and 3 cases of complex CHD (5.00%). Of the 7 screening indicators, heart murmur had the largest area under the ROC curve for the diagnosis of CHD. In addition, a combination of screening indicators (heart murmur, unique facial features, and other congenital malformations) was most effective for screening out CHD. The CHD patients were given surgical or intervention treatments, and followed up for 6 to 18 months. Ten patients improved without treatment, 13 patients received interventional or surgical treatment, 1 patient died of non-cardiac reasons. The remaining 36 patients were subjected to further follow-up.</p><p><b>CONCLUSIONS</b>Heart murmur alone and in combination with unique facial features and other congenital malformations are valuable tools for CHD screening in children aged 0-3 years. The "village/town-district/county-province/city" screening-diagnosis-evaluation systems are useful for the early detection, diagnosis, and treatment of CHD in infants and young children from the rural areas of Chongqing.</p>

Regulation of Energy Balance via BDNF Expressed in Nonparaventricular Hypothalamic Neurons.

Brain-derived neurotrophic factor (BDNF) expressed in the paraventricular hypothalamus (PVH) has been shown to play a key role in regulating energy intake and energy expenditure. BDNF is also expressed in other hypothalamic nuclei; however, the role in the control of energy balance for BDNF produced in these structures remains largely unknown. We found that deleting the Bdnf gene in the ventromedial hypothalamus (VMH) during embryogenesis using the Sf1-Cre transgene had no effect on body weight in mice. In contrast, deleting the Bdnf gene in the adult VMH using Cre-expressing virus led to significant hyperphagia and obesity. These observations indicate that the lack of a hyperphagia phenotype in the Sf1-Cre/Bdnf mutant mice is likely due to developmental compensation. To investigate the role of BDNF expressed in other hypothalamic areas, we employed the hypothalamus-specific Nkx2.1-Cre transgene to delete the Bdnf gene. We found that the Nkx2.1-Cre transgene could abolish BDNF expression in many hypothalamic nuclei, but not in the PVH, and that the resulting mutant mice developed modest obesity due to reduced energy expenditure. Thus, BDNF produced in the VMH plays a role in regulating energy intake. Furthermore, BDNF expressed in hypothalamic areas other than PVH and VMH is also involved in the control of energy expenditure.

Anticancer Opportunity Created by Loss of Tumor Suppressor Genes.

Deletion of oncosuppressors occurs frequently in the cancer genome. A great deal of effort has been made to therapeutically restore the lost function of oncosuppressors, with little clinically translatable success, however. Reassuringly, besides the disappointing restoration endeavors, oncosuppressor loss can be therapeutically exploited in several other ways, such as the "synthetic lethality" strategies and the "therapeutic vulnerability" created by codeletion of neighboring genes. The study by Liu et al showed that codeletion of p53 and a neighboring essential gene POLR2A rendered colon cancer cells highly sensitive to further inhibition of POLR2A both in vitro and in vivo In recent years, several studies have reported similar phenomenon in a wide range of cancer types. In this focus article, we will introduce several kinds of anticancer opportunities created by the loss of oncosuppressors and discuss their mechanisms. Given the frequency of oncosuppressor loss in cancer, its therapeutic exploitation rather merits further investigation and may open a new window for oncotherapy.

Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity.

G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 µM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure.

Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance; however, its underlying mechanism remains unknown. By analyzing BDNF-expressing neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits that control energy balance. The Bdnf gene in the PVH was mostly expressed in previously undefined neurons, and its deletion caused hyperphagia, reduced locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and reduced locomotor activity were associated with Bdnf deletion in anterior PVH, whereas BDNF neurons in medial and posterior PVH drive thermogenesis by projecting to spinal cord and forming polysynaptic connections to brown adipose tissues. Furthermore, BDNF expression in the PVH was increased in response to cold exposure, and its ablation caused atrophy of sympathetic preganglionic neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor activity, whereas those in medial and posterior PVH promote thermogenesis by releasing BDNF into spinal cord to boost sympathetic outflow.