EphB2-dependent prefrontal cortex activation promotes long-range social approach and partner responsiveness.

Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.

A potent new-scaffold androgen receptor antagonist discovered on the basis of a MIEC-SVM model.

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 µM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

Developmental characteristics of aggregated lymphoid nodules area in the abomasum of fetal Bactrian camels (Camelus bactrianus).

BACKGROUND: Bactrian camel is one of the important economic animals in northwest China. They live in arid desert, and their gestation period is about 13 months, which is longer than other ruminants (such as cattle and sheep). The harsh living conditions have made its unique histological characteristics a research focus. Aggregated lymphoid nodules area (ALNA) in the abomasum of Bactrian camels, as one of the most important sites for the induction of the immune response, provide a comprehensive and effective protective role for the organism, and their lack of information will affect the feeding management, reproduction and epidemic prevention of Bactrian camels. In this study, the histological characteristics of the fetal ALNA in the abomasum of Bactrian camels at different developmental gestation have been described by using light microscopy and histology . RESULTS: The ALNA in the abomasum of the Chinese Alashan Bactrian camel is a special immune structure that was first discovered and reported by Wen-hui Wang. To further establish the developmental characteristics of this special structure in the embryonic stage, the abomasum ALNA of 8 fetuses of Alashan Bactrian camels with different gestational ages (5~13 months) were observed and studied by anatomy and histology. The results showed that the aggregation of reticular epithelial cells (RECs) surrounded by a very small number of lymphoid cells was detected for the first time in the abomasum of fetal camel at 5 months gestation, which was presumed to be primitive ALNA. At 7 months gestation, the reticular mucosal folds region (RMFR) appeared, but the longitudinal mucosal folds region (LMFR) was not significant, and histological observations showed that there were diffusely distributed lymphocytes around the RECs. At 10months gestation, RMFR and LMFR were clearly visible, lymphoid follicles appeared in histological observation, lymphocytes proliferated vigorously. By 13 months, the volume of lymphoid follicles increased, forming the subepithelial dome (SED), and there was a primitive interfollicular area between the lymphoid follicles, which contained high endothelial vein (HEV), but no germinal center (GC) was found. In summary, ALNA of Bactrian camels is not fully mature before birth. CONCLUSIONS: Generally, the small intestine PPs of ruminants (such as cattle and sheep) is already mature before birth, while the ALNA in the abomasum of Bactrian camels is not yet mature in the fetal period. During the development of ALNA in Bactrian camel, the development of lymphoid follicles extends from submucosa to Lamina propria. Interestingly, the deformation of FAE changes with age from simple columnar epithelium at the beginning of pregnancy to Simple cuboidal epithelium, which is opposite to the FAE deformation characteristics of PPs in the small intestine of fetal cattle and sheep. These results are the basis of further research on the specificity of ALNA in the abomasum of Bactrian camels.

Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance.

As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

Discovery of novel antagonists targeting the DNA binding domain of androgen receptor by integrated docking-based virtual screening and bioassays.

Androgen receptor (AR), a ligand-activated transcription factor, is a master regulator in the development and progress of prostate cancer (PCa). A major challenge for the clinically used AR antagonists is the rapid emergence of resistance induced by the mutations at AR ligand binding domain (LBD), and therefore the discovery of novel anti-AR therapeutics that can combat mutation-induced resistance is quite demanding. Therein, blocking the interaction between AR and DNA represents an innovative strategy. However, the hits confirmed targeting on it so far are all structurally based on a sole chemical scaffold. In this study, an integrated docking-based virtual screening (VS) strategy based on the crystal structure of the DNA binding domain (DBD) of AR was conducted to search for novel AR antagonists with new scaffolds and 2-(2-butyl-1,3-dioxoisoindoline-5-carboxamido)-4,5-dimethoxybenzoicacid (Cpd39) was identified as a potential hit, which was competent to block the binding of AR DBD to DNA and showed decent potency against AR transcriptional activity. Furthermore, Cpd39 was safe and capable of effectively inhibiting the proliferation of PCa cell lines (i.e., LNCaP, PC3, DU145, and 22RV1) and reducing the expression of the genes regulated by not only the full-length AR but also the splice variant AR-V7. The novel AR DBD-ARE blocker Cpd39 could serve as a starting point for the development of new therapeutics for castration-resistant PCa.

Neural circuit mechanisms that govern inter-male attack in mice.

Individuals of many species fight with conspecifics to gain access to or defend critical resources essential for survival and reproduction. Such intraspecific fighting is evolutionarily selected for in a species-, sex-, and environment-dependent manner when the value of resources secured exceeds the cost of fighting. One such example is males fighting for chances to mate with females. Recent advances in new tools open up ways to dissect the detailed neural circuit mechanisms that govern intraspecific, particularly inter-male, aggression in the model organism Mus musculus (house mouse). By targeting and functional manipulating genetically defined populations of neurons and their projections, these studies reveal a core neural circuit that controls the display of reactive male-male attacks in mice, from sensory detection to decision making and action selection. Here, we summarize these critical results. We then describe various modulatory inputs that route into the core circuit to afford state-dependent and top-down modulation of inter-male attacks. While reviewing these exciting developments, we note that how the inter-male attack circuit converges or diverges with neural circuits that mediate other forms of social interactions remain not fully understood. Finally, we emphasize the importance of combining circuit, pharmacological, and genetic analysis when studying the neural control of aggression in the future.

Rapid tumor recurrence in a novel murine GBM surgical model is associated with Akt/PD-L1/vimentin signaling.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor without curable therapy. Surgical resection remains the first choice of patients with GBM but tumors relapse rapidly even combined with conventional chemoradiotherapy. The mechanism of GBM rapid recurrence is poorly understood, which is largely due to the lack of an appropriate animal model, thus heavily impedes the improvement of postoperative therapy. Here we established a highly reproducible mouse GBM surgical model by using the syngeneic G422TN-GBM cells, which faithfully recapitulates the features of rapid recurrence of human GBM after surgery. Implanting 2 × 103-5 × 104 of G422TN-GBM cells in mouse cerebral cortex caused death in all animal within 23 days, while surgery was an effective therapy but not curable. After complete removal of visible tumors on day 5-9 of tumor growth, the tumors recurred macroscopically within 5 days accompanied by increasing infiltrative cancer foci. Mechanistically, the rapid recurrence of resected tumors was positively correlated to early Akt activation, which subsequently upregulated PD-L1/Vimentin and promoted proliferation/migration of cancer cells. In addition, environmental astrocytic activation with strong PD-L1 signal was prominent. Taken together, we provided a novel GBM surgical recurrence model for preclinical studies and suggested complicated recurring mechanisms involving in strong oncogenic signaling as well as immune inhibitory signals from both GBM cells and their neighboring astrocytes.

Detection and structural characterization of the metabolites of dihydroresveratrol in rats by liquid chromatography coupled to high-resolution tandem mass spectrometry.

RATIONALE: Dihydroresveratrol has been demonstrated to possess a wide spectrum of bioactivities, such as anti-oxidant and anti-inflammatory effects. The aim of the present study was to investigate the metabolic profiles of dihydroresveratrol in rats. METHODS: The in vitro metabolism was elucidated by incubating dihydroresveratrol with rat hepatocytes for 2 h at 37°C. For in vivo metabolism, dihydroresveratrol was orally administered to rats at a single dose of 50 mg/kg and the resulting biliary and urinary samples were collected. All the samples were analyzed by liquid chromatography combined with electrospray ionization high-resolution mass spectrometry. The structures of the metabolites were proposed based on their accurate masses and their MS/MS product ions. RESULTS: A total of 16 metabolites including three phase I metabolites and 13 phase II metabolites were detected and structurally proposed. Among these metabolites, M6 and M14 were unambiguously identified as 3'-hydroxylresveratrol and resveratrol, respectively, using reference standards. Dihydroresveratrol was mainly metabolized into resveratrol (M14) and a glucuronide conjugate (M12), which were excreted into urine and bile as the major metabolites. CONCLUSIONS: The metabolic pathways of dihydroresveratrol involved hydroxylation, dehydrogenation, glucuronidation, glutathione (GSH) conjugation and methylation. The present study provided useful information with regard to the metabolic profiles of dihydroresveratrol in rats.

AGRP Neurons Project to the Medial Preoptic Area and Modulate Maternal Nest-Building.

AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.SIGNIFICANCE STATEMENT In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.

Diabetic retinopathy predicts cardiovascular mortality in diabetes: a meta-analysis.

BACKGROUND: The prognostic significance of diabetic retinopathy (DR) for cardiovascular diseases (CVD) remained unclear. Therefore, we performed this meta-analysis to assess whether DR predicted CVD mortality in diabetic patients. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library for cohort studies reporting the association of DR and CVD mortality. Then we pooled the data for analysis. RESULTS: After screening the literature, 10 eligible studies with 11,239 diabetic subjects were finally included in quantitative synthesis. The pooled risk ratio (RR) of DR, mild DR, and severe DR for CVD mortality was 1.83 (95% confidence interval (CI): 1.42, 2.36; p < 0.001), 1.13 (95% CI 0.81, 1.59; p = 0.46), and 2.26 (1.31, 3.91; p = 0.003), respectively, compared to those without DR. In type 2 DM, the patients with DR had a significantly higher CVD mortality (RR: 1.69; 95% CI 1.27, 2.24; p < 0.001). Subgroup analysis also showed a significantly higher CVD mortality in DR according to various regions, study design, data source, and follow-up period (all RR > 1; all P values < 0.05). Data from 2 studies showed no significant correlation of DR and CVD mortality in diabetic patients receiving cardiovascular surgery (RR: 2.40; 95% CI 0.63, 9.18; P = 0.200). CONCLUSIONS: DR is a risk marker of cardiovascular death, and severe DR predicts a doubled mortality of CVD in diabetes. These findings indicate the importance of early identification and management of diabetic patients with DR to reduce the risk of death.

Neural Circuit Mechanisms That Underlie Parental Care.

In mammals, parental care is essential for the survival of the young; therefore, it is vitally important to the propagation of the species. These behaviors, differing between the two sexes, are innate, stereotyped, and are also modified by an individual's reproductive experience. These characteristics suggest that neural mechanisms underlying parental behaviors are genetically hardwired, evolutionarily conserved as well as sexually differentiated and malleable to experiential changes. Classical lesion studies on neural control of parental behaviors, mostly done in rats, date back to the 1950s. Recent developments of new methods and tools in neuroscience, which allow precise targeting and activation/inhibition of specific populations of neurons and their projections to different brain structures, have afforded fresh opportunities to dissect and delineate the detailed neural circuit mechanisms that govern distinct components of parental behaviors in the genetically tractably organism, the laboratory mouse (Mus musculus). In this review, we summarize recent discoveries using modern neurobiological tools within the context of traditional lesion studies. In addition, we discuss interesting cross talk between neural circuits that govern parent care with those that regulate other innate behaviors such as feeding and mating.

A hypothalamic circuit that controls body temperature.

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.

The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

Single gold nanoparticle plasmonic spectroscopy for study of chemical-dependent efflux function of single ABC transporters of single live Bacillus subtilis cells.

ATP-binding cassette (ABC) membrane transporters serve as self-defense transport apparatus in many living organisms and they can selectively extrude a wide variety of substrates, leading to multidrug resistance (MDR). The detailed molecular mechanisms remain elusive. Single nanoparticle plasmonic spectroscopy highly depends upon their sizes, shapes, chemical and surface properties. In our previous studies, we have used the size-dependent plasmonic spectra of single silver nanoparticles (Ag NPs) to study the real-time efflux kinetics of the ABC (BmrA) transporter and MexAB-OprM transporter in single live cells (Gram-positive and Gram-negative bacterium), respectively. In this study, we prepared and used purified, biocompatible and stable (non-aggregated) gold nanoparticles (Au NPs) (12.4 ± 0.9 nm) to study the efflux kinetics of single BmrA membrane transporters of single live Bacillus subtillis cells, aiming to probe chemical dependent efflux functions of BmrA transporters and their potential chemical sensing capability. Similar to those observed using Ag NPs, accumulation of the intracellular Au NPs in single live cells (WT and ΔBmrA) highly depends upon the cellular expression of BmrA and the NP concentration (0.7 and 1.4 nM). The lower accumulation of intracellular Au NPs in WT (normal expression of BmrA) than ΔBmrA (deletion of bmrA) indicates that BmrA extrudes the Au NPs out of the WT cells. The accumulation of Au NPs in the cells increases with NP concentration, suggesting that the Au NPs most likely passively diffuse into the cells, similar to antibiotics. The result demonstrates that such small Au NPs can serve as imaging probes to study the efflux function of the BmrA membrane transporter in single live cells. Furthermore, the dependence of the accumulation rate of intracellular Au NPs in single live cells upon the expression of BmrA and the concentration of the NPs is about twice higher than that of the same sized Ag NPs. This interesting finding suggests the chemical-dependent efflux kinetics of BmrA and that BmrA could distinguish nearly identical sized Au NPs from Ag NPs and might possess chemical sensing machinery.

Inhibition of the RhoA/Rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension.

BACKGROUND: Recent research has shown that statins improve pulmonary arterial hypertension (PAH), but their mechanisms of action are not fully understood. This study aimed to investigate the role of RhoA/ROCK1 regulation in the therapeutic effects of simvastatin on PAH. METHODS: For in vivo experiments, rats (N = 40) were randomly assigned to four groups: control, simvastatin, monocrotaline (MCT), and MCT + simvastatin. The MCT group and MCT + simvastatin groups received proline dithiocarbamate (50 mg/kg, i.p.) on the first day of the study. The MCT + simvastatin group received simvastatin (2 mg/kg) daily for 4 weeks, after which pulmonary arterial pressure was measured by right heart catheterization. The protein and mRNA levels of Rho and ROCK1 were measured by immunohistochemistry, Western blot, and PCR. For in vitro experiments, human pulmonary endothelial cells were divided into seven groups: control, simvastatin, monocrotaline pyrrole (MCTP), MCTP + simvastatin, MCTP + simvastatin + mevalonate, MCTP + simvastatin + farnesyl pyrophosphate (FPP), and MCTP + simvastatin + FPP + geranylgeranyl pyrophosphate (GGPP). After 72 h exposed to the drugs, the protein and mRNA levels of RhoA and ROCK1 were measured by Western blot and PCR. RESULTS: The MCT group showed increased mean pulmonary arterial pressure, marked vascular remodeling, and increased protein and mRNA levels of RhoA and ROCK1 compared to the other groups (P < 0.05). In vitro, the MCTP group showed a marked proliferation of vascular endothelial cells, as well as increased protein and mRNA levels of RhoA and ROCK1 compared to the MCTP + simvastatin group. The MCTP + simvastatin + mevalonate group, MCTP + simvastatin+ FPP group, and MCTP + simvastatin + FPP + GGPP group showed increased mRNA levels of RhoA and ROCK1, as well as increased protein levels of RhoA, compared to the MCTP + simvastatin group. CONCLUSIONS: Simvastatin improved vascular remodeling and inhibited the development of PAH. The effects of simvastatin were mediated by inhibition of RhoA/ROCK1. Simvastatin decreased RhoA/ROCK1 overexpression by inhibition of mevalonate, FPP, and GGPP synthesis.

Elderly population have a decreased aneurysmal subarachnoid hemorrhage incidence rate than Middle aged population: a descriptive analysis of 8,144 cases in mainland China.

PURPOSE: Rupture of an intracranial aneurysm is a life-threatening acute cerebrovascular event. The purpose of this study was to investigate whether aneurysmal subarachnoid haemorrhage (SAH) incidence rate is higher or lower in elderly population than in middle aged population. MATERIALS AND METHODS: Aneurysmal SAH cases were collected retrospectively from the archives of 21 hospitals in Mainland China. All the cases were collected from September 2016 and backward consecutively for a period of time up to 8 years. SAH was initially diagnosed by brain computed tomography (CT). CT angiography (CTA) or digital subtraction angiography (DSA) was followed and SAH was confirmed to be due to cerebral aneurysm rupture. For cases when multiple bleeding occurred, the age of the first SAH was used in this study. The total incidence from all hospitals at each age group were summed together for females and males respectively; then adjusted by the total population number at each age group for females and males which was from the 2010 population census of the People's Republic of China. RESULTS: In total there were 8,144 cases of intracranial aneurysmal SAH, with 4,861 females and 3,283 males. For females the relative aneurysmal SAH incidence rate started to decrease after around 65 years old, while for males the relative aneurysmal SAH incidence rate started to decrease after around 53 years old. CONCLUSION: Our data tentatively suggest elderly patients may be at a reduced risk of rupture compared with patients who are younger while have similar other risk factors.

Sex differences in brain-derived neurotrophic factor signaling: Functions and implications.

Brain-derived neurotrophic factor (BDNF) regulates diverse processes such as neuronal survival, differentiation, and plasticity. Accumulating evidence suggests that molecular events that direct sexual differentiation of the brain interact with BDNF signaling pathways. This Mini-Review first examines potential hormonal and epigenetic mechanisms through which sex influences BDNF signaling. We then examine how sex-specific regulation of BDNF signaling supports the development and function of sexually dimorphic neural circuits that underlie male-specific genital reflexes in rats and song production in birds. Finally, we discuss the implications of sex differences in BDNF signaling for gender-biased presentation of neurological and psychiatric diseases such as Alzheimer's disease. Although this Mini-Review focuses on BDNF, we try to convey the general message that sex influences brain functions in complex ways and underscore the requirement for and challenge of expanding research on sex differences in neuroscience. © 2016 Wiley Periodicals, Inc.

Molecular characteristic of mcr-1 producing Escherichia coli in a Chinese university hospital.

BACKGROUND: Colistin has been considered as a last-line treatment option in severe infections caused by multidrug-resistant (MDR) gram-negative pathogens. However, the emergence of the mobile colistin resistance gene (mcr-1) has challenged this viewpoint. The aim of this study is to explore the prevalence of mcr-1 in Escherichia coli (E. coli) in a Chinese teaching hospital, and investigate their molecular characteristics. METHODS: A total of 700 E. coli isolates were used to screen mcr-1 by PCR and sequencing in a Chinese university hospital from August 2014 to August 2015. Susceptibility test of mcr-1-producing isolates was determined by Vitek -2 Compact system. 26 virulence factors (VFs), phylogenetic groups, Multi-locus sequence typing (MLST), and DNA Fingerprinting (ERIC-PCR) of strains were investigated by PCR. RESULTS: Four (0.6%) mcr-1 producing E. coli isolates were found in this study. The results of antibiotic susceptibility test showed that all four isolates were resistant to colistin, ciprofloxacin, levofloxacin, cefazolin, and trimethoprim/sulfamethoxazole, and were susceptible to amikacin, ertapenem and imipenem. In addition, all 4 isolates exhibited high-level resistance to aztreonam, cefotaxime and gentamicin. The numbers of VFs contained in mcr-1 positive isolates were no more than 4 in our study. MLST result demonstrated that these isolates were assigned to two sequence types: ST156 and ST167. The result of phylogenetic analysis showed that four mcr-1-positive isolates belong to two phylogenetic groups: A and B1 group. ERIC-PCR showed that four mcr-1 positive strains were categorized into three different genotypes. CONCLUSIONS: Our study demonstrated a low prevalence of mcr-1 in E. coli clinical isolates in a Chinese teaching hospital, and we have gained insights into the molecular characteristics of these mcr-1-positive strains. Increasing the surveillance of these infections, as well as taking effective infection control measures are urgently needed to take to control the transmission of mcr-1 gene.

Prediction of cervical lymph node metastasis in patients with papillary thyroid cancer using combined conventional ultrasound, strain elastography, and acoustic radiation force impulse (ARFI) elastography.

OBJECTIVES: To investigate the value of combined conventional ultrasound (US), strain elastography (SE) and acoustic radiation force impulse (ARFI) elastography for prediction of cervical lymph node metastasis (CLNM) in papillary thyroid cancer (PTC). METHODS: A consecutive series of 203 patients with 222 PTCs were preoperatively evaluated by US, SE, and ARFI including virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ). A multivariate analysis was performed to predict CLNM by 22 independent variables. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance. RESULTS: Multivariate analysis demonstrated that VTI area ratio (VAR) > 1 was the best predictor for CLNM, followed by abnormal cervical lymph node (ACLN), capsule contact, microcalcification, capsule involvement, and multiple nodules (all P < 0.05). ROC analyses of these characteristics showed the areas under the curve (Az), sensitivity, and specificity were 0.600-0.630, 47.7 %-93.2 %, and 26.9 %-78.4 % for US, respectively; and they were 0.784, 83.0 %, and 73.9 %, respectively, for VAR > 1. As combination of US characteristics with and without VAR, the Az, sensitivity, and specificity were 0.803 and 0.556, 83.0 % and 100.0 %, and 77.6 % and 11.2 %, respectively (P < 0.001). CONCLUSIONS: ARFI elastography shows superior performance over conventional US, particularly when combined with US, in predicting CLNM in PTC patients. KEY POINTS: • Conventional ultrasound is useful in predicting cervical lymph node metastasis preoperatively. • Virtual touch tissue imaging area ratio is the strongest predicting factor. • Predictive performance is markedly improved by combining ultrasound characteristics with VAR. • Acoustic radiation force impulse elastography may be a promising complementary tool.

Apelin: an endogenous peptide essential for cardiomyogenic differentiation of mesenchymal stem cells via activating extracellular signal-regulated kinase 1/2 and 5.

Growing evidence has shown that apelin/APJ system functions as a critical mediator of cardiac development as well as cardiovascular function. Here, we investigated the role of apelin in the cardiomyogenic differentiation of mesenchymal stem cells derived from Wharton's jelly of human umbilical cord in vitro. In this research, we used RNA interference methodology and gene transfection technique to regulate the expression of apelin in Wharton's jelly-derived mesenchymal stem cells and induced cells with a effective cardiac differentiation protocol including 5-azacytidine and bFGF. Four weeks after induction, induced cells assumed a stick-like morphology and myotube-like structures except apelin-silenced cells and the control group. The silencing expression of apelin in Wharton's jelly-derived mesenchymal stem cells decreased the expression of several critical cardiac progenitor transcription factors (Mesp1, Mef2c, NKX2.5) and cardiac phenotypes (cardiac α-actin, ß-MHC, cTnT, and connexin-43). Meanwhile, endogenous compensation of apelin contributed to differentiating into cells with characteristics of cardiomyocytes in vitro. Further experiment showed that exogenous apelin peptide rescued the cardiomyogenic differentiation of apelin-silenced mesenchymal stem cells in the early stage (1-4 days) of induction. Remarkably, our experiment indicated that apelin up-regulated cardiac specific genes in Wharton's jelly-derived mesenchymal stem cells via activating extracellular signal-regulated kinase (ERK) 1/2 and 5.