A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7.

To construct a grading score that predicts neurologic function 1 year after diagnosis of anti-NMDA receptor (NMDAR) encephalitis.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is expressed constitutively on regulatory T cells. So far, several studies have focused on association between CTLA-4 gene polymorphisms and recurrent pregnancy loss (RPL). However, above association between the CTLA-4 gene polymorphism and RPL susceptibility is uncertain. Therefore, we performed a timely meta-analysis of all current publications to clarify this relationship. We located articles from the PubMed and Chinese language (WanFang) databases that were published up until July 25, 2018. Finally, we obtained six case-control studies, containing 2405 total cases and 2607 total controls, based on search criteria for abortion susceptibility related to the CTLA-4 +49 G/A polymorphism. The odds ratios (OR) and 95% confidence intervals (CIs) revealed association strengths. There was significantly decreased association between this polymorphism and whole population risk (e.g. AA vs. GG: OR = 0.56, 95% CI = 0.38-0.81, P=0.002). Additionally, in ethnicity subgroups, similar association was found both in China (e.g. AA vs. GG: OR = 0.49, 95% CI = 0.39-0.63, P=0.002) and non-China (e.g. AG vs. GG: OR = 0.46, 95% CI = 0.34-0.63, P<0.001). Current analysis suggested CTLA-4 +49 G/A polymorphism may weakly decrease RPL risk for women of childbearing age.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.

GPI-anchoring is a prevalent Glycosylphosphatidylinositol modification process of posttranslational protein and is necessary for cell wall integrity in eukaryotes. To date, the function of GPI anchored-related protein remains unknown in phytopathogenic fungi.

Rice blast, caused by Magnaporthe oryzae, is an important rice disease occurring in all rice-growing areas. To manage blast disease effectively and in an environmentally friendly way, it is important to continually discover diverse resistant resources for breeding. In this study, genome-wide association study (GWAS) was used to map genes/loci resistant to rice blast in the open-access rice diversity panel 1 (RDP1), previously genotyped with a 44K single-nucleotide polymorphism array. Two geographically and genetically different M. oryzae isolates from Taiwan, D41-2 and 12YL-DL3-2, were used to challenge RDP1. Infected leaves were visually rated for lesion type (LT) and evaluated for proportion of diseased leaf area (%DLA) by image analysis software.

Periodontal diseases (PD) are complex oral inflammatory diseases initiated by keystone bacteria such as Porphyromonas gingivalis. A vaccine for PD is desirable as clinical treatment involves protracted maintenance strategies aimed to retain dentition. Although prior immunization approaches targeting P. gingivalis have reported variable success in limiting facets of disease such as oral bone loss, it remains that a vaccine for this disease may be attainable.

Adenosine A2A receptors (A2A R) play a key role in modulating dopamine-dependent locomotor activity, as heralded by the sensitization of locomotor activity upon chronic A2A R blockade, which is associated with elevated dopamine levels and altered corticostriatal synaptic plasticity. Since the orphan receptor GPR37 has been shown to modulate A2A R function in vivo, we aimed to test whether the A2A R-mediated sensitization of locomotor activity is GPR37-dependent and involves adaptations of synaptic plasticity. To this end, we administered a selective A2A R antagonist, SCH58261 (1 mg/kg, i.p.), daily for 14 days, and the locomotor sensitization, striatum-dependent cued learning, and corticostriatal synaptic plasticity (i.e., long-term depression) were compared in wild-type and GPR37-/- mice. Notably, GPR37 deletion promoted A2A R-associated locomotor sensitization but not striatum-dependent cued learning revealed upon chronic SCH58261 treatment of mice. Furthermore, chronic A2A R blockade potentiated striatal long-term depression in corticostriatal synapses of GPR37-/- but not of wild-type mice, thus correlating well with neurochemical alterations of the adenosinergic system. Overall, these results revealed the importance of GPR37 regulating A2A R-dependent locomotor sensitization and synaptic plasticity in the basal ganglia circuitry. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

Branching is a major determinant of crop yield, and enables vigorous shoot growth and the production of a dense canopy. Phytochrome A signal transduction 1 (PAT1) positively regulates phytochrome A signal transduction in response to light, but its effects on branching remain unknown. In this study, we mapped PAT1, and revealed a previously unknown role related to branching and flowering in leafy Brassica juncea. Earlier and increased branching was observed when PAT1 expression was down-regulated, implying that PAT1 negatively regulates shoot branching. Additionally, down-regulated PAT1 expression reversed the inhibited branching induced by far-red light, suggesting PAT1 is involved in the shade avoidance response. PAT1 negatively regulated branching only after bud initiation. The observed interaction between PAT1 and BRC1 implied that PAT1 influences bud outgrowth in a BRC1-dependent manner. Biochemical and genetic evidence indicate that PAT1 directly interacts with CONSTANS-LIKE 13 (COL13), which negatively regulates flowering, with the resulting PAT1-COL13 complex mediating shoot branching and flowering. Our findings reveal a new crosstalk modality between phytochrome signalling and flowering pathways during the regulation of shoot branching and flowering. The data presented herein may be useful for future studies involving the editing of the GRAS family transcription factor PAT1 gene to enhance crop productivity and enable earlier harvesting.

Despite the recognition of the lethality of cancer metastasis and the importance of developing specific anti-metastasis therapies directed at the cancer metastatic cascade, the dynamics of cancer metastasis remains poorly understood. In this study, we examined the dynamics of circulating tumor cell (CTC) survival in the bloodstream using experimental mouse models. CTCs were arrested in the capillaries by adhesion to vascular endothelium within a few minutes after injection into the bloodstream. The loss of CTCs from the circulation followed a bi-phasic decay pattern, with the number of CTCs in the bloodstream being closely associated with the number of blood circulation cycles. The calculated in vivo Vd (apparent volume of distribution) of the CTC revealed organ specific binding of the CTCs. Moreover, confocal microscopy, in vivo fluorescence imaging in syngeneic mouse metastatic models and analysis of blood circulation patterns support the notion of organ-specific tumor metastasis. The present study suggests that organ-specific tumor metastasis is influenced by cooperation between blood circulation patterns and 'seed-soil' compatibility factors. These new findings provide further insights for optimized cancer metastatic prevention strategies such as by creating a hostile circulation microenvironment and targeting the organ-specific 'seed-soil' compatibility factors.

The Retinal Pigment Epithelium (RPE) is a monolayer of cells located above the choroid. It mediates human visual cycle and nourishes photoreceptors. Hypoxia-induced oxidative stress to RPE is a vital cause of retinal degeneration such as the Age-related Macular Degeneration. Most of these retinal diseases are irreversible with no efficient treatment, therefore protecting RPE cells from hypoxia stress is an important way to prevent or slow down the progression of retinal degeneration. Betulinic acid (BA) and betulin (BE) are pentacyclic triterpenoids with anti-oxidative property, but little is known about their effect on RPE cells. We investigated the protective effect of BA, BE and their derivatives against cobalt chloride-induced hypoxia stress in RPE cells. Human ARPE-19 cells were exposed to BA, BE and their eighteen derivatives (named as H3H20) that we customized through replacing moieties at C3 and C28 positions. We found that cobalt chloride reduced cell viability, increased Reactive Oxygen Species (ROS) production as well as induced apoptosis and necrosis in ARPE-19 cells. Interestingly, the pretreatment of 3-O-acetyl-glycyl- 28-O-glycyl-betulinic acid effectively protected cells from acute hypoxia stress induced by cobalt chloride. Our immunoblotting results suggested that this derivative attenuated the cobalt chloride-induced activation of Akt, Erk and JNK pathways. All findings were further validated in human primary RPE cells. In summary, this BA derivate has protective effect against the acute hypoxic stress in human RPE cells and may be developed into a candidate agent effective in the prevention of prevalent retinal diseases.

For many species, social rank determines which individuals perform certain social behaviors and when. Higher ranking or dominant (DOM) individuals maintain status through aggressive interactions and perform courtship behaviors while non-dominant (ND) individuals do not. In some species ND individuals ascend (ASC) in social rank when the opportunity arises. Many important questions related to the mechanistic basis of social ascent remain to be answered. We probed whether androgen signaling regulates social ascent in male Astatotilapia burtoni, an African cichlid whose social hierarchy can be readily controlled in the laboratory. As expected, androgen receptor (AR) antagonism abolished reproductive behavior during social ascent. However, we discovered multiple AR- and status-dependent temporal behavioral patterns that typify social ascent and dominance. AR antagonism in ASC males increased the time between successive behaviors compared to DOM males. Socially ascending males, independent of AR activation, were more likely than DOM males to follow aggressive displays with another aggressive display. Further analyses revealed differences in the sequencing of aggressive and courtship behaviors, wherein DOM males were more likely than ASC males to follow male-directed aggression with courtship displays. Strikingly, this difference was driven mostly by ASC males taking longer to transition from aggression to courtship, suggesting ASC males can perform certain DOM-typical temporal behavioral patterns. Our results indicate androgen signaling is necessary for social ascent and hormonal signaling and social experience may shape the full suite of DOM-typical behavioral patterns.

Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. Current hormonal therapies targeting estrogen can be prescribed only for a short time. It indicates a need for non-hormonal therapy. ERK1/2 and AKT pathways control several intracellular signaling molecules that control growth and survival of cells. Objectives of the present study are to determine the dual inhibitory effects of ERK1/2 and AKT pathways: (i) on proliferation, survival, and apoptosis of human endometrioitc epithelial cells and stromal cells in vitro; (ii) on growth and survival of endometrioitc lesions in vivo in xenograft mouse model of endometriosis of human origin; and (iii) establish the associated ERK1/2 and AKT downstream intracellular signaling modules in the pathogenesis of endometriosis. Our results indicated that combined inhibition of ERK1/2 and AKT pathways highly decreased the growth and survival of human endometriotic epithelial cells and stromal cells in vitro and suppressed the growth of endometriotic lesions in vivo compared to inhibition of either ERK1/2 or AKT pathway individually. This cause-effect is associated with dysregulated intracellular signaling modules associated with cell cycle, cell survival, and cell apoptosis pathways. Collectively, our results indicate that dual inhibition of ERK1/2 and AKT pathways could emerge as potential non-hormonal therapy for the treatment of endometriosis.

During standard gene cloning, the recombinant protein appearing in bacteria as the result of expression leakage very often inhibits cell proliferation leading to blocking of the cloning procedure. Although different approaches can reduce transgene basal expression, the recombinant proteins, which even in trace amounts inhibit bacterial growth, can completely prevent the cloning process.

The nuclear distribution element genes are conserved from fungus to humans. The nematode Caenorhabditis elegans expresses two isoforms of nuclear distribution element genes, namely nud-1 and nud-2. While nud-1 was functionally demonstrated to be the worm nudC ortholog, bioinformatic analysis revealed that the nud-2 gene encodes the worm ortholog of the mammalian NDE1 (Nuclear Distribution Element 1 or NudE) and NDEL1 (NDE-Like 1 or NudEL) genes, which share overlapping roles in brain development in mammals and also mediate the axon guidance in mammalian and C. elegans neurons. A significantly higher NDEL1 enzyme activity was shown in treatment non-resistant compared to treatment resistant SCZ patients, who essentially present response to the therapy with atypical clozapine but not with typical antipsychotics. Using C. elegans as a model, we tested the consequence of nud genes suppression in the effects of typical and atypical antipsychotics. To assess the role of nud genes and antipsychotic drugs over C. elegans behavior, we measured body bend frequency, egg laying and pharyngeal pumping, which traits are controlled by specific neurons and neurotransmitters known to be involved in SCZ, as dopamine and serotonin. Evaluation of metabolic and behavioral response to the pharmacotherapy with these antipsychotics demonstrates an important unbalance in serotonin pathway in both nud-1 and nud-2 knockout worms, with more significant effects for nud-2 knockout. The present data also show an interesting trend of mutant knockout worm strains to present a metabolic profile closer to that observed for the wild-type animals after the treatment with the typical antipsychotic haloperidol, but which was not observed for the treatment with the atypical antipsychotic clozapine. Paradoxically, behavioral assays showed more evident effects for clozapine than for haloperidol, which is in line with previous studies with rodent animal models and clinical evaluations with SCZ patients. In addition, the validity and reliability of using this experimental animal model to further explore the convergence between the dopamine/serotonin pathways and neurodevelopmental processes was demonstrated here, and the potential usefulness of this model for evaluating the metabolic consequences of treatments with antipsychotics is also suggested.

Histone H2B monoubiquitination (H2Bub1) plays important roles in several physiological and developmental processes, but its roles in the regulation of plant stress responses remain elusive. Here, we report that H2Bub1 is crucially involved in abscisic acid (ABA) signaling and drought response in rice. We found that rice HISTONE MONOUBIQUITINATION2 (OsHUB2), an E3 ligase for H2Bub1, interacted with OsbZIP46, a key transcription factor regulating ABA signaling and drought response in rice. Genetic analyses suggest that OsHUB2, upregulated by drought and ABA, positively modulates ABA sensitivity and drought resistance. The H2Bub1 levels were increased in the target genes of OsbZIP46 under the drought stress and ABA treatments, which were positively correlated with their increased expression levels. Interestingly, MODD, a reported suppressor of ABA signaling and drought resistance by mediating OsbZIP46 deactivation and degradation, could reduce the H2Bub1 levels in the target genes of OsbZIP46 by recruiting a putative deubiquitinase OsOTLD1. Suppression of OsOTLD1 in vivo resulted in increased H2Bub1 levels and expression of OsbZIP46 target genes. Collectively, these findings established an elaborate mechanism of histone monoubiquitination in the fine-turning of ABA signaling and drought response by balancing H2Bub1 deposition and removal.

Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE.

No abstract available

Hedgehog (Hh) pathway hyperactivation has been observed in various tumors, including breast cancer, and Hh pathway inhibitors have demonstrated antitumor activity in breast cancer. The tumor microenvironment (TME) has been shown to play an important role in modulating cancer cell drug sensitivity, but the TME response to Hh pathway inhibitors is unclear. In the current study, we observed increased TME infiltration of macrophages in breast cancer tissue, and specifically, M2 polarized macrophages after neoadjuvant chemotherapy. Furthermore, we observed an enhanced tolerance to Hh pathway inhibitors in MDA-MB-231 cells after co-culturing with M2 macrophages. In addition, we demonstrated that Hh pathway inhibition significantly induced IL6 expression, and validated that the tolerance to Hh pathway inhibitors was IL6-dependent. This study demonstrates a role of macrophages in Hh pathway inhibition resistance and a role of macrophage-derived IL6 in this resistance of breast cancer cells to Hh inhibition. These data indicate that antagonizing IL6 together with Hh pathway inhibitors may be a novel therapeutic strategy for breast cancer.

Anandamide, a major endocannabinoid, participates in energy metabolism homeostasis and neurobehavioral processes. In a secondary analysis of an open-label, randomized controlled trial, we investigated the long-term effect of aerobic exercise on resting plasma anandamide, and explored its relationship with changes in body weight, cardiorespiratory fitness, and mood status in healthy, physically inactive individuals. Participants recruited between March 2013 to August 2015 at the UNIFESP's Neurology/Psychobiology Department were randomly allocated into a 12-weeks supervised moderate exercise program, or into waitlist, control condition. Thirty-four participants (age = 38 ± 11.5, BMI = 26.6 ± 3.6) were intention to treat-analysed (Exercise: n = 17; Control: n = 17). After intervention, there were significant decreases in plasma anandamide (p < .01), anger, anxiety, and body weight (all p < .05), whereas cardiorespiratory fitness increased (p < .05) in the exercise group. There were no significant changes in any variable for the control group. In the whole cohort, adjusted R2 of multiple linear regressions showed that 12.2% of change body weight was explained by changes in anandamide (β = 0.391, p = .033), while 27% of change in mood disturbance (β = 0.546, p = .003), and 13.1% of change in anger (β = 0.404, p = .03) was explained by changes in anandamide. Our data suggest that the weight loss and mood improvement through regular moderate exercise may involve changes in anandamide metabolism/signaling. Trials registration: #NCT01972607.