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Background: Psychiatric problems among college students on USA campuses are common. Little is known about similar problems in developing countries, particularly the Arab region. The goal of this study was to assess the frequency of selected psychiatric problems among college students in two Arab countries: Qatar and Lebanon, and to compare them to the USA., Methods: The Healthy Minds Study, an online confidential survey of common psychiatric symptoms designed for college campuses was used. We used the Patient Health Questionnaire-9 (PHQ-9) to screen for major depression, the Generalized Anxiety Disorder-7 (GAD-7) to screen for generalized anxiety and the SCOFF questionnaire to screen for eating disorders. Comparisons were made using ANOVA, Chi-Square tests and logistic regressions., Results: A total of 1841 students participated in the study. The rates of depression (PHQ-9 ≥ 12), generalized anxiety (GAD-7 ≥ 10) and eating disorders (SCOFF≥3) at the combined Arab universities were 34.6, 36.1 and 20.4% respectively. The corresponding rates in the USA were: 12.8, 15.9 and 6.8% (p < 0.001 for all measures). The impact of psychiatric problems on functioning in general and academic performance in particular was more severe in the Arab countries compared to the USA (p < 0.001). Independent predictors of psychiatric problems in general included location, female gender, financial difficulties and poor grades. Being religious had a protective association with mental health., Conclusion: The rates of depression, anxiety and eating disorders were significantly higher among college students in Qatar and Lebanon compared to the USA. Additional research is needed to determine whether these results reflect methodological limitations or true differences in psychopathology across these populations. If replicated, the results indicate that the psychiatric problems on college campuses in the USA are a microcosm of a global problem that needs global solutions.

Botryomycosis is a rare, chronic granulomatous infection caused by a response to bacteria, most commonly Staphylococcus aureus. Cutaneous manifestations, such as subcutaneous nodules, nonhealing ulcers, or sinus tracks, typically occur following inoculation of bacteria after trauma. Drainage from the skin lesions may contain yellow grains resembling those seen in actinomycosis and nocardiosis. A 20-year-old Hispanic male presented over the course of several years with a chronic nonhealing left posterior scalp wound. A car hit the patient when he was 2 years old and injured the scalp in the location of the skin lesion. Multiple wound cultures grew methicillin-resistant Staphylococcus aureus (MRSA), and biopsies were consistent with botryomycosis. He was treated with multiple surgical debridements, skin grafts, and various courses of oral and intravenous antibiotics with slight improvement. One reason for poor response to therapy was noncompliance with long-term home antibiotics. The most recent tissue culture grew MRSA in addition to Nocardia mexicana, and he experienced improvement on linezolid and minocycline. Although it is important to exclude nocardiosis and actinomycosis when diagnosing botryomycosis, our patient was diagnosed with botryomycosis after multiple biopsies and positive MRSA cultures 2 years prior to 1 positive N mexicana culture. Our case is a unique presentation of botryomycosis in an individual who subsequently developed Nocardia-positive wound cultures.

Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of Aβ in vitro. We characterized the transcriptional profiles of adult microglia from APP/PS1 mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7 , a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD., Competing Interests: Conflict of interest statement: Denali Therapeutics has licensed the Necrostatin program (including Nec-1s) from Harvard Medical School. J.Y. is a consultant of Denali Therapeutics.

Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration., (Copyright © 2016, American Association for the Advancement of Science.)

Necroptosis is a caspase-independent form of regulated cell death executed by the receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). Recently, necroptosis-based cancer therapy has been proposed to be a novel strategy for antitumor treatment. However, a big controversy exists on whether this type of therapy is feasible or just a conceptual model. Proponents believe that because necroptosis and apoptosis use distinct molecular pathways, triggering necroptosis could be an alternative way to eradicate apoptosis-resistant cancer cells. This hypothesis has been preliminarily validated by recent studies. However, some skeptics doubt this strategy because of the intrinsic or acquired defects of necroptotic machinery observed in many cancer cells. Moreover, two other concerns are whether or not necroptosis inducers are selective in killing cancer cells without disturbing the normal cells and whether it will lead to inflammatory diseases. In this review, we summarize current studies surrounding this controversy on necroptosis-based antitumor research and discuss the advantages, potential issues, and countermeasures of this novel therapy.

Macrophages are involved in tumor growth and progression. They infiltrate into tumors and cause inflammation, which creates a microenvironment favoring tumor growth and metastasis. However, certain stimuli may induce macrophages to act as tumor terminators. Here we report that the calcineurin B subunit (CnB) synergizes with IFN-γ to make macrophages highly cytotoxic to cancer cells. Furthermore, CnB and IFN-γ act synergistically to polarize mouse tumor-associated macrophages, as well as human monocyte-derived macrophages to an M1-like phenotype. This synergy is mediated by the crosstalk between CnB-engaged integrin αM-p38 MAPK signaling and IFN-γ-initiated p38/PKC-δ/Jak2 signaling. Interestingly, the signal transducer and activator of transcription 1 (STAT1) is a key factor that orchestrates the synergy of CnB and IFN-γ, and the phosphorylation status at Ser727 and Tyr701 of STAT1 is directly regulated by CnB and IFN-γ.

Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS.

The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma., (Copyright © 2013 UICC.)

Goldfish (Carassius auratus L.) are highly tolerant of environmental hypoxia, and with appropriate acclimation may survive and remain active for several days in the complete absence of oxygen. Previous work suggests that the hypoxia-induced activation of cardiac ATP-sensitive potassium (KATP) channels serves to increase tolerance of low oxygen in many species. For goldfish, we have previously characterized a nitric oxide (NO)- and cGMP-dependent pathway by which this channel activation occurs in acute hypoxia. The purpose of the present study was to resolve alterations in KATP channel activity and relevant gene expression in response to acclimation under moderately hypoxic conditions (2.6mg O2/L for seven days at 22°C). Intracellular action potential duration in excised ventricles from hypoxia-acclimated animals was significantly (p<0.05) reduced at both 50% and 90% of full repolarization relative to those from normoxia-acclimated fish. In cell-attached ventricular membrane patches from hypoxia-acclimated goldfish, sarcolemmal KATP channel open probability (NPo) was significantly enhanced vs. control. Of the two genes coding for the pore-forming subunits of cardiac KATP channels (Kir6.1 and Kir6.2), mRNA transcription of kcnj8 (revealed by quantitative real-time PCR) was unchanged while kcnj11 was downregulated in response to chronic low oxygen. The mRNA levels for hif1a (hypoxia inducible factor 1α) in the hearts of hypoxia-acclimated fish were significantly enhanced, as was nitric oxide synthase (nos2) and the sulfonylurea receptor regulatory subunit (sur2, abcc9). These data suggest that prior whole-animal acclimation to chronic hypoxia enhances cardioprotective sarcolemmal KATP currents by altering transcription of regulatory proteins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We used a series of gene disruptions and gene replacements to mutagenically characterize 30 kilobases of DNA in the erythromycin resistance gene (ermE) region of the Saccharopolyspora erythraea chromosome. Five previously undiscovered loci involved in the biosynthesis of erythromycin were found, eryBI, eryBII, eryCI, eryCII, and eryH; and three known loci, eryAI, eryG, and ermE, were further characterized. The new Ery phenotype, EryH, was marked by (i) the accumulation of the intermediate 6-deoxyerythronolide B (DEB), suggesting a defect in the operation of the C-6 hydroxylase system, and (ii) a block in the synthesis or addition reactions for the first sugar group. Analyses of ermE mutants indicated that ermE is the only gene required for resistance to erythromycin, and that it is not required for production of the intermediate erythronolide B (EB) or for conversion of the intermediate 3-alpha-mycarosyl erythronolide B (MEB) to erythromycin. Mutations in the eryB and eryC loci were similar to previously reported chemically induced eryB and eryC mutations blocking synthesis or attachment of the two erythromycin sugar groups. Insertion mutations in eryAI, the macrolactone synthetase, defined the largest (at least 9-kilobase) transcription unit of the cluster. These mutants help to define the physical organization of the erythromycin gene cluster, and the eryH mutants provide a source for the production of the intermediate DEB.

A mutant strain derived by chemical mutagenesis of Saccharopolyspora erythraea (formerly known as Streptomyces erythreus) was isolated that accumulated erythromycin C and, to a lesser extent, its precursor, erythromycin D, with little or no production of erythromycin A or erythromycin B (the 3"-O-methylation products of erythromycin C and D, respectively). This mutant lacked detectable erythromycin O-methyltransferase activity with erythromycin C, erythromycin D, or the analogs 2-norerythromycin C and 2-norerythromycin D as substrates. A 4.5-kilobase DNA fragment from S. erythraea originating approximately 5 kilobases from the erythromycin resistance gene ermE was identified that regenerated the parental phenotype and restored erythromycin O-methyltransferase activity when transformed into the erythromycin O-methyltransferase-negative mutant. Erythromycin O-methyltransferase activity was detected when the 4.5-kilobase fragment was fused to the lacZ promoter and introduced into Escherichia coli. The activity was dependent on the orientation of the DNA relative to lacZ. We have designated this genotype eryG in agreement with Weber et al. (J.M. Weber, B. Schoner, and R. Losick, Gene 75:235-241, 1989). It thus appears that a single enzyme catalyzes all of the 3"-O-methylation reactions of the erythromycin biosynthetic pathway in S. erythraea and that eryG codes for the structural gene of this enzyme.

A lethal zygosis-sensitive mutant of Streptomyces erythreus, ER720, was isolated. Pocks were formed when spores of the parental type were plated on a lawn of ER720, suggesting the loss of a transmissible plasmid, SEP1, from this strain. Recombination did not occur between derivatives of ER720 lacking SEP1, but it did occur if SEP1 was transferred to one of these strains or if these strains were crossed with other strains containing SEP1. SEP1 could also be transferred at high frequency between strains. This is consistent with SEP1 acting as a sex factor in S. erythreus.