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Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.

Multiple sclerosis (MS) is a chronic and debilitating autoimmune disease, characterized by chronic inflammatory demyelination in the nervous tissue and subsequent neurological dysfunction. Spermidine, a natural polyamine, has been shown to affect inflammation in some experimental models. We show here that spermidine could alleviate experimental autoimmune encephalomyelitis (EAE), a model for MS, through regulating the infiltration of CD4 + T cells and macrophages in central nervous system. Unexpectedly, we found that spermidine treatment of MOG-specific T cells did not affect their pathogenic potency upon adaptive transfer; however, spermidine diminished the ability of macrophages in activating MOG-specific T cells ex vivo . Depletion of macrophages in diseased mice completely abolished the therapeutic effect of spermidine, indicating a critical role of spermidine-activated macrophages. Mechanistically, spermidine was found to specifically suppress the expression of interleukin-1beta (IL-1 β ), IL-12 and CD80 while enhance the expression of arginase 1 in macrophages. Interestingly, macrophages from spermidine-treated mice could also reverse EAE progression, while pretreatment of those macrophages with the arginase 1 inhibitor abrogated the therapeutic effect. Therefore, our studies revealed a critical role of macrophages in spermidine-mediated treatment on EAE and provided novel information for better management of MS.

It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS.

Mesenchymal stromal cells (MSCs) are strongly immunosuppressive via producing nitric oxide (NO) and known to migrate into tumor sites to promote tumor growth, but the underlying mechanisms remain largely elusive. Here, we found that interferon alpha (IFNα)-secreting MSCs showed more dramatic inhibition effect on tumor progression than that of IFNα alone. Interestingly, IFNα-primed MSCs could also effectively suppress tumor growth. Mechanistically, we demonstrated that both IFNα and IFNβ (type I IFNs) reversed the immunosuppressive effect of MSCs on splenocyte proliferation. This effect of type I IFNs was exerted through inhibiting inducible NO synthase (iNOS) expression in IFNγ and TNFα-stimulated MSCs. Notably, only NO production was inhibited by IFNα; production of other cytokines or chemokines tested was not suppressed. Furthermore, IFNα promoted the switch from signal transducer and activator of transcription 1 (Stat1) homodimers to Stat1-Stat2 heterodimers. Studies using the luciferase reporter system and chromatin immunoprecipitation assay revealed that IFNα suppressed iNOS transcription through inhibiting the binding of Stat1 to iNOS promoter. Therefore, the synergistic anti-tumor effects of type I IFNs and MSCs were achieved by inhibiting NO production. This study provides essential information for understanding the mechanisms of MSC-mediated immunosuppression and for the development of better clinical strategies using IFNs and MSCs for cancer immunotherapy.

PurposeEnvironmental sustainability is a growing concern to healthcare providers, given the health impacts of climate change and air pollution, and the sizable footprint of healthcare delivery itself. Though many studies have focused on environmental footprints of operating rooms, few have quantified emissions from inpatient stays. This study quantifies solid waste and greenhouse gas emissions (GHGs) per bed-day in a regular inpatient (low intensity) and intensive care unit (high intensity).MethodsThis study uses hybrid environmental life cycle assessment (LCA) to quantify average emissions associated with resource use in an acute inpatient unit with 49 beds and 14,427 hospitalization days and an intensive care unit (ICU) with 12 beds and 2536 hospitalization days. The units are located in a single tertiary, private hospital in Brooklyn, NY, USA.Results and discussionAn acute care unit generates 5.5 kg of solid waste and 45 kg CO2-e per hospitalization day. The ICU generates 7.1 kg of solid waste and 138 kg CO2-e per bed day. Most emissions originate from purchase of consumable goods, building energy consumption, purchase of capital equipment, food services, and staff travel.ConclusionsThe ICU generates more solid waste and GHGs per bed day than the acute care unit. With resource use and emission data, sustainability strategies can be effectively targeted and tested. Medical device and supply manufacturers should also aim to minimize direct solid waste generation.

Study Objectives: The COVID-19 pandemic has challenged the population of affected areas in multiple dimensions. Adolescents have been especially affected with school closure and home confinement. The impact of the pandemic on sleep habits and quality of sleep and quality of life among adolescents has not been adequately characterized. We hypothesized that the COVID-19 pandemic has induced an evening shift of the daily rhythm among adolescents and adversely affected sleep quality and quality of life of high school students. Methods: Students were questioned about their usual bed and wake-up times and answered the Pittsburgh Sleep Quality Index Questionnaire, the Epworth Sleepiness Scale, the Horne-Osteberg Morningness-Eveningness Questionnaire, and the World Health Organization Quality of Life Questionnaire-abbreviated version before and during the pandemic. Results: Ninety-four students (64% females, aged 15 ± 1 years) participated in both phases of the study. Students delayed bed and wake-up times by 1.5 (0.5–2.0) and 2.0 (1.5–2.5) hours, respectively. Chronotype (per the Morningness-Eveningness Questionnaire) shifted toward eveningness during the pandemic. Sleep duration increased and quality of sleep (per the Pittsburgh Sleep Quality Index) improved only among those students with shorter sleep duration before the pandemic. During the pandemic, the physical and psychological domains of the World Health Organization Quality of Life Questionnaire worsened but the environmental domain improved as compared with the study before the pandemic. Conclusions: High school students have delayed bed and wake-up times and shifted chronotype toward eveningness during the COVID-19 pandemic. The worsening of the physical and psychological World Health Organization Quality of Life Questionnaire domains and improvement in the environmental domain highlight the conflicting experiences that high school students are facing during the COVID-19 pandemic. Citation: Genta FD, Rodrigues Neto GB, Sunfeld JPV, et al. COVID-19 pandemic impact on sleep habits, chronotype, and health-related quality of life among high school students: a longitudinal study. J Clin Sleep Med . 2021;17(7):1371–1377.

p53 plays a pivotal role in controlling the differentiation of mesenchymal stem cells (MSCs) by regulating genes involved in cell cycle and early steps of differentiation process. In the context of osteogenic differentiation of MSCs and bone homeostasis, the osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB (OPG/RANKL/RANK) axis is a critical signaling pathway. The absence or loss of function of p53 has been implicated in aberrant osteogenic differentiation of MSCs that results in higher bone formation versus erosion, leading to an unbalanced bone remodeling. Here, we show by microCT that mice with p53 deletion systemically or specifically in mesenchymal cells possess significantly higher bone density than their respective littermate controls. There is a negative correlation between p53 and OPG both in vivo by analysis of serum from p53 +/+ , p53 +/− , and p53 −/− mice and in vitro by p53 knockdown and ChIP assay in MSCs. Notably, high expression of Opg or its combination with low level of p53 are prominent features in clinical cancer lesion of osteosarcoma and prostate cancer respectively, which correlate with poor survival. Intra-bone marrow injection of prostate cancer cells, together with androgen can suppress p53 expression and enhance local Opg expression, leading to an enhancement of bone density. Our results support the notion that MSCs, as osteoblast progenitor cells and one major component of bone microenvironment, represent a cellular source of OPG, whose amount is regulated by the p53 status. It also highlights a key role for the p53-OPG axis in regulating the cancer associated bone remodeling.

The HSV-1 tegument protein Us11 counteracts the antiviral defense mechanisms by precluding the host protein shutoff. Previous works demonstrated that Us11 prevents heat-and staurosporine-induced apoptosis and inhibits autophagy. Therefore, in the present study, we investigated the hypothesis that HSV-1, through Us11, could recruit caspase-8, a key enzyme regulating programmed cell death. We first show that HSV-1 promotes the accumulation of caspase-8-p18 active fragments in both semi permissive THP-1 cells and fully permissive HEp-2 cells to HSV-1 replication. Using a recombinant virus R3630 (ΔUs11/ΔUs12) and a plasmid encoding Us11-recombinant protein we have proven that Us11 promotes p18 accumulation, which does not trigger the apoptotic signaling. Additional, in an in vitro model, we demonstrated that Us11-recombinant protein induces caspase-8-p18 cleavage by physically interacting with the caspase-8 recombinant protein. Finally, we found that, during HSV-1 replication, activated-caspase-8 cleaves Atg3 protein to potentially block autophagy and support its replication.

Y RNAs are a class of highly conserved small non-coding RNAs. Emerging evidences reported that Y RNAs and their Y RNA-derived small RNAs (YsRNAs) represent bioactive molecules and not simply structural RNAs involved in scaffolding and assembling. They can interact and regulate both localization and functions of several RNA-binding proteins implicated in a wide range of cellular processes such as DNA replication, RNA quality control and cellular stress responses. More evidences suggest functional involvement of Y RNAs in several type of disease such as cancer, immune related pathologies, neurological disorders and cardiovascular diseases. Nevertheless, there are many questions that still need to be answered for their functional and mechanistic understanding in a physiological and in a pathological context. In this review we will describe the current state of knowledge about YRNAs, their structure, biogenesis, functions and interaction with known proteins, as well their role in disease. The picture arising indicates their potential function as biomarkers for disease diagnosis, as well as therapeutical targets for building up tailored approaches in personalized medicine.

Clostridium difficile infection is a rare event in newborn. Since several studies show a high rate of asymptomatic neonatal colonization by non-toxigenic Clostridium strains, C. difficile is usually not searched in infants and children affected by bloody diarrhea and younger than 12 months. Nevertheless, Clostridium difficile infection should be suspected in patients with bloody diarrhea and other comorbidities. The long term hospitalization and the prolonged exposure to broad-spectrum antibiotic therapy, are also important risk factors for intestinal infection. We present the case of a 10-day newborn with thrombocytopenia associated with rectorrhagia and positivity of inflammation indices. Transfusion of platelets and immunoglobulins was performed with platelet normalization and empiric antibiotic therapy was practiced (ampicillin and gentamicin). A sudden clinical worsening occurred after ten day: he developed severe bloody diarrhea with systemic failure. Laboratory tests showed: neutrophilic leukocytosis,thrombocytosis, anemia, an important increase in inflammation indices. Several abdomen X-ray showed moderate gaseous distension of some intestinal loops with presence of hydroaerial levels. Abdominal ultrasound revealed diffuse thickening of the colon walls (a sign of colitis). The search of C. difficile in stools sample was positive for C. difficile producer of Toxin A and toxin B Enzym Immunoassay (EIA). The infant was successfully treated with vancomycin and metronidazole, without relapsing.