Density functional study of H<Subscript>2</Subscript>O molecule adsorption on α-U(001) surface

Periodic density functional theory (DFT) calculations were performed to investigate the adsorption of H₂O on U(001) surface. The metallic nature of uranium atom and different adsorption sites of U(001) surface play key roles in the H₂O molecular dissociate reaction. The long-bridge site is the most favorable site of H₂O-U(001) adsorption configuration. The triangle-center site of the H atom is the most favorable site of HOH-U(001) adsorption configuration. The interaction between H₂O and U surface is more evident on the first layer than that on any other two sub-layers. The dissociation energy of one hydrogen atom from H₂O is ?1.994 to ?2.215 eV on U(001) surface, while the dissociating energy decreases to ?3.351 to ?3.394 eV with two hydrogen atoms dissociating from H₂O. These phenomena also indicate that the O_ads can promote the dehydrogenation of H₂O. A significant charge transfer from the first layer of the uranium surface to the H and O atoms is also found to occur, making the bonding partly ionic.     

Innovative levers for sustainable integration of gender medicine into medical school curricula

Efforts to integrate gender medicine into medical school curricula have focused largely on the work of individual champions. Online sex and gender materials for undergraduate courses have also been developed and disseminated. Success has been sporadic, with varying uptake across schools within and between countries. International trends in medical school accreditation processes and the growing force of the millennial student voice offer untapped opportunities to promote more systematic integration of gender medicine on a national and international level. In this commentary, the president and CEO of the Association of Faculties of Medicine of Canada and the Scientific Director of the Institute of Gender and Health of the Canadian Institutes of Health Research jointly reflect on top-down and bottom-up levers for sustainable innovation in gender medicine for undergraduate medical training.     

Auditing sex- and gender-based medicine (SGBM) content in medical school curriculum: a student scholar model

Background

Sex- and gender-based medicine (SGBM) aims to (1) delineate and investigate sex- and gender-based differences in health, disease, and response to treatment and (2) apply that knowledge to clinical care to improve the health of both women and men. However, the integration of SGBM into medical school curricula is often haphazard and poorly defined; schools often do not know the current status of SGBM content in their curricula, even if they are committed to addressing gaps and improving SGBM delivery. Therefore, complete auditing and accounting of SGBM content in the existing medical school curriculum is necessary to determine the baseline status and prepare for successful integration of SGBM content into that curriculum.

Methods

A review of course syllabi and lecture objectives as well as a targeted data analysis of the Curriculum Management and Information Tool (CurrMIT) were completed prior to a real-time curriculum audit. Subsequently, six “student scholars,” three first-year and three second-year medical students, were recruited and trained to audit the first 2 years of the medical school curriculum for SGBM content, thus completing an audit for both of the pre-clinical years simultaneously. A qualitative analysis and a post-audit comparative analysis were completed to assess the level of SGBM instruction at our institution.

Results

The review of syllabi and the CurrMIT data analysis did not generate a meaningful catalogue of SGBM content in the curriculum; most of the content identified specifically targeted women’s or men’s health topics and not sex- or gender-based differences. The real-time student audit of the existing curriculum at Texas Tech revealed that most of the SGBM material was focused on the physiological/anatomical sex differences or gender differences in disease prevalence, with minimal coverage of sex- or gender-based differences in diagnosis, prognosis, treatment, and outcomes.

Conclusions

The real-time student scholar audit was effective in identifying SGBM content in the existing medical school curriculum that was not possible with a retrospective review of course syllabi and lecture objectives or curriculum databases such as the CurrMIT. The audit results revealed the need for improved efforts to teach SGBM topics in our school’s pre-clinical curriculum.

     

eGender—from e-Learning to e-Research: a web-based interactive knowledge-sharing platform for sex- and gender-specific medical education

Background

Sex and Gender Medicine is a novel discipline that provides equitable medical care for society and improves outcomes for both male and female patients. The integration of sex- and gender-specific knowledge into medical curricula is limited due to adequate learning material, systematic teacher training and an innovative communication strategy. We aimed at initiating an e-learning and knowledge-sharing platform for Sex and Gender Medicine, the eGender platform (http://egender.charite.de), to ensure that future doctors and health professionals will have adequate knowledge and communication skills on sex and gender differences in order to make informed decisions for their patients.

Methods

The web-based eGender knowledge-sharing platform was designed to support the blended learning pedagogical teaching concept and follows the didactic concept of constructivism. Learning materials developed by Sex and Gender Medicine experts of seven universities have been used as the basis for the new learning tools. The content of these tools is patient-centered and provides add-on information on gender-sensitive aspects of diseases. The structural part of eGender was designed and developed using the open source e-learning platform Moodle. The eGender platform comprises an English and a German version of e-learning modules: one focusing on basic knowledge and seven on specific medical disciplines. Each module consists of several courses corresponding to a disease or symptom complex. Self-organized learning has to be managed by using different learning tools, e.g., texts and audiovisual material, tools for online communication and collaborative work.

Results

More than 90 users from Europe registered for the eGender Medicine learning modules. The most frequently accessed module was “Gender Medicine—Basics” and the users favored discussion forums. These e-learning modules fulfill the quality criteria for higher education and are used within the elective Master Module “Gender Medicine—Basics” implemented into the accredited Master of Public Health at Charité—Berlin.

Conclusions

The eGender platform is a flexible and user-friendly electronical knowledge-sharing platform providing evidence-based high-quality learning material used by a growing number of registered users. The eGender Medicine learning modules could be key in the reform of medical curricula to integrate Sex and Gender Medicine into the education of health professionals.

     

GADD45B mediates podocyte injury in zebrafish by activating the ROS-GADD45B-p38 pathway

GADD45 gene has been implicated in cell cycle arrest, cell survival or apoptosis in a cell type specific and context-dependent manner. Members of GADD45 gene family have been found differentially expressed in several podocyte injury models, but their roles in podocytes are unclear. Using an in vivo zebrafish model of inducible podocyte injury that we have previously established, we found that zebrafish orthologs of gadd45b were induced upon the induction of podocyte injury. Podocyte-specific overexpression of zebrafish gadd45b exacerbated edema, proteinuria and foot-process effacement, whereas knockdown of gadd45b by morpholino-oligos in zebrafish larvae ameliorated podocyte injury. We then explored the role of GADD45B induction in podocyte injury using in vitro podocyte culture. We confirmed that GADD45B was significantly upregulated during the early phase of podocyte injury in cultured human podocytes and that podocyte apoptosis induced by TGF-β and puromycin aminonucleoside (PAN) was aggravated by GADD45B overexpression but ameliorated by shRNA-mediated GADD45B knockdown. We also showed that ROS inhibitor NAC suppressed PAN-induced GADD45B expression and subsequent activation of p38 MAPK pathway in podocytes and that inhibition of GADD45B diminished PAN-induced p38 MAPK activation. Taken together, our findings demonstrated that GADD45B has an important role in podocyte injury and may be a therapeutic target for the management of podocyte injury in glomerular diseases.Podocyte dysfunction, injury or loss is a common and decisive cause of various glomerular diseases and understanding the molecular mechanism underlying podocyte response to stress will be very helpful to undermine the pathogenesis of podocyte injury and the targeted therapy for glomerular diseases.The members of Gadd45 gene family, Gadd45a, Gadd45b and Gadd45r have been commonly implicated in stress signaling in response to physiological or environmental stressors, resulting in cell cycle arrest, DNA damage repair, cell survival, senescence and apoptosis.¹ Recently, this gene family has been found differentially expressed in several podocyte injury models. Zhang et al.² observed an induction of GADD45β mRNA expression by lipopolysaccharide in the lung, kidney and spleen, which had the highest GADD45β mRNA expression among all of the tissues examined. Jeffrey W Pippin reported that protein expression of GADD45 was increased in glomeruli from passive Heymann nephritis rats and cultured podocytes exposed in vitro to C5b-9. ³ More recently, Shi et al.⁴ reported that Gadd45b was upregulated in glomeruli of mice with podocyte-specific deletion of Dicer, suggesting the involvement of Gadd45b in podocyte injury. However, no functional characterization of Gadd45 genes in podocytes has been conducted to date and the role of GADD45B in the context of podocyte injury remains unclear.Zebrafish has emerged as a new vertebrate model system for renal glomerular research. The podocytes and renal glomeruli in zebrafish kidney are structurally, molecularly and functionally conserved, rendering zebrafish a valuable and relevant model for podocyte studies. To characterize the role of GADD45b in podocyte injury, we therefore employed zebrafish as an in vivo model system and human podocytes as an in vitro model. We observed the upregulation of GADD45B on podocyte injury in zebrafish renal glomeruli as well as in cultured human podocytes treated with TGF-β and PAN. We further showed that podocyte-specific overexpression of zebrafish orthologs of gadd45b predisposed podocytes to injury, whereas inhibition of gadd45b expression in zebrafish larvae ameliorated podocyte injury and reduced proteinuria. Furthermore, we found that the ROS-GADD45B-p38 pathway was involved in the regulation of GADD45B expression and deleterious role in podocyte injury. Collectively, we have identified GADD45B as an important player in podocyte injury.     

Modelling the spatial distribution of wildlife animals using presence and absence data

This study was conducted to analyze the habitat preference of six major mammals for various environmental factors based on 100 random points within a mountain area in South Korea. In-situ presence and absence data for the mammals were surveyed and collected, and twelve explanatory variables related to topography, water, greenness, and anthropogenic influence were applied to create a habitat distribution model. The best combination of variables was determined using Moran’s I coefficients and Akaike criteria information, and applied to estimate the habitat preference for each species using GRASP v.3.0. The predictive map showed that wildlife animals in this study were mainly categorized into two groups: Group I (Korean squirrel, Sciurus vulgaris, mole, Talpa micrura and water deer, Hydropotes inermis), showed equal preference for all mountainous areas; Group II (weasel, Mustela sibirica, leopard cat, Felis bengalensis and raccoon dog, Nyctereutes procyonoides) showed different preferences in a mountain.     

Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway

Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss.Bone is a dynamic organ that undergoes continuous remodeling throughout life. Bone homeostasis is maintained by a balanced bone-resorbing and bone-forming process. In this process, hematopoietic stem cells or monocytes/macrophage progenitor cell-derived osteoclasts (OCs) are mainly responsible for bone resorption.¹ Abnormal OC function is associated with numerous diseases, and most of them are due to excessive osteoclastic activity. These diseases include osteoporosis, rheumatoid arthritis and periodontitis.^{2, 3} Two of the most important regulating factors during OC differentiation are receptor activator of nuclear factor κB ligand (RANKL) and macrophage-colony-stimulating factor (M-CSF).^{4, 5} Binding of RANKL to RANK results in the initiation of the TNF receptor-associated factor 6 signaling, which activates nuclear factor-κB, Akt and MAP kinase (ERk, JNK and p-38), and eventually leads to the proliferation, differentiation and maturation of OCs.^{6, 7}Lipopolysaccharide (LPS) is an important component of the outer membrane of Gram-negative bacteria. In LPS-induced bone loss, many factors are involved including local host response, prostanoids and cytokine production, inflammatory cell recruitment and OC activation.^{8, 9, 10} Experimental evidence have shown that LPS-mediated inflammation is highly dependent on reactive oxygen species (ROS) and the associated downstream MAPK signaling pathways including ERK, JNK and p-38.^{11, 12} ROS has been shown having an important role in the process of OC differentiation, survival, activation and bone resorption.^{13, 14, 15, 16} It has also been proved that ROS production in OC and intracellular hydrogen peroxide accumulation is critical for osteoclastogenesis and skeletal homeostasis.¹⁷ Recently, a study reported that LPS induces OC formation via the ROS-mediated JNK and STAT3 pathway, which could be blocked by peroxiredoxin II.¹⁸Dihydroartemisinin (DHA) is the main active metabolite isolated from the plant Artemisia annua. DHA has been widely used as first-line therapeutics against falciparum malaria.¹⁹ Recent evidence suggested that DHA has antitumor effects because of its unique cytotoxicity mechanism.²⁰ In particular, studies reported that DHA is pro-apoptotic in tumor cell lines regarding breast and prostate cancer.^{21, 22} Although the detailed mechanism of DHA cytotoxicity and pro-apoptotic effects is not fully understood, DHA-mediated ROS production has a central role.^{23, 24} However, the effect of DHA on bone health has not been studied.In the present study, we reported that DHA could attenuate LPS-induced OC differentiation, fusion and bone-resorption activity in vitro. Our data showed that DHA-induced cell apoptosis during LPS-induced osteoclastogenesis via intracellular ROS generation and mitochondria-mediated pathways. DHA administration in LPS-induced mouse models decreased OC number and reversed bone loss in vivo.     

Proteomic Analysis of Mamestra Brassicae Nucleopolyhedrovirus Progeny Virions from Two Different Hosts

Mamestra brassicae nucleopolyhedrovirus (MabrNPV) has a wide host range replication in more than one insect species. In this study, a sequenced MabrNPV strain, MabrNPV-CTa, was used to perform proteomic analysis of both BVs and ODVs derived from two infected hosts: Helicoverpa armigera and Spodoptera exigua. A total of 82 and 39 viral proteins were identified in ODVs and BVs, respectively. And totally, 23 and 76 host proteins were identified as virion-associated with ODVs and BVs, respectively. The host proteins incorporated into the virus particles were mainly involved in cytoskeleton, signaling, vesicle trafficking, chaperone and metabolic systems. Some host proteins, such as actin, cyclophilin A and heat shock protein 70 would be important for viral replication. Several host proteins involved in immune response were also identified in BV, and a C-type lectin protein was firstly found to be associated with BV and its family members have been demonstrated to be involved in entry process of other viruses. This study facilitated the annotation of baculovirus genome, and would help us to understand baculovirus virion structure. Furthermore, the identification of host proteins associated with virions produced in vivo would facilitate investigations on the involvement of intriguing host proteins in virus replication.