Penetrating brain injury caused by tired bullet: First report from Somalia.

Background: Brain injuries caused by a tired bullet can range from headaches to severe brain injury and death. The question which poses a dilemma is whether extraction of retained bullets could decrease the late complications. This study aims to investigate the radiological findings, the neurological status of the patients, and different modalities of management for craniocerebral tired bullet injury. Method: This study retrospectively reviewed 21 patients with a tired bullet injury to the brain who were admitted into our hospital over five years. All patients were assessed for the Glasgow outcome scale as outpatients. Result: Of the 21 patients in the study, 11 (52.3%) were males, and 10 (47.6%) were females. The most common entry point of the bullet was frontal in 8 (38.0%) patients, followed by parietal in 7 (33.3%), and orbital in 5 (23.8%). The mortality rate was 23.8% (n = 5 patients). Bad outcomes were documented in patients with low GCS, with all patients who died having a GCS of (3-8). Bullet retrieval was performed for 7 of 21 patients, while all patients who were not candidates for emergency operation underwent local wound debridement. The GOS score was good [4 and 5] in 71.4% (15 of 21 patients). Conclusion: This study revealed that two-thirds of patients with tired bullet injury underwent conservative treatment with an excellent long-term outcome, particularly for patients with high GCS on admission. The mortality rate was high among children under 15 years and those with a GCS of 3-8.

Social contacts and other risk factors for respiratory infections among internally displaced people in Somaliland.

BACKGROUND: Populations affected by humanitarian crises experience high burdens of acute respiratory infections (ARI), potentially driven by risk factors for severe disease such as poor nutrition and underlying conditions, and risk factors that may increase transmission such as overcrowding and the possibility of high social mixing. However, little is known about social mixing patterns in these populations. METHODS: We conducted a cross-sectional social contact survey among internally displaced people (IDP) living in Digaale, a permanent IDP camp in Somaliland. We included questions on household demographics, shelter quality, crowding, travel frequency, health status, and recent diagnosis of pneumonia, and assessed anthropometric status in children. We present the prevalence of several risk factors relevant to transmission of respiratory infections, and calculated age-standardised social contact matrices to assess population mixing. RESULTS: We found crowded households with high proportions of recent self-reported pneumonia (46% in children). 20% of children younger than five are stunted, and crude death rates are high in all age groups. ARI risk factors were common. Participants reported around 10 direct contacts per day. Social contact patterns are assortative by age, and physical contact rates are very high (78%). CONCLUSIONS: ARI risk factors are very common in this population, while the large degree of contacts that involve physical touch could further increase transmission. Such IDP settings potentially present a perfect storm of risk factors for ARIs and their transmission, and innovative approaches to address such risks are urgently needed.

Molecular basis of V-ATPase inhibition by bafilomycin A1.

Pharmacological inhibition of vacuolar-type H+-ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a, thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7'-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c.

The East Side Table Make-at-Home Meal-Kit Program is feasible and acceptable: A pilot study.

Drawing from marketing literature, shopper solutions and food bundles (that group items to be used together) can promote purchase intention, efficacy, and related outcomes. Similarly, meal kits boxes (food bundles with step-by-step instructions to prepare home-cooked meals) have potential to be an accessible intervention to facilitate healthy, at-home food preparation and intake. This manuscript describes the feasibility, acceptability, and preliminary outcomes of a community-designed and -led program promoting healthy food skills, accessibility, and intake through meal kits. This pilot study was designed using community-based participatory research principles and 60 participants enrolled in the study. Participating families received a free meal kit weekly during the 10-week program. Meal-kit boxes also included language-appropriate recipe cards, step-by-step instructions, and supplemental educational material including links to videos with related food preparation tips and fact sheets about the meal. Data were collected at baseline, post-program, and follow-up (3 months post-program). Specifically, validated measures were used to assess food insecurity, food availability, cooking preparation techniques, self-efficacy, and fruit/vegetable intake. Process data were also collected. Descriptive statistics, paired t-tests, and Wilcoxon sign-ranked tests were used to describe data and evaluate outcomes. Content analysis was used to code open-ended survey responses into categories. Study findings indicated retention rates were high (≥90%); 83% made eight or more meal kits. At post-program, significant increases were observed in cooking/meal preparation self-efficacy, cooking techniques, and healthy food availability. At follow-up, only healthy food availability remained significantly higher. Findings suggest that meal-kit programs are feasible and acceptable, and there is a potential for these programs to influence factors important to increasing healthy home-cooked meals and dietary intake. Future research should use more rigorous designs and explore meal-kit dosage.

Cryo-EM structures of intact V-ATPase from bovine brain.

The vacuolar-type H+-ATPases (V-ATPase) hydrolyze ATP to pump protons across the plasma or intracellular membrane, secreting acids to the lumen or acidifying intracellular compartments. It has been implicated in tumor metastasis, renal tubular acidosis, and osteoporosis. Here, we report two cryo-EM structures of the intact V-ATPase from bovine brain with all the subunits including the subunit H, which is essential for ATPase activity. Two type-I transmembrane proteins, Ac45 and (pro)renin receptor, along with subunit c", constitute the core of the c-ring. Three different conformations of A/B heterodimers suggest a mechanism for ATP hydrolysis that triggers a rotation of subunits DF, inducing spinning of subunit d with respect to the entire c-ring. Moreover, many lipid molecules have been observed in the Vo domain to mediate the interactions between subunit c, c", (pro)renin receptor, and Ac45. These two structures reveal unique features of mammalian V-ATPase and suggest a mechanism of V1-Vo torque transmission.

Full-Service Twin Cities Mobile Market Impact: Qualitative Findings From Focus Groups With Customers.

BACKGROUND: Creative solutions are required to mitigate poor food access and related health disparities in underserved, at-risk populations because healthy food access is an important social determinant of health. Mobile markets (ie, mobile grocery stores) present a potential solution to mitigate poor food access and related health disparities. However, no research has yet evaluated the impact of a full-service mobile market that sells healthy items from all food groups and pantry staples in underserved communities. OBJECTIVE: Therefore, the objective of this focus group research study was to inductively understand the impact of the full-service, Twin Cities Mobile Market, a mobile grocery store, that visits underserved, low-income communities. DESIGN: Qualitative focus group research. PARTICIPANTS/SETTING: Four moderated and audio-recorded, qualitative focus groups with customers (n = 29) were held in community rooms at mobile market stops. ANALYSIS: Focus group transcripts were analyzed using Krueger's systematic analysis process and content analysis to discover major categories and themes and subthemes within the categories. RESULTS: Findings indicate the full-service mobile market may facilitate purchase and eating of healthy foods through decreasing barriers and increasing access to quality, affordable healthy foods. Findings also indicate mobile market shopping may positively influence customer behaviors and health outcomes (eg, dietary intake and management of weight, diabetes, blood pressure, and mental health). CONCLUSIONS: Our results provide support for the potential impact of full-service mobile markets, encouraging continued mobile market service and future rigorous research on the effectiveness of the full-service mobile market model.

Structure of nevanimibe-bound tetrameric human ACAT1.

Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)1. The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis2,3. ACAT1 has also been implicated in Alzheimer's disease4, atherosclerosis5 and cancers6. Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe7, an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity8. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.

Structural basis for itraconazole-mediated NPC1 inhibition.

Niemann-Pick C1 (NPC1), a lysosomal protein of 13 transmembrane helices (TMs) and three lumenal domains, exports low-density-lipoprotein (LDL)-derived cholesterol from lysosomes. TMs 3-7 of NPC1 comprise the Sterol-Sensing Domain (SSD). Previous studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itraconazole abolishes NPC1 activity in cells. However, the itraconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown. Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD. Functional assays confirm that blocking this tunnel abolishes NPC1-mediated cholesterol egress. Intriguingly, the palmitate anchor of Hedgehog occupies a similar site in the homologous tunnel of Patched, suggesting a conserved mechanism for sterol transport in this family of proteins and establishing a central function of their SSDs.

Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition.

3-ß-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder.