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Long-term sequelae of coronavirus disease (COVID)-19 are frequent and of major concern. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection affects the host gut microbiota, which is linked to disease severity in patients with COVID-19. Here, we report that the gut microbiota of post-COVID subjects had a remarkable predominance of Enterobacteriaceae strains with an antibiotic-resistant phenotype compared to healthy controls. Additionally, short-chain fatty acid (SCFA) levels were reduced in feces. Fecal transplantation from post-COVID subjects to germ-free mice led to lung inflammation and worse outcomes during pulmonary infection by multidrug-resistant Klebsiella pneumoniae. transplanted mice also exhibited poor cognitive performance. Overall, we show prolonged impacts of SARS-CoV-2 infection on the gut microbiota that persist after subjects have cleared the virus. Together, these data demonstrate that the gut microbiota can directly contribute to post-COVID sequelae, suggesting that it may be a potential therapeutic target.

Ion currents through potassium channels are gated. Constriction of the ion conduction pathway at the inner helix bundle, the textbook gate of Kir potassium channels, has been shown to be an ineffective permeation control, creating a rift in our understanding of how these channels are gated. Here we present evidence that anionic lipids act as interactive response elements sufficient to gate potassium conduction. We demonstrate the limiting barrier to K+ permeation lies within the ion conduction pathway and show that this gate is operated by the fatty acyl tails of lipids that infiltrate the conduction pathway via fenestrations in the walls of the pore. Acyl tails occupying a surface groove extending from the cytosolic interface to the conduction pathway provide a potential means of relaying cellular signals, mediated by anionic lipid head groups bound at the canonical lipid binding site, to the internal gate.

Apoptosis, the intrinsic programmed cell death process, is mediated by the Bcl-2 family members Bak and Bax. Activation via formation of symmetric core dimers and oligomerization on the mitochondrial outer membrane (MOM) leads to permeabilization and cell death. Although this process is linked to the MOM, the role of the membrane in facilitating such pores is poorly understood. We recently described Bak core domain dimers, revealing lipid binding sites and an initial role of lipids in oligomerization. Here we describe simulations that identified localized clustering and interaction of triacylglycerides (TAGs) with a minimized Bak dimer construct. Coalescence of TAGs occurred beneath this Bak dimer, mitigating dimer-induced local membrane thinning and curvature in representative coarse-grain MOM and model membrane systems. Furthermore, the effects observed as a result of coarse-grain TAG cluster formation was concentration dependent, scaling from low physiological MOM concentrations to those found in other organelles. We find that increasing the TAG concentration in liposomes mimicking the MOM decreased the ability of activated Bak to permeabilize these liposomes. These results suggest that the presence of TAGs within a Bak-lipid membrane preserves membrane integrity and is associated with reduced membrane stress, suggesting a possible role of TAGs in Bak-mediated apoptosis.

BACKGROUND: Poor physical activity and excessive sedentary behaviour are well-established risk factors for morbidity and mortality. In the presence of emerging social problems, including loneliness and social isolation, these risks may be even greater. We aimed to investigate the joint effects of social health and movement behaviours on mortality and cardiovascular disease (CVD). METHODS: 497,544 UK Biobank participants were followed for an average of 11 years. Loneliness and social isolation were measured via self-report. Physical activity was categorised around current World Health Organisation (WHO) guidelines as low (< 600 metabolic equivalent of task [MET]-mins/week), moderate (600 < 1200) and high (≥ 1200). Sedentary behaviour was classified as low (≤ 3.5 h/day), moderate (3.5 ≤ 5) and high (> 5.5). We derived 24 social health-movement behaviour combinations, accordingly. Mortality and hospitalisations were ascertained to May 2020 for all-cause and CVD mortality, and non-fatal cardiovascular events. RESULTS: Social isolation amplified the risk of both all-cause and CVD death across all physical activity and sedentary levels (hazard ratio, 95% confidence interval [HR, 95% CIs] for all-cause mortality; 1.58 [1.49 to 1.68] for low active-isolated vs. 1.26 [1.22 to 1.30] for low active-not isolated). Loneliness was only found to amplify the risk of death from cardiovascular disease among the high active and low sedentary participants. Loneliness and social isolation did not add to the risk of non-fatal cardiovascular events across most activity levels. CONCLUSION: The detrimental associations of poor physical activity and sedentary behaviour with mortality were consistently amplified by social isolation. Our study supports the need to target the socially isolated as a priority group in preventive public health strategies.

Abstract Background With economic and social changes, participation in occupational and transport-related physical activity is declining among Nepalese adults, highlighting the growing importance of leisure-time physical activity. However, limited information is available to guide public health policies and interventions to promote leisure-time physical activity in Nepal. This study aimed to qualitatively explore the socioecological influences of participation in leisure-time physical activity among Nepalese adults aged 40 years and above. Methods A total of 51 adults (30 females and 21 males) participated in one of the nine focus groups conducted in Kathmandu, Nepal. A semi-structured guide based on the social-ecological model of physical activity was used to facilitate these focus groups. Data were analysed using a reflexive thematic analysis approach in NVivo 12. Results Participation in leisure-time physical activity was minimal and leisure time was mostly spent resting, socialising, or engaging in sedentary activities such as watching television. Walking was the most common form of leisure-time physical activity, and men reported being more active than women. Individual-level barriers included lack of knowledge, lack of skill, lack of motivation, considering oneself as sufficiently active and engagement in sedentary screen activities. Family and household responsibilities, lack of support and fear of being judged constituted the interpersonal barriers while environmental barriers included an absence of a supportive social norm, lack of open spaces, weather conditions and perceived lack of safety. Health benefits, prioritising physical activity, social support, provision of group-based activities and age-appropriate public exercise facilities were identified as major fa

ObjectiveTo determine the prevalence and sociodemographic factors associated with active commuting and leisure-time physical activity (LTPA) among adults in western Nepal.DesignCross-sectional study.SettingAdults from semiurban areas in western Nepal.Participants2815 adults aged 25–65 years who participated in the ‘Community-Based Management of Hypertension in Nepal (COBIN)’ Study. Multiple logistic regression analysis was used to identify the sociodemographic factors associated with active commuting and LTPA.OutcomeSelf-reported participation in active commuting and LTPA.ResultsMost study participants (96%) commuted actively (walked or cycled) from one place to another. Our results showed that only a small proportion (3.7%) of participants engaged in moderate or vigorous LTPA. Compared with those in paid employment, the odds of commuting actively were higher among people working in agriculture or as labourers (OR: 4.57, 95% CI: 2.46 to 8.48), those retired/unemployed (OR: 2.98, 95% CI: 1.42 to 6.25) and those in unpaid employment (OR: 1.85, 95% CI: 1.06 to 3.22). Adults who were overweight or had obesity were less likely to commute actively. Compared with adults aged 25–34 years, older adults were less likely (OR: 0.35, 95% CI: 0.17 to 0.72) to engage in LTPA. Women were 0.46 times less likely to engage in LTPA compared with men.ConclusionMost adults engaged in active commuting for work or travel. Less than 5% participated in any form of moderate or vigorous LTPA. Longitudinal studies incorporating objective assessment of physical activity and a range

Previous research suggests that a range of factors influence an individual’s physical activity (PA) participation, but studies among Nepalese adults are limited. In this qualitative study, we aimed to explore the multilevel influences upon PA participation among community-dwelling adults aged 40 years and above living in an urban setting in Kathmandu, Nepal. Men ( n = 21) and women ( n = 30) were purposively sampled to participate in one of nine focus group discussions. Types of PA undertaken constituted activities related to housework, farm work, and active travel. Individual-level barriers included lack of knowledge, lack of motivation, perceptions of already being active, personal limitations, and lack of time. Interpersonal barriers included household responsibilities and lack of support. Broader environmental barriers included lack of infrastructure for active commuting, poor safety, rising use of motorized transport, lack of resting areas, weak social norms about PA, declining agricultural engagement, mechanization, and improved access to technology and facilities. Some differences were observed between the gender and disease groups. Health benefits, integration into domestic work, opportunities for social interaction, and social support were the facilitators. Interventions focusing on families, highlighting the short- and long-term benefits of PA, addressing gender roles, and ensuring women are better supported represent opportunities to promote PA. Community-based interventions will be essential to establish social norms around PA and improve social support.

Substantial cross-sectional evidence and limited longitudinal research indicates that the availability of recreational facilities (e.g., parks, fitness centres) is associated with physical activity participation. However, few intervention trials have investigated how recreational infrastructure can be used to reduce inactivity levels in communities. The MOVE Frankston study aimed to assess the impact of low intensity strategies to promote use of a multi-purpose leisure and aquatic centre in a socioeconomically diverse, metropolitan community. This randomised controlled trial of two years’ duration compared public awareness raising (control condition) with two interventions: mailed information about the centre and a free entry pass (I-O); and this minimal intervention supplemented by customer relations management support through telephone contact, mailed promotional materials and additional incentives (I+S). Participants (n = 1320) were inactive adults living in the City of Frankston, Melbourne Australia. There were 928 people (70.3%) followed up at 12 months (61.2% female, 52% ≥55 yrs). Compared with controls, attendance at the Centre once or more was higher in both the I-O (OR 1.79, 95% CI 1.28–2.50) and I+S groups (OR 1.46, 95% CI 1.03–2.07). The proportion of people using the centre weekly did not differ by group. The odds of being in contemplation or preparation to use the Centre were higher in both the I-O (OR 1.76, 95% CI 1.28–2.42) and I+S groups (OR 1.48, 95% CI 1.07–2.06). Total physical activity and related social and cognitive factors did not differ between the groups. The findings show that the low intensity promotional strategies prompted occasional attendance and increased readiness to use this recreational facility, a level of behaviour change unlikely to reduce non-communicable disease risk. It is recommended that more frequent customer relations contact, and involvement of healthcare providers, be tested as strategies to encourage inactive adults to

The objective of this systematic review was to determine the effectiveness of lifestyle interventions to improve the management of type 2 diabetes mellitus (T2DM) among migrants and ethnic minorities. Major searched databases included MEDLINE (via PubMed), EMBASE (via Ovid) and CINAHL. The selection of studies and data extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In the meta-analysis, significant heterogeneity was detected among the studies (I2 >50%), and hence a random effects model was used. Subgroup analyses were performed to compare the effect of lifestyle interventions according to intervention approaches (peer-led vs community health workers (CHWs)-led). A total of 17 studies were included in this review which used interventions delivered by CHWs or peer supporters or combination of both. The majority of the studies assessed effectiveness of key primary (hemoglobin (HbA1c), lipids, fasting plasma glucose) and secondary outcomes (weight, body mass index, blood pressure, physical activity, alcohol consumption, tobacco smoking, food habits and healthcare utilization). Meta-analyses showed lifestyle interventions were associated with a small but statistically significant reduction in HbA1c level (-0.18%; 95% CI -0.32% to -0.04%, p=0.031). In subgroup analyses, the peer-led interventions showed relatively better HbA1c improvement than CHW-led interventions, but the difference was not statistically significant (p=0.379). Seven studies presented intervention costs, which ranged from US$131 to US$461 per participant per year. We conclude that lifestyle interventions using either CHWs or peer supporters or a combination of both have shown modest effectiveness for T2DM management among migrants of different background and origin and ethnic minorities. The evidence base is promising in terms of developing culturally appropriate, clinically sound and cost-effective intervention approaches to respond to the growing

Substantial cross-sectional evidence and limited longitudinal research indicates that the availability of recreational facilities (e.g., parks, fitness centres) is associated with physical activity participation. However, few intervention trials have investigated how recreational infrastructure can be used to reduce inactivity levels in communities. The MOVE Frankston study aimed to assess the impact of low intensity strategies to promote use of a multi-purpose leisure and aquatic centre in a socioeconomically diverse, metropolitan community. This randomised controlled trial of two years' duration compared public awareness raising (control condition) with two interventions: mailed information about the centre and a free entry pass (I-O); and this minimal intervention supplemented by customer relations management support through telephone contact, mailed promotional materials and additional incentives (I+S). Participants (n = 1320) were inactive adults living in the City of Frankston, Melbourne Australia. There were 928 people (70.3%) followed up at 12 months (61.2% female, 52% ≥55 yrs). Compared with controls, attendance at the Centre once or more was higher in both the I-O (OR 1.79, 95% CI 1.28-2.50) and I+S groups (OR 1.46, 95% CI 1.03-2.07). The proportion of people using the centre weekly did not differ by group. The odds of being in contemplation or preparation to use the Centre were higher in both the I-O (OR 1.76, 95% CI 1.28-2.42) and I+S groups (OR 1.48, 95% CI 1.07-2.06). Total physical activity and related social and cognitive factors did not differ between the groups. The findings show that the low intensity promotional strategies prompted occasional attendance and increased readiness to use this recreational facility, a level of behaviour change unlikely to reduce non-communicable disease risk. It is recommended that more frequent customer relations contact, and involvement of healthcare providers, be tested as strategies to encourage inactive adults to

BACKGROUND: The International Society for Physical Activity and Health (ISPAH) is a leading global organization working to advance research, policy, and practice to promote physical activity. Given the expanding evidence base on interventions to promote physical activity, it was timely to review and update a major ISPAH advocacy document-Investments that Work for Physical Activity (2011). METHODS: Eight investment areas were agreed upon through consensus. Literature reviews were conducted to identify key evidence relevant to policymakers in each sector or setting. RESULTS: The 8 investment areas were as follows: whole-of-school programs; active transport; active urban design; health care; public education; sport and recreation; workplaces; and community-wide programs. Evidence suggests that the largest population health benefit will be achieved by combining these investments and implementing a systems-based approach. CONCLUSIONS: Establishing consensus on 'what works' to change physical activity behavior is a cornerstone of successful advocacy, as is having appropriate resources to communicate key messages to a wide range of stakeholders. ISPAH has created a range of resources related to the new investments described in this paper. These resources are available in the 'advocacy toolkit' on the ISPAH website (www.ispah.org/resources).

Relatively little is known about the transgenerational effects of chronic maternal exposure to low-level traffic-related air pollution (TRAP) on the offspring lung health, nor are the effects of removing such exposure before pregnancy. Female BALB/c mice were exposed to PM2.5 (PM2.5, 5 µg/day) for 6 weeks before mating and during gestation and lactation; in a subgroup, PM was removed when mating started to model mothers moving to cleaner areas during pregnancy to protect their unborn child (Pre-exposure). Lung pathology was characterised in both dams and offspring. A subcohort of female offspring was also exposed to ovalbumin to model allergic airways disease. PM2.5 and Pre-exposure dams exhibited airways hyper-responsiveness (AHR) with mucus hypersecretion, increased mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction in the lungs. Female offspring from PM2.5 and Pre-exposure dams displayed AHR with increased lung inflammation and mitochondrial ROS production, while males only displayed increased lung inflammation. After the ovalbumin challenge, AHR was increased in female offspring from PM2.5 dams compared with those from control dams. Using an in vitro model, the mitochondria-targeted antioxidant MitoQ reversed mitochondrial dysfunction by PM stimulation, suggesting that the lung pathology in offspring is driven by dysfunctional mitochondria. In conclusion, chronic exposure to low doses of PM2.5 exerted transgenerational impairment on lung health.

The canonical mechanistic model explaining potassium channel gating is of a conformational change that alternately dilates and constricts a collar-like intracellular entrance to the pore. It is based on the premise that K+ ions maintain a complete hydration shell while passing between the transmembrane cavity and cytosol, which must be accommodated. To put the canonical model to the test, we locked the conformation of a Kir K+ channel to prevent widening of the narrow collar. Unexpectedly, conduction was unimpaired in the locked channels. In parallel, we employed all-atom molecular dynamics to simulate K+ ions moving along the conduction pathway between the lower cavity and cytosol. During simulations, the constriction did not significantly widen. Instead, transient loss of some water molecules facilitated K+ permeation through the collar. The low free energy barrier to partial dehydration in the absence of conformational change indicates Kir channels are not gated by the canonical mechanism.

BACKGROUND: The Infectious Diseases Society of America influenza guidelines no longer require fever as part of their influenza case definition in patients requiring hospitalization. However, the impact of fever or lack of fever on clinical decision-making and patient outcomes has not been studied. METHODS: We conducted a retrospective review of adult patients admitted to our tertiary health service between April 2016 and June 2019 with laboratory-confirmed influenza, with and without fever (≥37.8ºC). Patient demographics, presenting features, and outcomes were analyzed using Pearson's chi-square test, the Wilcoxon rank-sum test, and logistic regression. RESULTS: Of 578 influenza inpatients, 219 (37.9%) had no fever at presentation. Fever was less likely in individuals with a nonrespiratory syndrome (adjusted odds ratio [aOR], 0.44; 95% CI, 0.26-0.77), symptoms for ≥3 days (aOR, 0.53; 95% CI, 0.36-0.78), influenza B infection (aOR, 0.45; 95% CI, 0.29-0.70), chronic lung disease (aOR, 0.55; 95% CI, 0.37-0.81), age ≥65 (aOR, 0.36; 95% CI, 0.23-0.54), and female sex (aOR, 0.69; 95% CI, 0.48-0.99). Patients without fever had lower rates of testing for influenza in the emergency department (64.8% vs 77.2%; P = .002) and longer inpatient stays (median, 2.4 vs 1.9 days; P = .015). These patients were less likely to receive antiviral treatment (55.7% vs 65.6%; P = .024) and more likely die in the hospital (3.2% vs 0.6%; P = .031), and these differences persisted after adjustment for potential confounders. CONCLUSIONS: Absence of fever in influenza is associated with delayed diagnosis, longer length of stay, and higher mortality.

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins-a human des-octapeptide insulin analog-as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24-PheB25-TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.

Early studies of the free-living nematode C. elegans informed us how BCL-2-regulated apoptosis in humans is regulated. However, subsequent studies showed C. elegans apoptosis has several unique features compared with human apoptosis. To date, there has been no detailed analysis of apoptosis regulators in nematodes other than C. elegans. Here, we discovered BCL-2 orthologues in 89 free-living and parasitic nematode taxa representing four evolutionary clades (I, III, IV and V). Unlike in C. elegans, 15 species possess multiple (two to five) BCL-2-like proteins, and some do not have any recognisable BCL-2 sequences. Functional studies provided no evidence that BAX/BAK proteins have evolved in nematodes, and structural studies of a BCL-2 protein from the basal clade I revealed it lacks a functionally important feature of the C. elegans orthologue. Clade I CED-4/APAF-1 proteins also possess WD40-repeat sequences associated with apoptosome assembly, not present in C. elegans, or other nematode taxa studied.

Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

PfSERA5, a significantly abundant protein present within the parasitophorous vacuole (PV) and essential for normal growth during the blood-stage life cycle of the malaria parasite Plasmodium falciparum, displays structural similarity to many other cysteine proteases. However, PfSERA5 does not exhibit any detectable protease activity and therefore the role of the PfSERA5 papain-like domain (PfSERA5E), thought to remain bound to its cognate prodomain, remains unknown. In this study, we present a revised structure of the central PfSERA5E domain at a resolution of 1.2 Å, and the first structure of the "zymogen" of this papain-like domain including its cognate prodomain (PfSERA5PE) to 2.2 Å resolution. PfSERA5PE is somewhat structurally similar to that of other known proenzymes, retaining the conserved overall folding and orientation of the prodomain through, and occluding, the archetypal papain-like catalytic triad "active-site" cleft, in the same reverse direction as conventional prodomains. Our findings are congruent with previously identified structures of PfSERA5E and of similar "zymogens" and provide a foundation for further investigation into the function of PfSERA5.

BACKGROUND: The built environment is reported to influence physical activity in populations, but longitudinal evidence about the impact of building new physical activity infrastructure is limited. This study aimed to prospectively investigate the uptake and usage of the newly established Peninsula Aquatic and Recreation Centre (PARC), a large multi-purpose recreation facility in Melbourne, Australia. METHODS: Physically inactive adults (n = 549) from the City of Frankston were recruited before the opening of PARC and followed up 12 months later to measure frequency of attendance at the Centre, and the purposes and barriers to use. Multivariable methods were used to identity the demographic, cognitive and social predictors of attendance, and the relationship between PARC use and improvements in leisure-time physical activity. RESULTS: Over 12 months 8.7% of the sampled residents used PARC once per month or more, 17.5% attended less than once per month, and 73.8% did not use the Centre. Lap swimming was the dominant purpose for attendance, and the major barriers were cost of transport and cost of entry. Independent predictors of usage were being female, having children, living within 5 km of the Centre, and expressing strong intentions for use prior to its opening. Use of PARC was not associated with progression to a higher level of total leisure-time physical activity. CONCLUSIONS: While installation of multi-purpose aquatic and recreation facilities may be considered an investment towards physical activity in populations, regular use by inactive people is likely to be low. Strategies to reduce barriers, including cost and transport, and to motivate use should be trialled in order to improve the public health impacts of this form of infrastructure.

OBJECTIVE: To identify the key mechanisms that clinicians perceive improve care in the intensive care unit (ICU), as a result of their involvement in post-ICU programs. METHODS: Qualitative inquiry via focus groups and interviews with members of the Society of Critical Care Medicine's THRIVE collaborative sites (follow-up clinics and peer support). Framework analysis was used to synthesize and interpret the data. RESULTS: Five key mechanisms were identified as drivers of improvement back into the ICU: (1) identifying otherwise unseen targets for ICU quality improvement or education programs-new ideas for quality improvement were generated and greater attention paid to detail in clinical care. (2) Creating a new role for survivors in the ICU-former patients and family members adopted an advocacy or peer volunteer role. (3) Inviting critical care providers to the post-ICU program to educate, sensitize, and motivate them-clinician peers and trainees were invited to attend as a helpful learning strategy to gain insights into post-ICU care requirements. (4) Changing clinician's own understanding of patient experience-there appeared to be a direct individual benefit from working in post-ICU programs. (5) Improving morale and meaningfulness of ICU work-this was achieved by closing the feedback loop to ICU clinicians regarding patient and family outcomes. CONCLUSIONS: The follow-up of patients and families in post-ICU care settings is perceived to improve care within the ICU via five key mechanisms. Further research is required in this novel area.

Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbours a leucine-rich repeat domain and four PDZ domains that mediate most of Scribble's interactions with other proteins. It has become increasingly clear that post-translational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated human Scribble interactions with MCC (Mutated in Colorectal Cancer). We systematically evaluated the ability of all four individual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a minor effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the unphosphorylated MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC must extend beyond a simple modulation of the affinity for Scribble PDZ domains.

BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (-)-jerantinines A and E from sustainably sourced (-)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (-)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin-(-)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

BACKGROUND: There is increasing pressure to address the social determinants of health (SDoH) and health inequities through the implementation of culturally acceptable interventions particularly in Sub-Saharan Africa (SSA) where health outcomes are generally poor. Available evaluation research on cash transfers (CTs) suggests that the programs may influence the wider determinants of health in SSA; yet, there has been no attempt to synthesize the evidence regarding their contribution to tackling the SDoH and health inequalities. To date, nearly all the reviews on CTs' impact on health have predominantly featured evidence from Latin America with limited transferability to the social, cultural, and political environments in SSA. Therefore, the aim of this study is to undertake a systematic review to assess the role of CTs in tackling the wider determinants of health and health inequalities in SSA. METHODS/DESIGN: A systematic review of published and unpublished literature on CTs' impact on health and health determinants covering the period 2000-2016 will be undertaken. Studies will be considered for inclusion if they present quantitative or qualitative data, including all relevant study designs. The SDoH conceptual framework will be used to guide the data extraction process. EPPI Reviewer software will be used for data management and analysis. Studies included in the review will be analyzed by narrative synthesis and/or meta-analysis as appropriate for the nature of the data retrieved. DISCUSSION: This review will provide empirical evidence on the impact of CTs on SDoH to inform CT policy, implementation, and research in SSA. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). SYSTEMATIC REVIEW REGISTRATION: This protocol has been registered with the PROSPERO international prospective register of systematic reviews, reference CRD42015025015 .