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Summary: PUMA is a proapoptotic BCL-2 family member that drives the apoptotic response to a diversity of cellular insults. Deciphering the spectrum of PUMA interactions that confer its context-dependent proapoptotic properties remains a high priority goal. Here, we report the synthesis of PUMA SAHBs, structurally stabilized PUMA BH3 helices that, in addition to broadly targeting antiapoptotic proteins, directly bind to proapoptotic BAX. NMR, photocrosslinking, and biochemical analyses revealed that PUMA SAHBs engage an α1/α6 trigger site on BAX to initiate its functional activation. We further demonstrated that a cell-permeable PUMA SAHB analog induces apoptosis in neuroblastoma cells and, like expressed PUMA protein, engages BCL-2, MCL-1, and BAX. Thus, we find that PUMA BH3 is a dual antiapoptotic inhibitor and proapoptotic direct activator, and its mimetics may serve as effective pharmacologic triggers of apoptosis in resistant human cancers. [Copyright &y& Elsevier]

The article presents the results of the nationwide survey of the current state of outreach practices of the Supreme Court Justices across the U.S. It analyzed that the judicial outreach is very important and also informs that the judges are willing to participate in outreach activities. It presents two tables reflecting the importance of judicial outreach and other showing the personal policy of justices toward requests of judicial outreach.

Background: The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods: Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results: In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P <.001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng, P <.001), and less tau pathophysiology (p-tau181, P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P =.002), more synaptic injury (Ng, P <.001), and higher levels of glial activation (YKL-40, P =.01). Conclusion: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. Trial registration: NCT03186989 since June 14, 2017 [ABSTRACT FROM AUTHOR]

Background: The need for research-based knowledge to inform health policy formulation and implementation is a chronic global concern impacting health systems functioning and impeding the provision of quality healthcare for all. This paper provides a systematic overview of the literature on knowledge translation (KT) strategies employed by health system researchers and policy-makers in African countries.Methods: Evidence mapping methodology was adapted from the social and health sciences literature and used to generate a schema of KT strategies, outcomes, facilitators and barriers. Four reference databases were searched using defined criteria. Studies were screened and a searchable database containing 62 eligible studies was compiled using Microsoft Access. Frequency and thematic analysis were used to report study characteristics and to establish the final evidence map. Focus was placed on KT in policy formulation processes in order to better manage the diversity of available literature.Results: The KT literature in African countries is widely distributed, problematically diverse and growing. Significant disparities exist between reports on KT in different countries, and there are many settings without published evidence of local KT characteristics. Commonly reported KT strategies include policy briefs, capacity-building workshops and policy dialogues. Barriers affecting researchers and policy-makers include insufficient skills and capacity to conduct KT activities, time constraints and a lack of resources. Availability of quality locally relevant research was the most reported facilitator. Limited KT outcomes reflect persisting difficulties in outcome identification and reporting.Conclusion: This study has identified substantial geographical gaps in knowledge and evidenced the need to boost local research capacities on KT practices in low- and middle-income countries. Evidence mapping is also shown to be a useful approach that can assist local decision-making to enhance KT in policy and practice. [ABSTRACT FROM AUTHOR]

Background Hospital-acquired diabetic ketoacidosis (HADKA) can complicate hospital admission in people with type 1 diabetes (T1D) and type 2 diabetes (T2D). We aimed to determine the characteristics of such patients and the reasons for HADKA. Methods A retrospective analysis of patients referred to diabetes services with HADKA at Morriston Hospital between January 2016 and January 2022 was undertaken. Patients that were included were admitted without diabetic ketoacidosis (DKA), were aged 18 years and over, and who subsequently developed DKA in hospital. Results Twenty-five patients were included with a mean age of 65.2 years; nine (32.0%) were men, 13 (52.0%) had T1D and 12 (48.0%) had T2D. Patients had a mean pre-admission glycated haemoglobin of 84.7 mmol/mol, and 17 (68.0%) were insulin-treated. Most were admitted under medicine (n=14; 56.0%) and the remainder under surgery (n=11; 44.0%). More common reasons for HADKA were erroneous insulin administration (n=9; 36.0%), infection (n=7; 28.0%) and surgery (n=5; 20.0%). Five (20.0%) patients required intensive care admission, and the mean length of hospital stay was 42.6 days (range 2--173). Three (12.0%) patients died during the hospital admission. Conclusion HADKA was identified in a significant number of patients at our hospital and was associated with significant mortality. Earlier recognition of ketonaemia and associated medication use may prevent HADKA and improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) are a family of enzymes that are typically released from intracellular stores to act on specific extracellular substrates. MMP expression and activity can be increased in a neuronal activity-dependent manner, and further increased in response to tissue injury. MMP substrates include cell adhesion molecules (CAMs) that are abundantly expressed in the brain and well positioned for membrane proximal cleavage. Importantly, CAM integrity is important to synaptic structure and axon-myelin interactions, and shed ectodomains may themselves influence cellular function.Methods: In the present study, we have examined proteolysis of N-cadherin (N-cdh) by MMP-7, a family member that has been implicated in disorders including HIV dementia, multiple sclerosis, and major depression. With in vitro digest assays, we tested N-cdh cleavage by increasing concentrations of recombinant enzyme. We also tested MMP-7 for its potential to stimulate N-cdh shedding from cultured neural cells. Since select CAM ectodomains may interact with cell surface receptors that are expressed on microglial cells, we subsequently tested the N-cdh ectodomain for its ability to stimulate activation of this cell type as determined by nuclear translocation of NF-κB, Iba-1 expression, and TNF-α release.Results: We observed that soluble N-cdh increased Iba-1 levels in microglial lysates, and also increased microglial release of the cytokine TNF-α. Effects were associated with increased NF-κB immunoreactivity in microglial nuclei and diminished by an inhibitor of the toll-like receptor adaptor protein, MyD88.Conclusions: Together, these in vitro results suggest that soluble N-cdh may represent a novel effector of microglial activation, and that disorders with increased MMP levels may stimulate a cycle in which the products of excess proteolysis further exacerbate microglial-mediated tissue injury. Additional in vivo studies are warranted to address this issue. [ABSTRACT FROM AUTHOR]

Spatially and functionally distinct domains of heterochromatin and euchromatin play important roles in the maintenance of chromosome stability and regulation of gene expression, but a comprehensive knowledge of their composition is lacking. Here, we develop a strategy for the isolation of native Schizosaccharomyces pombe heterochromatin and euchromatin fragments and analyze their composition by using quantitative mass spectrometry. The shared and euchromatin-specific proteomes contain proteins involved in DNA and chromatin metabolism and in transcription, respectively. The heterochromatin-specific proteome includes all proteins with known roles in heterochromatin formation and, in addition, is enriched for subsets of nucleoporins and inner nuclear membrane (INM) proteins, which associate with different chromatin domains. While the INM proteins are required for the integrity of the nucleolus, containing ribosomal DNA repeats, the nucleoporins are required for aggregation of heterochromatic foci and epigenetic inheritance. The results provide a comprehensive picture of heterochromatin-associated proteins and suggest a role for specific nucleoporins in heterochromatin function. • Strategy for affinity purification of native chromatin fragments • Heterochromatin and euchromatin have overlapping and non-overlapping proteomes • The heterochromatin proteome includes inner nuclear membrane proteins and nucleoporins • Inner-ring nucleoporins are required for clustering and maintenance of heterochromatin Iglesias et al. describe a strategy for identification of proteins associated with native heterochromatin and euchromatin DNA domains. In addition to previously identified proteins, the heterochromatin-specific proteome contains inner nuclear membrane proteins and a specific subset of nucleoporins, some of which function in epigenetic inheritance and clustering together of distal heterochromatic regions. [ABSTRACT FROM AUTHOR]

Background: Cancer screening programs hold much potential for reducing the cervical cancer disease burden in developing countries. The aim of this study was to determine the feasibility of mobile health (mHealth) phone technology to improve management and follow-up of clients with cervical cancer precursor lesions.Methods: A sequential mixed methods design was employed for this study. Quantitative data was collected using a cross-sectional survey of 364 women eligible for a Pap smear at public sector health services in Cape Town, South Africa. Information was collected on socio-demographic status; cell phone ownership and patterns of use; knowledge of cervical cancer prevention; and interest in Pap smear results and appointment reminders via SMS-text messages. Descriptive statistics, crude bivariate comparisons and logistic regression models were employed to analyze survey results. Qualitative data was collected through 10 in-depth interviews with primary health care providers and managers involved in cervical cancer screening. Four focus group discussions with 27 women attending a tertiary level colposcopy clinic were also conducted. Themes related to loss of mobile phones, privacy and confidentiality, interest in receiving SMS-text messages, text language and clinic-based management of a SMS system are discussed. Thematic analyses of qualitative data complemented quantitative findings.Results: Phone ownership amongst surveyed women was 98% with phones mostly used for calls and short message service (SMS) functions. Over half (58%) of women reported loss/theft of mobile phones. Overall, there was interest in SMS interventions for receiving Pap smear results and appointment reminders. Reasons for interest, articulated by both providers and clients, included convenience, cost and time-saving benefits and benefits of not taking time off work. However, concerns were expressed around confidentiality of SMS messages, loss/theft of mobile phones, receiving negative results via SMS and accessibility/clarity of language used to convey messages. Responsibility for the management of a clinic-based SMS system was also raised.Conclusions: Results indicated interest and potential for mHealth interventions in improving follow-up and management of clients with abnormal Pap smears. Health system and privacy issues will need to be addressed for mHealth to achieve this potential. Next steps include piloting of specific SMS messages to test feasibility and acceptability in this setting. [ABSTRACT FROM AUTHOR]