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Abstract Background Human trafficking is a human rights violation and urgent public health challenge. It involves the exploitation of a person by means of force, intimidation or deceit and causes severe health risks. Though it occurs all over the world, its true extent is still unknown. Refugees are especially vulnerable to human trafficking due to language barriers and difficult living conditions. Therefore, the purpose of this study was to estimate the prevalence and design a screening tool to identify survivors of all forms of human trafficking among refugees in a German state registration and reception centre. Methods In cooperation with the local authorities and the Ministry of Justice and for Migration Baden-Württemberg, we interviewed newly arrived refugees at an initial reception centre in Southern Germany to assess the prevalence of human trafficking. We used both a combination of the Adult Human Trafficking Screening Tool and a publication by Mumma et al. to assess all forms of human trafficking. Results In total, 13 of the 176 refugees had experienced trafficking, which corresponded to a prevalence of 7.3% (95%-CI = [3.5%, 11.3%]). Across all languages the questionnaire had a sensitivity of 76.9% and a specificity of 84.0% at a recommended cut-off of six positive responses. The recommended cut-off differed slightly for the Arabic, Farsi, Turkish, and English version. In an exploratory descriptive analysis on subregions, refugees from West Africa had a substantially higher prevalence (33.3%, 8 out of 24) for human trafficking within our sample, especially women. However, when we excluded this region from our analysis, we found no significant gender difference for the rest of the sample. Conclusions The high prevalence of trafficking in most regions, regardless of gender, suggests that more effort is needed to identify and protect all trafficked persons. The designed screening tool seems to be a promising tool to detect an especially vulnerable group of refugees and provides assistance in identifying survivors of human trafficking.

Abstract Astrocytes play a role in healthy cognitive function and Alzheimer’s disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

Background:The CDK 4/6 inhibitors, including palbociclib and ribociclib, are the standard first-line treatment for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Proton pump inhibitors are one of the most globally prescribed types of medications as part of the treatment for gastroesophageal reflux and heartburn complaints. Medication interactions have been demonstrated, leading to a decrease in the effectiveness of chemotherapy drugs such as capecitabine and pazopanib. However, their role and interaction with targeted therapies such as CDK inhibitors are still poorly understood.Methods:We searched PubMed, Embase and Web of Science databases for studies that investigated the use of PPI with CDK 4/6 inhibitors versus CDK4/6 alone for advanced or metastatic breast cancer. We systematically searched for the currently available CDK inhibitors: palbociclib, ribociclib and abemaciclib. We computed hazard ratios (HRs), with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I2 statistics. R, version 4.2.3, was used for statistical analyses.Results:A total of 2,737 patients with advanced breast cancer in 9 studies were included, with six studies described the status menopausal as 217 (7.9%) pre-menopause and 1851 (67.6%) post-menopause, for endocrine sensitivity only five studies described1489 (54.4%) patients were endocrine-sensitive and 498 (182%) endocrine-resistent, 910 (33.2%) patients used PPIs. The overall Progression-Free Survival was in favor of the PPI non-users (HR 2.0901; 95% CI 1.410–2.9498; p < 0.001). As well as the subgroup taking palbociclib, revealing statistical relevance for the PPI non-users (HR 2.2539; 95% CI 1.3213–3.8446; p = 0.003) and ribociclib subgroup with a slight decrease in hazard ratio (HR 1.74 95% CI 1.02–2.97; p = 0.04; I2 = 40%). In the multivariate analysis, there was no statistical signifance with ECOG (HR 0.9081; 95% CI 0.4978–16566; p 0.753) and Age (HR 1.2772; 95% CI 0.8790–1.8559; p = 0.199). Either, the univariate analysis did not show statistical significance.Conclusion:Women with HR+ and HER2-advanced metastatic breast undergoing treatment with targeted therapies, specifically CDK 4/6 inhibitors, should be monitored for the use of proton pump inhibitors. Therefore, the use of PPIs should be discussed, weighing the advantages and disadvantages for specific cases. It should be individualized based on the necessity in clinical practice for these cases.Systematic Review Registration:identifier CRD42023484755

Abstract A comprehensive literature reports on the correlation between elevated levels of urokinase-type plasminogen activator receptor (uPAR) and the severity of diseases with chronic inflammation including solid cancers. Molecular imaging is widely used as a non-invasive method to locate disease dissemination via full body scans and to stratify patients for targeted treatment. To date, the only imaging probe targeting uPAR that has reached clinical phase-II testing relies on a high-affinity 9-mer peptide (AE105), and several studies by positron emission tomography (PET) scanning or near-infra red (NIR) fluorescence imaging have validated its utility and specificity in vivo. While our previous studies focused on applying various reporter groups, the current study aims to improve uPAR-targeting properties of AE105. We successfully stabilized the small uPAR-targeting core of AE105 by constraining its conformational landscape by disulfide-mediated cyclization. Importantly, this modification mitigated the penalty on uPAR-affinity typically observed after conjugation to macrocyclic chelators. Cyclization did not impair tumor targeting efficiency of AE105 in vivo as assessed by PET imaging and a trend towards increased tracer uptake was observed. In future studies, we predict that this knowledge will aid development of new fluorescent AE105 derivatives with a view to optical imaging of uPAR to assist precision guided cancer surgery.

Background: The health and safety of people are often endangered during emergencies and disasters. Efficient emergency management systems ensure that mitigation, preparedness, response, and recovery actions exist to preserve the health, safety, and welfare of the public. Failure to carry out appropriate responses can have adverse consequences for both emergency responders and casualties; hence, the need for emergency preparedness. This study sought to assess the state of emergency preparedness capacity of the Kwame Nkrumah University of Science and Technology hospital in Ghana. Methods: A facility-based cross-sectional study was conducted between December 2018 and February 2019 using three guidelines developed respectively by the World Health Organization, the Ministry of Health-Ghana, and the Ghana Health Service. The hospital's emergency preparedness was assessed regarding the emergency policies, plan, protocol, equipment, and medications. Results: Overall, the hospital's emergency preparedness level was weak (57.36%). Findings revealed that the hospital had inadequate emergency equipment, and supplies for emergency care delivery, especially during upsurge. It also did not have an emergency planning committee. There were noticeable deficiencies in some emergency resources such as chest tubes, basic airway supplies, and many emergency drugs. Other vital emergency tools such as pulse oximeter, thermometer, and emergency medications were inadequate. The hospital had a strong emergency plan and policies on assessment (77.8% and 78%) respectively. Conclusion: The Kwame Nkrumah University of Science and Technology hospital is not prepared sufficiently for an emergency surge, and this poses a major health challenge. Emergency items must be made available, and the organization and planning of emergency service provisions must be improved to avoid preventable deaths during an emergency surge.

Torture seeks to undermine not only the physical and emotional well-being of an individual, but to damage the coherence of entire communities. Thus, torture and state repression are used to weaken entire subpopulations. After the failed coup d'état in Türkiye in 2016 and during the subsequently following state of emergency that lasted until 2018, allegations of torture and other degrading treatment in Türkiye spread widely. Since then, the number of asylum-seekers in Germany has risen considerably. This paper analyses the reports of twenty Turkish citizens that fled to Germany to seek asylum in the aftermath of the events. In semi-structured interviews held in Turkish, we assessed the experiences of torture and state repression, psychological consequences, and the current well-being and living situation. All interviewees described illicit violence of state authorities and government supporters, especially while under arrest. Though the methods varied, there was a constant pattern of imbalance of power. The psychological impact of these methods were present after relocation to Germany and included signs of PTSD, anxiety disorders, and major depression. The reports of torture, state repression, and their psychological impact emphasise the importance for policy makers to address the prevention of human rights violations and support the needs of survivors.

Abstract Objectives We determined the prevalence and risk factors of hypertension among public servants of Ejisu Juaben municipality. Results The overall prevalence of hypertension was 29.3% (95%CI:22.5–36.1%) and only 8.6% of the participants were aware of their hypertensive status. Respondents who were > 40 years were twice as likely to develop hypertension compared to those who were ≤ 40 years [adjusted odds ratio (AOR) = 2.37, 95% confidence interval (CI) 1.05–5.32]. Those who were married were 2.54 times more likely to be hypertensive compared with those unmarried [AOR = 2.54, 95%CI: 1.06–6.08]. Compared to health workers, Judicial and Security service workers were almost five times more likely to be hypertensive [AOR = 4.77, 95%CI: 1.20–18.96]. Being overweight [AOR = 2.25, 95%CI: 1.06–6.41] and obese [AOR = 4.80, 95%CI: 1.82–12.91] was associated with increased odds of hypertension. The prevalence of hypertension among the participants in this study is high. Employee wellness programs are needed at workplaces and the Ghana Health Service must adopt targeted intervention programs such as regular screening for non-communicable diseases and promotion of physical activities at the workplace.

Study Region: Mkonga village, ∼35 km southwest of the capital city of Lilongwe on the central plains in Malawi, Africa, located at the crest of a local topographic-high characterized by crystalline basement. Study Focus: Groundwater aquifer systems in the shallow buried crystalline basement are geologically complex reservoir targets with historically low drilling success rates. Understanding the basement weathering profiles and their implications for aquifer architecture is crucial for drilling productive wells. This is particularly critical in developing countries where water demands are rising. This study employs an integrated approach of 2-D seismic reflection and 2-D electrical resistivity imaging, constrained by borehole data to characterize the local basement aquifers in the crystalline-dominated terranes of central Malawi. New Hydrological Insights for the Region: The integrated geophysical and borehole data reveal a layered weathering profile: shallow thin laterite and sub-lateritic layers, the saprolite, the saprock, and the fractured/fresh basement. We identify four potential water-bearing zones consisting of the base of the sub-laterite layer, the saprolite, the saprock and the fractured basement. The most productive boreholes are those that intersect low resistivity anomalies (< 20 ohm-m) that are collocated with strong but discontinuous reflectors. These targets are interpreted to represent water-bearing zones that connect the saprolite and saprock to recharge pathways at the base of the sub-laterite.

BackgroundAround 1800 pediatric transplantations were performed in 2021, which is approximately 5% of the annual rate of solid organ transplantations carried out in the United States. Effective family self-management in the transition from hospital to home-based recovery promotes successful outcomes of transplantation. The use of mHealth to deliver self-management interventions is a strategy that can be used to support family self-management for transplantation recipients and their families. ObjectiveThe study aims to evaluate the acceptability of an mHealth intervention (myFAMI) that combined use of a smartphone app with triggered nurse communication with family members of pediatric transplantation recipients. MethodsThis is a secondary analysis of qualitative data from family members who received the myFAMI intervention within a larger randomized controlled trial. Eligible participants used the app in the 30-day time frame after discharge and participated in a 30-day postdischarge telephone interview. Content analysis was used to generate themes. ResultsA total of 4 key themes were identified: (1) general acceptance, (2) positive interactions, (3) home management after hospital discharge, and (4) opportunities for improvement. ConclusionsAcceptability of the intervention was high. Family members rated the smartphone application as easy to use. myFAMI allowed the opportunity for families to feel connected to and engage with the medical team while in their home environment. Family members valued and appreciated ongoing support and education specifically in this first 30 days after their child’s hospital discharge and many felt it contributed positively to the management of their child’s medical needs at home. Family members provided recommendations for future refinement of the app and some suggested that a longer follow-up period would be beneficial. The development and refinement of mHealth care delivery strategies hold potential for improving outcomes for solid organ transplantation patients and their families and as a model to consider in other chronic illness populations. Trial RegistrationClinicalTrials.gov NCT03533049; https://clinicaltrials.gov/ct2/show/NCT03533049

One of the fundamental problems in continental rift segmentation and propagation is how strain is accommodated along large rift-bounding faults (border faults) since the segmentation of propagating border faults control the expression of rift zones, syn-rift depo-centers, and long-term basin evolution. In the Southern Malawi Rift, where previous studies on the early-stage rifting only assessed border fault structure from surficial and topographic expression, we integrate surface and subsurface data to investigate border fault segmentation, linkage, and growth as proxies for strain accommodation along the Bilila-Mtakataka Fault (BMF) System. We used 30 m-resolution topographic relief maps, electrical resistivity tomography (ERT), and high-resolution aeromagnetic data to characterize the detailed fault geometry and provide a more robust estimate of along-fault displacement distribution. Our results reveal a discrepancy between sub-aerial segmentation of the BMF geometry (six segments), scarp height (five segments) reflecting the most recent episodes of fault offset, and cumulative throw (three composite segments) reflecting the long-term fault offset. We also observe that although the BMF exhibits continuity of sub-aerial scarps along its length, the throw distribution shows a higher estimate at the Northern-to-Central segment relay zone (423 m absolute, 364 m moving median) compared to the Central-to-Southern segment relay zone (371 m absolute, 297 m moving median). The ERT profiles across the relay zones suggest a shallower basement and a possible canyon-mouth alluvial fan stratigraphy at the Central-to-Southern segment relay zone, contrasting the deeper basement and “simpler” electrical stratigraphy at the Northern-to-Central relay. The results suggest a more complex long-term evolution of the BMF than was assumed in previous studies. A comparison of BMF’s maximum displacement-vs-length with those of other Malawi Rift border faults and global normal fault populations suggest that although the BMF has possibly reached its maximum length, it remains largely under-displaced as its 580–837 m maximum displacement is significantly lower than that of faults of equivalent length. We suggest that the BMF may continue to accrue significant strain as tectonic extension progresses in the Southern Malawi Rift, thus posing a major seismic hazard in the region.

Compared to folded proteins, the sequences of intrinsically disordered proteins (IDPs) are enriched in polar and charged amino acids. Glutamate is one of the most enriched amino acids in IDPs, while the chemically similar amino acid aspartate is less enriched. So far, the underlying functional differences between glutamates and aspartates in IDPs remain poorly understood. In this study, we examine the differential effects of aspartate and glutamates in IDPs by comparing the function and conformational ensemble of glutamate and aspartate variants of the disordered protein Dss1, using a range of assays, including interaction studies, nuclear magnetic resonance spectroscopy, small-angle X-ray scattering and molecular dynamics simulation. First, we analyze the sequences of the rapidly growing database of experimentally verified IDPs (DisProt) and show that glutamate enrichment is not caused by a taxonomy bias in IDPs. From analyses of local and global structural properties as well as cell growth and protein-protein interactions using a model acidic IDP from yeast and three Glu/Asp variants, we find that while the Glu/Asp variants support similar function and global dimensions, the variants differ in their binding affinities and population of local transient structural elements. We speculate that these local structural differences may play roles in functional diversity, where glutamates can support increased helicity, important for folding and binding, while aspartates support extended structures and form helical caps, as well as playing more relevant roles in, e.g., transactivation domains and ion-binding.

Little is known about rift kinematics and strain distribution during the earliest phase of extension due to the deep burial of the pre-rift and earliest rift structures beneath younger, rift-related deposits. Yet, this exact phase of basin development ultimately sets the stage for the location of continental plate divergence and breakup. Here, we investigate the structure and strain distribution in the multiphase Late Paleozoic-Cenozoic magma-poor Rukwa Rift, East Africa during the earliest phase of extension. We utilize aeromagnetic data that image the Precambrian Chisi Shear Zone (CSZ) and bounding terranes, and interpretations of 2-D seismic reflection data to show that, during the earliest rift phase (Permo-Triassic ‘Karoo’): 1) the rift was defined by the Lupa border fault, which exploited colinear basement terrane boundaries, and a prominent intra-basinal fault cluster (329° ± 9.6) that trends parallel to and whose location was controlled by the CSZ (326°); 2) extensional strain in the NW section of the rift was accommodated by both the intra-basinal fault cluster and the border fault, where the intra-basinal faulting account for up to 64% of extension; in the SE where the CSZ is absent, strain is primarily focused on the Lupa Fault. Here, the early-rift strain is thus, not accommodated only by the border fault as suggested by existing magma-poor early-rift models; instead, strain focuses relatively quickly on a large border fault and intra-basinal fault clusters that follow pre-existing intra-basement structures; 3) two styles of early-rift strain localization are evident, in which strain is localized onto a narrow discrete zone of basement weakness in the form of a large rift fault (Style-1 localization), and onto a broader discrete zone of basement weakness in the form of a fault cluster (Style-2 localization). We argue that the CSZ and adjacent terrane boundaries represent zones of mechanical weakness that controlled the first-order strain distribution and rift development during the earliest phase of extension. The established early-rift structure, modulated by structural inheritance, then persisted through the subsequent rift phases. The results of our study, in a juvenile and relatively well-exposed and data-rich rift, are applicable to understanding the structural evolution of deeper, buried ancient rifts.

Ursodeoxycholic acid (UDCA) is commonly used to treat several liver disorders in adults and children, including primary sclerosing cholangitis (PSC) for which it is not U.S. Food and Drug Administration approved. UDCA treatment has an uncertain impact on disease outcomes and has been reported in high doses to be associated with worse outcome in adults with PSC. In this context, controlled withdrawal and reintroduction of UDCA in children with PSC were studied. Prior to study initiation, participants were required to have alanine aminotransferase (ALT) and gamma‐glutamyl transpeptidase (GGT) 100 IU/L (flare group). None developed elevated bilirubin. All flares responded to UDCA reinstitution. Serum GGT, interleukin‐8, and tumor necrosis factor α levels were higher in the flare group at baseline. Liver biochemistries increased in children with PSC during controlled UDCA withdrawal; one third increased above 100 IU/L and one third remained normal during UDCA withdrawal. Conclusion: The impact of prolonged UDCA use in childhood PSC and the significance of a biochemical flare are unclear. Further studies of the natural history and treatment of pediatric PSC and UDCA use are needed.

Many patients infected with the SARS-CoV-2 virus (COVID-19) continue to experience symptoms for weeks to years as sequelae of the initial infection, referred to as Long COVID. Although many studies have described the incidence and symptomatology of Long COVID, there are little data reporting the potential burden of Long COVID on surgical departments. A previously constructed database of survey respondents who tested positive for COVID-19 was queried, identifying patients reporting experiencing symptoms consistent with Long COVID. Additional chart review determined whether respondents had a surgical or non-routine invasive procedure on or following the date of survey completion. Outcomes from surgeries on patients reporting Long COVID symptoms were compared to those from asymptomatic patients. A total of 17.4% of respondents had surgery or a non-routine invasive procedure in the study period. A total of 48.8% of these patients reported experiencing symptoms consistent with Long COVID. No statistically significant differences in surgical outcomes were found between groups. The results of this analysis demonstrate that Long COVID does not appear to have created a significant burden of surgical disease processes on the healthcare system despite the wide range of chronic symptoms and increased healthcare utilization by this population. This knowledge can help guide surgical operational resource allocation as a result of the pandemic and its longer-term sequelae.

The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

Geophysical investigations documenting enhanced magnetic susceptibility (MS) within the water table fluctuation zone at hydrocarbon contaminated sites suggest that MS can be used as a proxy for investigating microbial mediated iron reduction during intrinsic bioremediation. Here, we investigated the microbial community composition over a 5-year period at a hydrocarbon-contaminated site that exhibited transient elevated MS responses. Our objective was to determine the key microbial populations in zones of elevated MS. We retrieved sediment cores from the petroleum-contaminated site near Bemidji, MN, United States, and performed MS measurements on these cores. We also characterized the microbial community composition by high-throughput 16S rRNA gene amplicon sequencing from samples collected along the complete core length. Our spatial and temporal analysis revealed that the microbial community composition was generally stable throughout the period of investigation. In addition, we observed distinct vertical redox zonations extending from the upper vadose zone into the saturated zone. These distinct redox zonations were concomitant with the dominant microbial metabolic processes as follows: (1) the upper vadose zone was dominated by aerobic microbial populations; (2) the lower vadose zone was dominated by methanotrophic populations, iron reducers and iron oxidizers; (3) the smear zone was dominated by iron reducers; and (4) the free product zone was dominated by syntrophic and methanogenic populations. Although the common notion is that high MS values are caused by high magnetite concentrations that can be biotically formed through the activities of iron-reducing bacteria, here we show that the highest magnetic susceptibilities were measured in the free-phase petroleum zone, where a methanogenic community was predominant. This field study may contribute to the emerging knowledge that methanogens can switch their metabolism from methanogenesis to iron reduction with associated magnetite precipitation in hydrocarbon contaminated sediments. Thus, geophysical methods such as MS may help to identify zones where iron cycling/reduction by methanogens is occurring.

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder, most cases of which lack a clear causative event. This has made the disease difficult to characterize and, thus, diagnose. Although some cases are genetically linked, there are many diseases and lifestyle factors that can lead to an increased risk of developing AD, including traumatic brain injury, diabetes, hypertension, obesity, and other metabolic syndromes, in addition to aging. Identifying common factors and trends between these conditions could enhance our understanding of AD and lead to the development of more effective treatments. Although the immune system is one of the body’s key defense mechanisms, chronic inflammation has been increasingly linked with several age-related diseases. Moreover, it is now well accepted that chronic inflammation has an important role in the onset and progression of AD. In this review, the different inflammatory signals associated with AD and its risk factors will be outlined to demonstrate how chronic inflammation may be influencing individual susceptibility to AD. Our goal is to bring attention to potential shared signals presented by the immune system during different conditions that could lead to the development of successful treatments.

Motifs within proteins help us categorize their functions. Intrinsically disordered proteins (IDPs) are rich in short linear motifs, conferring them many different roles. IDPs are also frequently highly charged and, therefore, likely to interact with ions. Canonical calcium-binding motifs, such as the EF-hand, often rely on the formation of stabilizing flanking helices, which are a key characteristic of folded proteins, but are absent in IDPs. In this study, we probe the existence of a calcium-binding motif relevant to IDPs. Upon screening several carefully selected IDPs using NMR spectroscopy supplemented with affinity quantification by colorimetric assays, we found calcium-binding motifs in IDPs which could be categorized into at least two groups—an Excalibur-like motif, sequentially similar to the EF-hand loop, and a condensed-charge motif carrying repetitive negative charges. The motifs show an affinity for calcium typically in the ~100 μM range relevant to regulatory functions and, while calcium binding to the condensed-charge motif had little effect on the overall compaction of the IDP chain, calcium binding to Excalibur-like motifs resulted in changes in compaction. Thus, calcium binding to IDPs may serve various structural and functional roles that have previously been underreported.

Summary: Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis. : Httex1 aggregation into inclusions has paradoxically been reported as either toxic or beneficial in Huntington’s disease. Ramdzan et al. define a dual mechanism of toxicity that explains this paradox. Soluble Httex1 triggers a fast death by apoptosis, whereas Httex1 inclusions invoke quiescence and redirect death to a slower necrotic pathway. Keywords: Huntington’s disease, flow cytometry, ribosome quality control, stress granule, RNA granule, P bodies, translation

Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

Heme has a critical role in the chemical framework of the cell as an essential protein cofactor and signaling molecule that controls diverse processes and molecular interactions. Using a phylogenomics-based approach and complementary structural techniques, we identify a family of dimeric hemoproteins comprising a domain of unknown function DUF2470. The heme iron is axially coordinated by two zinc-bound histidine residues, forming a distinct two-fold symmetric zinc-histidine-iron-histidine-zinc site. Together with structure-guided in vitro and in vivo experiments, we further demonstrate the existence of a functional link between heme binding by Dri1 (Domain related to iron 1, formerly ssr1698) and post-translational regulation of succinate dehydrogenase in the cyanobacterium Synechocystis, suggesting an iron-dependent regulatory link between photosynthesis and respiration. Given the ubiquity of proteins containing homologous domains and connections to heme metabolism across eukaryotes and prokaryotes, we propose that DRI (Domain Related to Iron; formerly DUF2470) functions at the molecular level as a heme-dependent regulatory domain.

The purpose of this study was to investigate five Japanese graduate (master's level) students' experiences in online courses in international development and peace through sport that used English as the medium of instruction. The study was situated in the framework of andragogy theory and used a descriptive-qualitative design using an in-depth, semistructured interview approach using online oral and written interviews. Three emergent themes were established. These recurrent themes were (a) "learning online specialized content using English as a second language", (b) "students' struggles in group projects through online education", and (c) "students' opinions about the improvement of online education". To better support Japanese graduate students' online learning, this study encourages academic departments, administrators, and faculty to better design appropriate courses and online activities. This will contribute to a greater appreciation for the richness of sports development and peace and to increasing the availability of meaningful academic and social experiences for graduate students at Japanese universities.

Two independent temporal-spatial clusters of hospital-onset Rhizopus infections were evaluated using whole-genome sequencing (WGS). Phylogenetic analysis confirmed that isolates within each cluster were unrelated despite epidemiological suspicion of outbreaks. The ITS1 region alone was insufficient for accurate analysis. WGS has utility for rapid rule-out of suspected nosocomial Rhizopus outbreaks.

Objective To describe the scale-up of cervical cancer screening and treatment for women living with human immunodeficiency virus (HIV), aged 25-49 years in Uganda, and to analyse the programme data. Methods The health ministry targeted existing HIV clinics in a 2-year scale-up of cervical cancer screening services from October 2020. In preparation, we trained health workers to assess women attending HIV clinics for screening eligibility, provided either by human papillomavirus (HPV) testing and/or visual inspection with acetic acid. Clinic staff treated women with precancerous cervical lesions with thermocoagulation or referred women with suspected cancer to external services. We analysed data reported every 6 months for the number of clinics offering screening, screening uptake, the number of positive diagnoses and the number of women who received treatment. Findings The number of HIV clinics offering cervical cancer screening services increased from 11, before the programme launch, to 1571. During the programme, screening uptake increased from 5.0% (6506/130 293) to 107.3% (151872/141 527) of targets. The cumulative proportion of positive diagnoses was 5.9% (23 970/407 323) overall, but was much lower for screening offering visual inspection only compared with clinics offering HPV testing. Although the proportion of women receiving treatment if positive increased from 12.8% (53/413) to 84.3% (8087/9592), the World Health Organization target of 90% was not reached. Conclusion We demonstrated marked increases, potentially replicable by other countries, in screening and treatment. These increases could be improved further by expanding HPV testing and same-day treatment of precancerous lesions. Objectif Decrire Intensification du depistage et du traitement du cancer du col de l'uterus chez les femmes vivant avec le virus de l'immunodeficience humaine (VIH) et agees de 25 a 49 ans en Ouganda, puis analyser les donnees du programme. Methodes Le Ministere de la Sante a cible les cliniques de prise en charge du VIH existantes dans le cadre d'un renforcement des services lies au cancer du col de l'uterus sur une periode de deux ans, a partir d'octobre 2020. En amont, nous avons forme des professionnels de la sante a examiner les femmes frequentant les cliniques du VIH afin de determiner leur admissibility au depistage, par un test de detection du papillomavirus humain (HPV) et/ou une inspection visuelle apres application d'acide acetique. Le personnel des cliniques a traite les femmes presentant des lesions precancereuses du col de l'uterus par thermocoagulation, ou les ont renvoyees vers des services externes lorsqu'elles etaient susceptibles d'etre atteintes d'un cancer. Nous avons analyse les donnees transmises tous les six mois concernant le nombre de cliniques proposant un depistage, la participation au depistage, le nombre de diagnostics positifs et le nombre de femmes ayant repu un traitement. Resultats Le nombre de cliniques du VIH disposant de services de depistage du cancer du col de l'uterus a augmente: 11 avant le lancement du programme, 1571 apres. Au cours de ce programme, la participation au depistage est passee de 5,0% (6506/130 293) a 107,3% (151 872/141 527) des cibles. Le pourcentage cumule de diagnostics positifs s'elevait a 5,9% (23 970/407 323) au total; cependant, il etait nettement moins important dans des cliniques effectuant uniquement des inspections visuelles que dans celles proposant un test de detection du HPV. Bien que le pourcentage de femmes ayant regu un traitement en cas de diagnostic positif ait progresse de 12,8% (53/413) a 84,3% (8087/9592), l'objectif de l'Organisation mondiale de la Sante, fixe a 90%, n'a pas ete atteint. Conclusion Nous avons observe des hausses considerables, susceptibles de se reproduire dans d'autres pays, en matiere de depistage et de prise en charge. Ces hausses pourraient etre accentuees par le developpement des tests de detection du HPV et de traitement des lesions precancereuses le jour meme. Objetivo Describir la ampliacion del cribado y tratamiento del cancer de cuello uterino para mujeres con el virus de la inmunodeficiencia humana (VIH) de entre 25 y 49 anos en Uganda, y analizar los datos del programa. Metodos El Ministerio de Salud se centro en las clinicas de VIH existentes en una ampliacion de dos anos de los servicios de cribado del cancer de cuello uterino a partir de octubre de 2020. Como preparacion, formamos a profesionales sanitarios para que evaluaran a las mujeres que acudian a las clinicas de VIH para determinar si cumplian los requisitos para someterse al cribado, mediante pruebas del virus del papiloma humano (VPH) o inspeccion visual con acido acetico. El personal clinico trato a las mujeres que presentaban lesiones cervicales precancerosas con termocoagulacion o derivo a las mujeres con sospecha de cancer a servicios externos. Se analizaron los datos comunicados cada seis meses sobre el numero de clinicas que ofrecian el cribado, la aceptacion del cribado, el numero de diagnosticos positivos y el numero de mujeres que recibieron tratamiento. Resultados El numero de clinicas de VIH que ofrecen servicios de cribado del cancer de cuello uterino aumento de 11, antes del lanzamiento del programa, a 1571. Durante el programa, la aceptacion del cribado aumento del 5,0% (6506/130 293) al 107,3% (151 872/141 527) de los objetivos. El porcentaje acumulado de diagnosticos positivos fue del 5,9% (23 970/407 323) en general, pero fue mucho menor en el caso de los diagnosticos en clinicas que solo ofrecian inspeccion visual en comparacion con las clinicas que ofrecian pruebas del VPH. Aunque el porcentaje de mujeres que recibieron tratamiento en caso positivo aumento del 12,8% (53/413) al 84,3% (8087/9592), no se alcanzo el objetivo del 90% que habia fijado la Organizacion Mundial de la Salud. Conclusion Se registraron aumentos notables, potencialmente reproducibles en otros paises, en el cribado y el tratamiento. Estos aumentos podrian mejorarse aun mas ampliando las pruebas del VPH y el tratamiento en el mismo dia de las lesiones precancerosas. [phrase omitted], Introduction Cervical cancer is a disease of the female reproductive tract caused primarily by oncogenic types of human papillomavirus (HPV). In 2020, it was the fourth most common cancer among [...]

BackgroundMultidisciplinary approaches to weight loss have been shown to improve outcomes in bariatric patients. Few studies have been performed assessing the utility and compliance of fitness tracking devices after bariatric surgery. We aim to determine whether use of an activity tracking device assists bariatric patients in improving postoperative weight loss behaviors.MethodsA fitness wearable was offered to patients undergoing bariatric surgery from 2019 to 2022. A telephone survey was conducted to elucidate the impact of the device on the patient's postoperative weight loss efforts 6 to 12 months after surgery. Weight loss outcomes of sleeve gastrectomy (SG) patients receiving the fitness wearable (FW) were compared to those of a group of SG patients who did not receive one (non-FW).ResultsThirty-seven patients were given a fitness wearable, 20 of whom responded to our telephone survey. Five patients reported not using the device and were excluded. 88.2% reported that using the device had a positive impact on their overall lifestyle. Patients felt that using the fitness wearable to keeping track of their progress helped them both to achieve short-term fitness goals and sustain them in the long run. From the patients that utilized the device, 44.4% of those that discontinued felt like it helped them build a routine that they maintained even after they were no longer using it. Demographic data between FW and non-FW groups (age, sex, CCI, initial BMI, and surgery BMI) did not differ significantly. The FW group trended towards greater %EWL at 1 year post-operation (65.2% versus 52.4%, p = 0.066) and had significantly greater %TWL at 1 year post-operation (30.3% versus 22.3%, p = 0.02).ConclusionThe use of an activity tracking device enhances a patient's post-bariatric surgery experience, serving to keep patients informed and motivated, and leading to improved activity that may translate to better weight loss outcomes.

BACKGROUND: Autologous fat grafting (AFG) has shown promise in the treatment of complex wounds, with trials reporting good healing rates and safety profile. We aim to investigate the role of AFG in managing complex anorectal fistulas. METHODS: This was a retrospective review of a prospectively maintained IRB-approved database. We examined the rates of symptom improvement, clinical closure of fistula tracts, recurrence, complications, and worsening fecal incontinence. Perianal disease activity index (PDAI) was obtained for patients undergoing combination of AFG and fistula plug treatment. RESULTS: In total, 52 unique patients underwent 81 procedures, of which Crohns was present in 34 (65.4%) patients. The majority of patients previously underwent more common treatments such as endorectal advancement flap or ligation of intersphincteric fistula tract. Fat-harvesting sites and processing technique were selected by the plastic surgeons based on availability of trunk fat deposits. When analyzing patients by their last procedure, 41 (80.4%) experienced symptom improvement, and 29 (64.4%) experienced clinical closure of all fistula tracts. Recurrence rate was 40.4%, and complication rate was 15.4% (7 postoperative abscesses requiring I&D and 1 bleeding episode ligated at bedside). The abdomen was the most common site of lipoaspirate harvest at 63%, but extremities were occasionally used. There were no statistically significant differences in outcomes when comparing single graft treatment to multiple treatments, Crohns and non-Crohns, different methods of fat preparation, and diversion. CONCLUSION: AFG is a versatile procedure that can be done in conjunction with other therapies and does not interfere with future treatments if recurrence occurs. It is a promising and affordable method to safely address complex fistulas.