Browse Articles

Decoding potential lncRNA and disease associations through graph representation learning and gradient boosting with histogram

Transforming multi-stakeholder engagement towards coproduction of optimized maternal, newborn, and child health and a resilient community health system in rural Ethiopia: A qualitative study

Introduction In Ethiopia, Maternal, Newborn, and Child Health (MNCH) outcomes have been improving, however, the current level of Maternal and under-five children mortality remains the highest in the world. Despite the rhetoric around the significance of multi-stakeholder engagement as a buzzword in development theories and polices to improve health and other development outcomes, there is limited evidence on how multi-stakeholders intersect and mutually reinforce each other toward the coproduction of improved MNCH outcomes and a resilient community health system. The aim of this manuscript is to examine barriers to and facilitators of coproduction in the context of multi-stakeholder engagement to optimize MNCH outcomes and a resilient community health system in rural Ethiopia. Methods We conducted a qualitative case study in West Shewa Zone, rural Ethiopia. A purposive sampling technique was used to recruit participants. Data sources were two focus groups discussions with CHWs, twelve key informant interviews with multilevel public health policy actors, and a policy document review related to the CHW program to triangulate the finding. Thematic analysis of the qualitative data was conducted. Our study was informed by multiple theoretical frameworks including the World Health Organization’s building block framework, state- society synergy model to inform the research processes and analysis. Results In the context of multi-stakeholder approach, our analysis revealed the multilevel barriers to and facilitators of coproduction in the community health landscape in rural Ethiopia. The major barriers of coproduction include lack of vertical and horizontal alignment, lack of continuum of and sustainable engagement practice,lack of systemic coordination platforms, and Inadequate coordination and implementation capacity. Major facilitators of coproduction include embedded integrated community health system, promising macro-level multi-stakeholder and community-level engagement and coproduction aspects. Conclusions Our study reveals mixed policy and practice-related results, the current multi-stakeholder engagement is necessary but insufficient and fragmented to coproduce optimized MNCH outcomes and ensure a resilient health system in rural Ethiopia. Moving beyond the current multi-stakeholder engagement as a buzzword in health polices to practice through, embracing meaningful coproduction frameworks is fundamental while building on multi-stakeholder engagement efforts to optimize MNCH outcomes and a resilient community health system. A coproduction framework leverages the intersection and mutual reinforcement of multi-stakeholder synergy throughout the CHWs’ program cycle through shared power and joint assessment, planning, implementing, decision making and evaluating. Fostering effective multi-stakeholder engagement synergy requires balanced shared power, alignment to community priorities, systemic mapping, coordination and monitoring, and continuum and sustainability of engagement strategies. Beyond donor initiatives and a dependency approach, proactive health diplomacy strategies are also important to sustain the existing and attract new actors to realize sustainable positive health outcomes and a resilient community health policy and strategy.

G-quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes

DNA secondary G-quadruplex (G4) structures can impair and even obstruct DNA replication. Defects in processing G4 structures are associated with replication stress, a common property of both B cell cancers and hyperproliferative premalignant cells. Genome instability arising from replication stress is a hallmark of cancer and strongly contributes to the chromosome rearrangements in B cell cancers. Here, we define the impact of G4-stabilizing ligands on generating genome instability in primary and malignant B cells. Treatment with the G4-stabilizing compound pyridostatin (PDS) causes breaks and chromosome rearrangements at ribosomal DNA and pericentromeric major satellite regions in both mouse primary B cell culture and CH12 lymphoma cells. PDS also causes extensive pericentromeric DNA damage in immortalized human B cell lines. Remarkably, PDS causes high level of tetraploid metaphase cells correlated with high level of dicentric chromosomes specifically in primary but not in CH12 B cells. Unlike primary B cells, CH12 cells undergo checkpoint activation and strong G2/M arrest in response to PDS treatment thus preventing tetraploid appearance. Altogether, these results highlight the difference between primary and malignant B cells in response to PDS, revealing the therapeutic potential of G4-stabilizing drugs to selectively suppress tumor cell growth and proliferation.

Preservation of bioactive compounds in mulberry species (Morus spp.) under different drying conditions

Factors affecting diabetes related hospitalization and in-hospital outcomes of adults with diabetes in south Ethiopia: A prospective observational study

Background and objective Globally, diabetes mellitus is emerging as one of the most common chronic illnesses, and its prevalence has been increasing in the last decades. International Diabetes Federation reports that the number of people with diabetes in Ethiopia is 1.7 million. The prevalence of diabetes mellitus in Ethiopia is rising, and it is expected to increase to 2,031,000 in 2030. Diabetic patients have frequent hospitalization, which is associated with increased morbidity and mortality. The objective of this study was to assess reason for hospitalization and predictors for diabetes related hospitalization and in-hospital treatment outcome of adults with diabetes mellitus in Dilla University, a referral hospital in South Ethiopia. Method A hospital-based prospective observational study was conducted at medical, emergency, COVID-19 treatment center, and intensive care unit wards of Dilla University Referral Hospital from September 1, 2020, to May 30, 2021. All adult patients with diabetes mellitus who met the inclusion criteria were consecutively included in the study and followed until discharge or referral or death. To identify the predictors for in-hospital treatment outcome and diabetes related admission, logistic regression was run. Variables with p-value ≤ 0.05 on multivariate regression were considered statistically significant. Results A total of 153 patients were enrolled in the study. Diabetic ketoacidosis was the commonest reason for hospitalization (32%), followed by infection (22.2%) and cardiovascular diseases (9.2%). COVID-19 is the major cause of infection-related admission (13.7%). The mean length of hospital stay was 9.92 ± 7.97 days, ranging from 2 to 50 days. Higher proportion were discharged with improvement(71.9%) while 15.7% were self-discharge and 12.24% died in the hospital, mainly due to infections. The presence of comorbidity (AOR = 3.27, 95% CI: 1.39–7.68), obesity (AOR = 3.93, 95% CI: 1.42–10.9), patients with age group of 50–59 (AOR = 0.13, 95% CI: 0.03–0.56), ≥ 60 (AOR = 0.06, 95% CI: 0.018–0.25), and knowledge about diabetic foot ulcer complication (AOR = 0.33, 95% CI: 0.12–0.89) were predictors of diabetes-related admission. Regarding treatment outcome, poor exercise practice (AOR = 2.41, 95% CI: 1.014–5.77, p = 0.046), hypertension (AOR = 3.17, 95% CI: 1.39–7.19, p = 0.006), unsatisfactory knowledge about DM (AOR = 3.5, 95% CI: 1.12–10.9, p = 0.030), and being unmarried (AOR = 3.34, 95% CI: 1.47–7.58, p = 0.004) were predictors of poor treatment outcome. Conclusion Generally, this study showed that hyperglycemic emergencies, infections, and cardiovascular diseases were the most common reasons for hospitalization. The mortality rate is high, which is 12.24%, and urges attention to the care of hospitalized patients. Health care professionals should strengthen patient education on glycemic control and self-care practice, since the majority of patients have poor self-care practice and poor metabolic control.

A β-cap on the FliPQR protein-export channel acts as the cap for initial flagellar rod assembly

The FliPQR complex constitutes a channel for export of the flagellar proteins involved in axial structure assembly. It also serves as a template for the assembly of the rod structure, which consists of FliE, FlgB, FlgC, FlgF, and FlgG. FliP, FliQ, and FliR assemble into a right-handed helical structure within the central pore of the flagellar basal body MS-ring, and the complex has two gates on the cytoplasmic and periplasmic sides. The periplasmic gate, formed by the N-terminal α-helices of FliP and FliR, remains closed until six FliE subunits assemble onto FliP and FliR to form the first layer of the rod, but it has remained unclear how each FliE subunit opens the gate and assembles in the absence of the rod cap required for efficient assembly of other rod proteins. Here, we present a cryoelectron microscopy structure of the FliPQR complex in closed form at 3.0 Å resolution. A β-cap, formed by the N-terminal β-strands of FliP and FliR, is located at the top of the FliPQR complex and tightly seals the closed gate. The β-cap has a narrow pore that efficiently and accurately leads the first FliE subunit to its assembly site. Interactions of FliE with FliP and FliR induce a conformational change in FliP and FliR, with their N-terminal α-helices move up and outward to open the gate. Consequently, each of the N-terminal β-strands of FliP and FliR detaches from the β-cap one after another, thereby creating a docking site for the next FliE subunit to efficiently assemble.

Safety and efficacy of very short flow diverters for the treatment of intracranial internal carotid artery aneurysms

Computational modeling and analysis of medical resource shortages in hospital alliance: A simulation-driven approach

Hospital alliances, as an innovative model of hospital management, are dedicated to achieving resource sharing across the entire healthcare network. During the COVID-19 pandemic in China, these alliances played a pivotal role in combating the outbreak. However, a significant challenge emerged: the difficulty in accurately quantifying medical resource shortages at individual hospitals hindered the efficient allocation of these critical resources. To address this issue, this study proposes an integrated urgent medical resource evaluation model designed to scientifically assess the urgency of medical resource needs within the alliance. Methodologically, the model innovatively combines the SEIR system dynamics model, complex network analysis, and entropy-weighted TOPSIS to construct a multi-dimensional evaluation framework. A case study has been conducted to validate the effectiveness of the proposed methodology. Contrary to conventional expectations, the findings reveal that small-scale hospitals exhibit higher medical resource urgency compared to their large-scale counterparts within the alliance. Based on these results, we recommend that policymakers prioritize addressing medical resource shortages in small-scale hospitals during pandemics.

Correction for Pan et al., β-Catenin regulates myogenesis by relieving I-mfa-mediated suppression of myogenic regulatory factors in P19 cells

Correction: Factors associated with pressure ulcers among middle-old and oldest-old inpatients in an acute care hospital

The determinants of international students studying in China: An empirical research based on the “Belt and Road” perspective

This paper explores the factors influencing international students’ decisions to study in China, based on data from 2003 to 2018. Using a two-way fixed effect model and a comprehensive theoretical framework that integrates push-pull theory, human capital theory, and proximity theory, the study investigates the roles of economic, educational, national stability, and sociocultural determinants. The findings reveal that economic factors, particularly the trade relations between the home country and China, play a significant role in attracting international students. National stability, the number of Confucius Institutes, and language similarity also emerge as key influences. Moreover, educational factors such as Chinese university rankings and scholarships are crucial in drawing students. The study further shows that international students from B&R countries are more sensitive to economic and sociocultural factors than those from non-B&R countries. Postgraduate students are more focused on China’s economic development and educational strength, while undergraduates prioritize national stability and sociocultural aspects. These findings offer insights for policymakers and higher education institutions, providing strategic recommendations to effectively attract and support international students in a rapidly changing global landscape.

Protein functional site annotation using local structure embeddings

The rapid expansion of protein sequence and structure databases has resulted in a significant number of proteins with ambiguous or unknown function. While advances in machine learning techniques hold great potential to fill this annotation gap, current methods for function prediction are unable to associate global function reliably to the specific residues responsible for that function. We address this issue by introducing PARSE (Protein Annotation by Residue-Specific Enrichment), a knowledge-based method which combines pretrained embeddings of local structural environments with traditional statistical techniques to simultaneously predict function and provide residue-level annotations. For the task of predicting the catalytic function of enzymes, PARSE achieves comparable or superior global performance to state-of-the-art machine learning methods (F1 score > 85%) while simultaneously annotating the specific residues involved in each function with much greater precision. Since it does not require supervised training, our method can make one-shot predictions for very rare functions and is not limited to a particular type of functional label (e.g. Enzyme Commission numbers or Gene Ontology codes). Finally, we leverage the AlphaFold Structure Database to perform functional annotation at a proteome scale. By applying PARSE to the dark proteome—predicted structures which cannot be classified into known structural families—we predict several bacterial metalloproteases. Each of these proteins shares a strongly conserved catalytic site despite highly divergent sequences and global folds, illustrating the value of local structure representations for new function discovery.

Knowledge, attitude, and factors associated with household chemical safety practices among caregivers of children in Kampala, Uganda

Generating random graphs with prescribed graphlet frequency bounds derived from probabilistic networks

Testing or benchmarking network algorithms in bioinformatics requires a diverse set of networks with realistic properties. Real networks are often supplemented by randomly generated synthetic ones, but most graph generative models do not take into account the distribution of subgraph patterns, i.e. motifs or graphlets. Moreover, in many cases, biological interactions are uncertain events and must be modeled by probabilistic graph edges. The uncertainty is often ignored in practice, which can lead to incorrect conclusions about the properties of biological networks. In this work, we instead derive bounds on the graphlet counts and degree distribution of a probabilistic target network and use this information as input to a novel random graph generation algorithm. The algorithm grows graphs incrementally by making small modifications in every step, which allows for an efficient graphlet counting method. Using this method, we can update graphlet counts after each iteration in a time independent of the total node number on sparse graphs. We evaluate our model on synthetic and real networks of different sizes and with different degrees of uncertainty. Although computation times strongly depend on the size of graphlets taken into account, our experiments demonstrate that graphs with over 10 000 edges and well-controlled frequencies of all three- and four-node graphlets can be generated in under an hour.

Evolution of developmental bias explains divergent patterns of phenotypic evolution in two nematode clades

Rates of phenotypic evolution vary across traits, and these evolutionary patterns themselves evolve. Understanding how development contributes to such patterns remains a challenge because it requires large-scale measurement of phenotypic variation resulting from random mutations across multiple species. Using the experimentally tractable system of nematode vulval development, we quantified the evolution and mutational sensitivity of six cell fates across two clades. First, we find that the cell whose fate evolves fastest is distinct for each clade: P3.p in Caenorhabditis and P4.p in Oscheius . Second, we show that this evolutionary pattern matches the pattern of variation within species of each clade. Third, we find that within each clade, the differential effect on each cell of random mutation, quantified as their mutational phenotypic variance, is sufficient to explain the observed phenotypic evolution. Finally, we propose that the difference between clades is explained by a simple spatial shift across cells of the sensitive region in a Wnt dose–response curve. These findings underscore the importance of integrating the evolving structure of the genotype–phenotype map and measures of developmental sensitivity into the understanding of phenotypic change at both micro- and macroevolutionary scales.

Health-related quality of life and patient experiences regarding care transitions in hospitalized older patients with chronic diseases

Correction: A neural network model of mathematics anxiety: The role of attention

Cancer cells subvert the primate-specific KRAB zinc finger protein ZNF93 to control APOBEC3B

ZNF93 is a primate-restricted Krüppel-associated box zinc finger protein responsible for repressing 20- to 12-My-old L1 transposable elements. Here, we reveal that ZNF93 also regulates the key cancer driver APOBEC3B—a mutagenic enzyme linked to tumorigenesis and cancer progression. ZNF93 depletion impairs DNA synthesis, activates replication and DNA damage checkpoints, and triggers proinflammatory phenotypes. Conversely, its overexpression enhances resistance to exogenous genotoxic stress, mirroring the effects observed with APOBEC3B depletion. ZNF93 expression correlates with cell proliferation rates and is overexpressed in many cancer types. These findings suggest that ZNF93 serves as a critical guardian of genome integrity, co-opted by cancer cells to counterbalance APOBEC3B-induced and L1-derived genomic instability and inflammation.

Combination of knockout serum replacement and plasma rich in growth factors does not support in vitro spermatogenesis in mice

Abstract Cancer treatments can lead to infertility, particularly in prepubertal boys who cannot preserve sperm before therapy. In vitro spermatogenesis offers a promising strategy for fertility preservation in this population by enabling the development of sperm from immature testicular tissue under controlled conditions. This study investigates the effects of a novel culture medium containing plasma rich in growth factors (PRGF) and knockout serum replacement (KSR) on in vitro spermatogenesis. Testicular tissues from five-day-old male NMRI mice were cultured in either a medium containing 5% KSR + 5% PRGF or a control medium containing 10% KSR for 42 days. Histological analysis revealed significant degeneration of peripheral seminiferous tubules in the 5% KSR + 5% PRGF group compared to the control. Gene expression analysis showed reduced levels of spermatogenesis markers (Plzf, Tekt1, Tnp1) and the proliferation marker Ki67, alongside elevated expression of the pro-apoptotic marker Bax. Immunofluorescence confirmed fewer spermatogonial stem cells (PLZF), spermatocytes (SYCP3), and proliferating cells (Ki67), with complete absence of post-meiotic marker ACRBP in the 5% KSR + 5% PRGF group. Additionally, higher Bax and lower Bcl-2 fluorescence intensities were observed in this group. These findings indicate that a medium supplemented with 5% KSR and 5% PRGF is ineffective for supporting complete in vitro spermatogenesis and may promote apoptosis. Importantly, these results provide insights into culture system design for future applications in fertility preservation strategies for prepubertal cancer patients at risk of gonadotoxicity.

Estimating prevalence and identifying predictors of zero-dose pentavalent and never-immunized children under two years of age in Kashmore and Sujawal Districts of Sindh, Pakistan: An analysis of household survey data

Introduction Despite intensified global efforts to enhance immunization coverage, one in five children continue to miss out on life-saving vaccines, leaving them vulnerable to a range of vaccine-preventable diseases. In 2022, 14.3 million children failed to receive even a single dose of the pentavalent vaccine (Penta-1) by their first birthday, classified as “zero-dose penta”. Additionally, some children have not received any vaccinations at all and have had no contact with healthcare services—these are referred to as “never-immunized” children. Collectively, both groups—zero-dose penta and never-immunized children—are termed “true zero-dose” to emphasize the critical need for targeted interventions that ensure no child is left behind in immunization efforts. Methods We conducted a household (HH) survey from August 10 to December 19, 2022, in Kashmore and Sujawal, two districts in Sindh, Pakistan, with low immunization coverage. The survey targeted children aged 12−23 months who had not received the Penta-1 vaccine by their first birthday. Our study aimed to determine the community-based prevalence of zero-dose penta and never-immunized children, compare their sociodemographic characteristics and immunization histories, and identify predictors of these outcomes. Results Of the 2,091 children surveyed, 497 (23.8%) were zero-dose penta, and 587 (28.1%) were never-immunized. Together, these groups constitute 51.9% of the survey population, referred to as ‘true zero-dose’. The remaining 1,007 (48.1%) were either fully or partially immunized. Multivariate analysis indicated that absence of antenatal care (ANC) significantly increased the risk of children being classified as zero-dose penta (RRR = 1.68; 95% CI: 1.04–2.72; p < 0.035) and never-immunized (RRR = 2.07; 95% CI: 1.25–3.45; p < 0.005). Furthermore, the absence of Lady Health Worker (LHW) visits significantly increased the risk of children being classified as zero-dose penta (RRR = 2.55; 95% CI: 1.26–5.16; p < 0.009), and the absence of vaccinator visits significantly increased the risk of being never-immunized (RRR = 4.44; 95% CI: 2.68–7.36; p < 0.001). Conclusion Despite global efforts for achieving universal immunization, half of the surveyed children remained true zero-dose, highlighting significant gaps in the ability of immunization programs to reach underserved communities. To address this issue, it is essential to enhance ANC coverage and leverage frontline health workers (FHWs) to identify and engage with clusters of zero-dose children effectively. These measures will ensure that no child is left behind, advancing health equity and safeguarding future generations.