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Glioblastoma cells rely on connexin 43 (Cx43)‐based gap junctions (GJs) for intercellular communication, enabling them to integrate into a widely branched malignant network. Although there are promising prospects for new targeted therapies, the lack of clinically feasible GJ inhibitors has impeded their adoption in clinical practice. In the present study, we investigated tonabersat (TO), a blood–brain‐barrier‐penetrating drug with GJ‐inhibitory properties, in regard to its potential to disassemble intercellular connectivity in glioblastoma networks. Fluorescence‐guided measurements of calcein cell‐to‐cell transfer were used to study functional intercellular connectivity. Specific DNA fragmentation rates of propidium iodide‐stained nuclei were measured as a surrogate readout for cell death using flow cytometry. CRISPR/Cas9‐mediated gene editing of Cx43 served as a validation tool of cellular effects related to Cx43 GJ inhibition. 3′ mRNA sequencing was performed for molecular downstream analysis. We found that TO reduced intercellular GJ‐mediated cytosolic traffic and yielded a significant reduction of tumor microtube (TM) length. TO‐mediated inhibition of cellular tumor networks was accompanied by a synergistic effect for temozolomide‐induced cell death. CRISPR/Cas9 Cx43‐knockout revealed similar results, indicating that TO‐mediated inhibitory effects rely on the inhibition of Cx43‐based GJs. Gene set enrichment analyses found that GJ‐mediated synergistic cytotoxic effects were linked to a significant upregulation of cell death signaling pathways. In conclusion, TO disrupts TM‐based network connectivity via GJ inhibition and renders glioblastoma cells more susceptible to cytotoxic therapy. Given its previous use in clinical trials for migraine therapy, TO might harbor the potential of bridging the idea of a GJ‐targeted therapeutic approach from bench to bedside. Tonabersat (TO) inhibits Cx43‐based gap junctions (GJs) in glioblastoma, leading to both functional and morphological breakdown of malignant cell‐to‐cell connectivity. This increases sensitivity to temozolomide (TMZ)‐induced cell death, reduces tumor cell proliferation, and enhances TMZ‐activated molecular pathways that drive growth arrest and apoptosis. TO's potential as a clinically feasible drug holds promise for advancing new therapeutic approaches in glioblastoma treatment.

Despite significant evidence around barriers hindering timely access to cataract surgery in low- and middle-income countries (LMICs), little is known about the strategies necessary to overcome them and the factors associated with improved access. Despite significant evidence that certain groups, women for example, experience disproportionate difficulties in access, little is known about how to improve the situation for them. Two reviews were conducted recently: Ramke et al., 2018 reported experimental and quasi-experimental evaluations of interventions to improve access of cataract surgical services, and Mercer et al., 2019 investigated interventions to improve gender equity. The aim of this systematic review was to collate, appraise and synthesise evidence from studies on factors associated with uptake of cataract surgery and strategies to improve the uptake in LMICs. We performed a literature search of five electronic databases, google scholar and a detailed reference review. The review identified several strategies that have been suggested to improve uptake of cataract surgery including surgical awareness campaigns; use of successfully operated persons as champions; removal of patient direct and indirect costs; regular community outreach; and ensuring high quality surgeries. Our findings provide the basis for the development of a targeted combination of interventions to improve access and ensure interventions which address barriers are included in planning cataract surgical services. Future research should seek to examine the effectiveness of these strategies and identify other relevant factors associated with intervention effects.

In Nigeria, patent and proprietary medicine vendors (PPMVs) are permitted to sell a limited range of medication. They are important providers of health care despite their limitations and may be trained to manage specific conditions, such as malaria, but not ear and eye conditions. In this study, PPMV's knowledge and management of ear and eye problems and community members health seeking behaviour were explored, as well as whether community members would access PPMVs if they were trained in primary ear and eye care. Quantitative and qualitative methods were used in a cross-sectional observation study: a survey of 1,591 adults in 40 clusters in two urban and two rural areas; 64 focus group discussions with community members and four with health professionals in two ear, nose, throat and eye clinics; in-depth interviews with ten community leaders, 11 primary health care workers, and 21 hospital staff. A check list was used to assess 36 PPMVs' facilities and structured questionnaires were administered to 36 PPMVs and 401 hospital patients in ear and eye outpatient departments. Community members reported that eye and ear problems were frequent but less common than other conditions. Health seeking behaviour was influenced by accessibility, availability, cost of medication, and trust in the provider. Most PPMVs had no formal training, had little knowledge of ear and eye conditions and were enthusiastic about being trained to manage them. Living far (>5km) from a health facility, being male, uneducated and poor were significantly associated with willingness to access PPMV after training in primary ear or eye care. PPMVs might be able to play a role in delivering primary ear and eye health care for common conditions, in collaboration with local clinicians. To do this, PPMVs would require training in eye and ear conditions and skills in their detection and counselling clients as well as reliable supply chains for medication, and skills in stock control, record keeping and facility management.

Despite the importance of labour market participation and the high number of people with disabilities in rural Africa who rely on subsistence agriculture to survive, very few studies have documented labour market outcomes among farmers with and without disabilities in Africa. We examined how labour market participation differed by disability and other factors among smallholder farmers in Western Kenya. We use cross-sectional data collected between January and April 2022 from sorghum farmers enrolled in a trial evaluating the impact of a programme designed to improve labour market participation among sorghum farmers in rural Western Kenya. Disability and Labour market outcomes were assessed using questions from the Washington Group /ILO Labor Force Survey Disability Module the ILO Labour Force Survey module respectively. Univariate and multiple regression analyses were conducted to identify socio-demographic characteristics and other related factors associated with labour market participation. Among 4459 participants, disability was reported by 20.3% of women and 12.3% of men. Labour market participation was reported by 77.1% and 81.3% of women and men, respectively. Adjusting for demographic confounders, having a disability was associated with a lower likelihood of labour market participation (odds ratio 0.59, 95% confidence interval, 0.42-0.83, P = 0.001). These findings were similar in a modified model that looked at functional difficulties separately from anxiety and depression. Women, older participants, and those who were dependent on others were also more likely not to report participation in the labour market. Increased recognition and understanding of functional limitations among smallholder farmers is vital for the success of economic empowerment programmes aimed at increasing labour market participation among the most vulnerable populations.

Atomic-resolution structure determination is crucial for understanding protein function. Cryo-EM and NMR spectroscopy both provide structural information, but currently cryo-EM does not routinely give access to atomic-level structural data, and, generally, NMR structure determination is restricted to small (<30 kDa) proteins. We introduce an integrated structure determination approach that simultaneously uses NMR and EM data to overcome the limits of each of these methods. The approach enables structure determination of the 468 kDa large dodecameric aminopeptidase TET2 to a precision and accuracy below 1 Å by combining secondary-structure information obtained from near-complete magic-angle-spinning NMR assignments of the 39 kDa-large subunits, distance restraints from backbone amides and ILV methyl groups, and a 4.1 Å resolution EM map. The resulting structure exceeds current standards of NMR and EM structure determination in terms of molecular weight and precision. Importantly, the approach is successful even in cases where only medium-resolution cryo-EM data are available. NMR structure determination is challenging for proteins with a molecular weight above 30 kDa and atomic-resolution structure determination from cryo-EM data is currently not the rule. Here the authors describe an integrated structure determination approach that simultaneously uses NMR and EM data and allows them to determine the structure of the 468 kDa dodecameric aminopeptidase TET2 complex.

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19 -MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans. Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure.

The lack of academic integrity combined with the prevalence of fraud and other forms of unethical behavior are problems that higher education faces in both developing and developed countries, at mass and elite universities, and at public and private institutions. While academic misconduct is not new, massification, internationalization, privatization, digitalization, and commercialization have placed ethical challenges higher on the agenda for many universities. Corruption in academia is particularly unfortunate, not only because the high social regard that universities have traditionally enjoyed, but also because students—young people in critical formative years—spend a significant amount of time in universities. How they experience corruption while enrolled might influence their later personal and professional behavior, the future of their country, and much more. Further, the corruption of the research enterprise is especially serious for the future of science. The contributors to Corruption in Higher Education: Global Challenges and Responses bring a range of perspectives to this critical topic.

Glioblastoma is a malignant brain tumor and one of the most lethal cancers in human. Temozolomide constitutes the standard chemotherapeutic agent, but only shows limited efficacy in glioblastoma patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter status. Recently, it has been shown that glioblastoma cells communicate via particular ion-channels—so-called gap junctions. Interestingly, inhibition of these ion channels has been reported to render MGMT promoter-methylated glioblastoma cells more susceptible for a therapy with temozolomide. However, given the percentage of about 65% of glioblastoma patients with an unmethylated MGMT promoter methylation status, this treatment strategy is limited to only a minority of glioblastoma patients. In the present study we show that—in contrast to temozolomide—pharmacological inhibition of intercellular cytosolic traffic via gap junctions reinforces the antitumoral effects of chemotherapeutic agent lomustine, independent of MGMT promoter methylation status. In view of the growing interest of lomustine in glioblastoma first and second line therapy, these findings might provide a clinically-feasible way to profoundly augment chemotherapeutic effects for all glioblastoma patients.

A number of neglected tropical diseases are targeted for elimination or eradication. An effective surveillance system is critical to determine if these goals have been achieved and maintained. Trachoma has two related but morphologically different presentations that are monitored for elimination, the active infectious form of trachoma and trachomatous trichiasis (TT), the progression of the disease. There are a number of lessons learnt from the Guinea worm surveillance system that are particularly compatible for TT surveillance and the onchocerciasis surveillance system which can provide insights for surveillance of the infectious form of trachoma. A literature search of peer-reviewed published papers and grey literature was conducted using PUBMED and Google Scholar for articles relating to dracunculiasis or Guinea worm, onchocerciasis and trachoma, along with surveillance or elimination or eradication. The abstracts of relevant papers were read and inclusion was determined based on specified inclusion and exclusion criteria. The credibility and bias of relevant papers were also critically assessed using published criteria. A total of 41 papers were identified that were eligible for inclusion into the review. The Guinea worm programme is designed around a surveillance-containment strategy and combines both active and passive surveillance approaches, with a focus on village-based surveillance and reporting. Although rumour reporting and a monetary incentive for the identification of confirmed Guinea worm cases have been reported as successful for identifying previously unknown transmission there is little unbiased evidence to support this conclusion. More rigorous evidence through a randomised controlled trial, influenced by motivational factors identified through formative research, would be necessary in order to consider applicability for TT case finding in an elimination setting. The onchocerciasis surveillance strategy focuses on active surveillance through sentinel surveillance of villages and breeding sites. It relies on an entomological component, monitoring infectivity rates of black flies and an epidemiological component, tracking exposure to infection in humans. Challenges have included the introduction of relatively complex diagnostics that are not readily available in onchocerciasis endemic countries and target thresholds, which are practically unattainable with current diagnostic tests. Although there is utility in monitoring for infection and serological markers in trachoma surveillance, it is important that adequate considerations are made to ensure evidence-based and achievable guidelines for their utility are put in place. The experiences of both the Guinea worm and onchocerciasis surveillance strategies have very useful lessons for trachoma surveillance, pre- and post-validation. The use of a monetary reward for identification of TT cases and further exploration into the use of infection and serological indicators particularly in a post-validation setting to assist in identifying recrudescence would be of particular relevance. The next step would be a real-world evaluation of their relative applicability for trachoma surveillance.

In Nigeria, patent and proprietary medicine vendors (PPMVs) are permitted to sell a limited range of medication. They are important providers of health care despite their limitations and may be trained to manage specific conditions, such as malaria, but not ear and eye conditions. In this study, PPMV's knowledge and management of ear and eye problems and community members health seeking behaviour were explored, as well as whether community members would access PPMVs if they were trained in primary ear and eye care. Quantitative and qualitative methods were used in a cross-sectional observation study: a survey of 1,591 adults in 40 clusters in two urban and two rural areas; 64 focus group discussions with community members and four with health professionals in two ear, nose, throat and eye clinics; in-depth interviews with ten community leaders, 11 primary health care workers, and 21 hospital staff. A check list was used to assess 36 PPMVs' facilities and structured questionnaires were administered to 36 PPMVs and 401 hospital patients in ear and eye outpatient departments. Community members reported that eye and ear problems were frequent but less common than other conditions. Health seeking behaviour was influenced by accessibility, availability, cost of medication, and trust in the provider. Most PPMVs had no formal training, had little knowledge of ear and eye conditions and were enthusiastic about being trained to manage them. Living far (>5km) from a health facility, being male, uneducated and poor were significantly associated with willingness to access PPMV after training in primary ear or eye care. PPMVs might be able to play a role in delivering primary ear and eye health care for common conditions, in collaboration with local clinicians. To do this, PPMVs would require training in eye and ear conditions and skills in their detection and counselling clients as well as reliable supply chains for medication, and skills in stock control, record keeping and facility management.