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Thousands of human small and alternative open reading frames (smORFs and alt-ORFs, respectively) have recently been annotated. Many alt-ORFs are co-encoded with canonical proteins in multicistronic configurations, but few of their functions are known. Here, we report the detection of alt-RPL36, a protein co-encoded with human RPL36. Alt-RPL36 partially localizes to the endoplasmic reticulum, where it interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 increases plasma membrane PI(4,5)P 2 levels, upregulates PI3K-AKT-mTOR signaling, and increases cell size. Alt-RPL36 contains four phosphoserine residues, point mutations of which abolish interaction with TMEM24 and, consequently, alt-RPL36 effects on PI3K signaling and cell size. These results implicate alt-RPL36 as an upstream regulator of PI3K-AKT-mTOR signaling. More broadly, the RPL36 transcript encodes two sequence-independent polypeptides that co-regulate translation via different molecular mechanisms, expanding our knowledge of multicistronic human gene functions. Many alternative ORFs are co-encoded with characterized proteins, but their function is often not understood. Here, the authors discover that ribosomal protein L36 is co-encoded with alternative protein, which they identify as an upstream regulator of PI3K-AKT-mTOR signaling.

The triple burden of malnutrition in many low- and middle-income countries (LMICs) is partly a result of changing food environments and a shift from traditional diets to high-calorie Western-style diets. Exploring the relationship between food sources and food- and nutrition-related outcomes is important to understanding how changes in food environments may affect nutrition in LMICs. This study examined associations of household food source with household food insecurity, individual dietary diversity and individual body mass index in Western Kenya. Interview-administered questionnaire and anthropometric data from 493 adults living in 376 randomly-selected households were collected in 2019. Adjusted regression analyses were used to assess the association of food source with measures of food insecurity, dietary diversity and body mass index. Notably, participants that reported rearing domesticated animals for consumption (‘own livestock’) had lower odds of moderate or severe household food insecurity (odds ratio (OR) = 0.29 (95% CI: 0.09, 0.96)) and those that reported buying food from supermarkets had lower odds of moderate or severe household food insecurity (borderline significant, OR = 0.37 (95% CI: 0.14, 1.00)), increased dietary diversity scores (Poisson coefficient = 0.17 (95% CI: 0.10, 0.24)) and higher odds of achieving minimum dietary diversity (OR = 2.84 (95% CI: 1.79, 4.49)). Our findings provide insight into the relationship between food environments, dietary patterns and nutrition in Kenya, and suggest that interventions that influence household food source may impact the malnutrition burden in this context.

Delays in initiating cancer treatment time to treatment initiation (TTI) can negatively impact patient outcomes. This study aimed to quantify the association between TTI and survival in breast, cervical and prostate cancer patients at Inkosi Albert Luthuli Central Hospital (IALCH) in KwaZulu-Natal, South Africa, as a microcosm of Sub-Saharan Africa (SSA). We analyzed electronic medical records of patients diagnosed with breast, cervical or prostate cancer at IALCH between 2010 and 2020. Median TTI was calculated for different treatment modalities. To assess the link between treatment delay and mortality, we employed a Cox proportional hazards model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), treating breast cancer and patients over 40 as competing events. Additionally, Kruskal-Wallis one-way analysis and linear regression were used to compare TTI across racial groups. The study included patients with breast (44%), cervical (44%) and prostate cancer (12%). Mean age at diagnosis was 62.6, 56.6 and 73.0 years, respectively. Breast cancer patients experienced the longest delays for mastectomy (median 18.4 weeks), followed by prostate cancer patients waiting for radiotherapy (median 16.6 weeks). Significantly longer TTI for radiotherapy was observed in patients younger than 40 with cervical (HR = 2.30, 95% CI: 2.16-2.44, < 0.001) or prostate cancer (HR = 1.42, 95% CI: 1.03-1.95, = 0.033) compared to older breast cancer patients. Similar trends were seen for younger patients with cervical cancer receiving chemotherapy. Notably, all racial groups exhibited substantial delays in initiating treatment for all three cancers (breast < 0.001, prostate = 0.004 and cervical cancer < 0.001). This study identified significant delays in treatment initiation (TTI) for breast, prostate and cervical cancer patients at Inkosi Albert Luthuli Central Hospital (IALCH) in South Africa. These delays were concerning, particularly for younger patients and individuals across all racial backgrounds. Delays in treatment initiation have been linked to increased mortality risk in other studies, highlighting the urgency of addressing this issue. Furthermore, this study serves as a valuable model for future research throughout SSA to collectively address the challenges of treatment delays and improve cancer care for the region.

The rising cancer incidence and mortality in sub-Saharan Africa (SSA) warrants an increased focus on adopting or developing approaches that can significantly increase access to treatment in the region. One such approach recommended by the recent Lancet Oncology Commission for sub-Saharan Africa is hypofractionated radiotherapy (HFRT), which can substantially increase access to radiotherapy by reducing the overall duration of time (in days) each person spends being treated. Here we highlight challenges in adopting such an approach identified during the implementation of the HypoAfrica clinical trial. The HypoAfrica clinical trial is a longitudinal, multicentre study exploring the feasibility of applying HFRT for prostate cancer in SSA. This study has presented an opportunity for a pragmatic assessment of potential barriers and facilitators to adopting HFRT. Our results highlight three key challenges: quality assurance, study harmonisation and machine maintenance. We describe solutions employed to resolve these challenges and opportunities for longer term solutions that can facilitate scaling-up use of HFRT in SSA in clinical care and multicentre clinical trials. This report provides a valuable reference for the utilisation of radiotherapy approaches that increase access to treatment and the conduct of high-quality large-scale/multi-centre clinical trials involving radiotherapy. Not available yet.

Abstract Thousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, and hundreds are now known to be required for cell proliferation. Many alt-ORFs are co-encoded with proteins of known function in multicistronic human genes, but the functions of only a handful are currently known in molecular detail. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36 (ribosomal protein L36). Alt-RPL36 partially localizes to the endoplasmic reticulum, where it interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increases PI(4,5)P2 levels in the plasma membrane, upregulates the PI3K-AKT-mTOR signaling pathway, and increases cell size. Four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolishes interaction with TMEM24 and, consequently, abolishes alt-RPL36 effects on PI3K signaling and cell size. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2 synthesis upstream of the PI3K-AKT-mTOR signaling pathway. More broadly, these results show that the alt-RPL36 transcript can express two sequence-independent polypeptides from overlapping ORFs that regulate the same process – protein synthesis – via different molecular mechanisms (PI3K signaling and ribosome composition), expanding our knowledge of the mechanisms by which multicistronic human genes function. Competing Interest Statement The authors have declared no competing interest. Footnotes * Figures 2, 6, 7 and 8 revised. Supplemental files updated.

The presence of emerging contaminants such as pharmaceutical and personal care products in many aqueous matrices have been reported. One of such matrix is streams of wastewater, including wastewater treatment plants inflows and outflows and wastewater flow by-passing wastewater treatment plants. Their persistence arises from their resistant to breakdown, hence they may remain in the environment over long time, with a potential to cause adverse effects including endocrine disruption, gene toxicity, the imposition of sex organs, antibiotic resistance and many others in some aquatic organisms exposed to arrays of residues of pharmaceutical and personal care products. Among the treatment techniques, advanced oxidation processes have been reported to be a better technique through which these PPCPs can be degraded in the WWTPs. Heterogeneous photocatalysis using various photocatalyst immobilized on solid support such as activated carbon, graphene and carbon nanotubes in AOPs have been shown to be a viable and efficient method of PPCPs degradation. This is because, the performance of most WWTPs is limited since they were not designed to degrade toxic and recalcitrant PPCPs. This review highlight the occurrence, concentration of PPCPs in wastewater and the removal efficiency of heterogeneous photocatalysis of TiO2 immobilized on solid supports.

In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced. Asthma is associated with mucus overproduction; however, the immunological consequences of excess mucus remain poorly understood. Here the authors show that formation of airway plugs by mucus promotes airway hypersensitivity, while deletion of mucous component Muc5ac ablates it independently of inflammation.

Antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) and other viral infections are among the emerging contaminants considered for ecological risk assessment. These compounds have been reported to be widely distributed in water bodies and other aquatic environments, while data concerning the risk they may pose to unintended non-target species in a different ecosystem (environment) is scanty. In South Africa and other developing countries, lamivudine is one of the common antiretrovirals applied. Despite this, little is known about its environmental impacts as an emerging contaminant. The present study employed a battery of ecotoxicity bioassays to assess the environmental threat lamivudine poses to aquatic fauna and flora. Daphnia magna (filter feeders), the Ames bacterial mutagenicity test, Lactuca sativa (lettuce) germination test, and the Allium cepa root tip assay were conducted, testing lamivudine at two concentrations (10 and 100 µg/L), with environmental relevance. The Daphnia magna toxicity test revealed a statistically significant response (p << 0.05) with a mortality rate of 85% on exposure to 100 µg/L lamivudine in freshwater, which increased to 100% at 48-h exposure. At lower concentrations of 10 µg/L lamivudine, 90% and 55% survival rates were observed at 24 h and 48 h, respectively. No potential mutagenic effects were observed from the Ames test at both concentrations of lamivudine. Allium cepa bioassays revealed a noticeable adverse impact on the root lengths on exposure to 100 µg/L lamivudine. This impact was further investigated through microscopic examination, revealing some chromosomal aberration in the exposed Allium cepa root tips. The Lactuca sativa bioassay showed a slight adverse impact on both the germination rate of the seeds and their respective hypocotyl lengths compared to the control. Overall, this indicates that lamivudine poses an ecological health risk at different trophic levels, to both flora and fauna, at concentrations previously found in the environment.

Environmental effects of active pharmaceutical compounds (APCs) in the environment are not well characterized, hence the need for comprehensive evaluation. This study employed three bioassays using three organisms, namely, Allium cepa , Daphnia magna , and Salmonella typhimurium , in the ecotoxicity study of lone and a mixture of selected APCs, namely, lamivudine (L), an antiretroviral, and ciprofloxacin (C) and sulfamethoxazole (S), antibiotics, at a concentration range between 10 and 100 ppb, in order to evaluate the potential of the lone and ternary mixture to exert synergistic toxicity. Study results from exposure to lone APCs showed that the L, C, and S trio individually had fatal impacts on daphnids, with mortality rates of 100, 75, and 95%, respectively, after 48 h. Sulfamethoxazole showed a mutagenic tendency, with a mutation ratio (background/sample ratio) of 2.0. Lamivudine showed a lethal impact on the root length of A. cepa ( p  > 0.05, p  = 3.60E–3). Further microscopic examination of the A. cepa root tip revealed chromosomal aberrations on exposure to each compound. The LCS-mix ecotoxicology bioassays indicated a synergistic effect on the daphnids, probably due to potentiation. Although the LCS mix had a cytotoxic effect (evidenced by the absence of bacteria colonies) on exposed TA 98 P450 Salmonella typhimurium strain, this effect was not observed in other bacterial strains. Microscopic examination of A. cepa exposed to the LCS-mix revealed an aberration in the mitotic stage of the cell. The impact of combination of the pharmaceuticals in aqueous ecosystems was greater than when exposed to the tested individual pharmaceutical compounds. Study result showed that these compounds have tendencies to pose a higher risk to exposed living entities when in combined/potentiated forms, and this could lead to distortion of the regular functioning of the ecosystem, particularly bacterial and other microbial populations that are listed among primary producers of the aquatic food web.

Metal-organic frameworks (MOFs) constructed using Fe (III) ion and benzene-1,3,5-tricarboxylate ligand by a solvent-based method and formulated as [Fe3(btc)2] is herein reported. The synthesized compound was characterized by powder X-ray diffraction (PXRD), Braunuer Emmet Teller (BET) analysis, and Scanning Electron Microscope (SEM). The diffraction pattern of the drug-loaded MOFs showed the appearance of new peaks and a decrease in the intensity of some peaks. The BET pore volume of synthesized [Fe3(btc)2] and [Fe3(btc)2]@COD` were 0.290cc g−1 and 0.059 cc g−1 respectively while the BET surface area of synthesized [Fe3(btc)2] and [Fe3(btc)2]@COD` were 849.63 m2 g−1 and 203.4 m2 g−1 respectively confirming the incorporation of codeine into [Fe3(btc)2], the BET analysis confirmed that the codeine was loaded into the pore cavity of [Fe3(btc)2]. The [Fe3(btc)2] was observed to encapsulate 249 mg of codeine drug per 200 mg of [Fe3(btc)2], with a loading efficiency of 91%. Binding energy calculations (DFT) revealed strong interactions, with HOMO localized on codeine and LUMO on trimesic acid, reducing the HOMO-LUMO gap from 5.3 eV (MOF) to 4.19 eV (MOF-Codeine). Molecular dynamics (100 ns) showed stable codeine binding via hydrogen bonding and π-cation interactions, enhanced by water-mediated effects. Molecular docking confirmed stronger binding affinity for codeine (Glide score: -4.349 kcal/mol) compared to nitrogen (-2.632 kcal/mol), attributed to hydrogen bonding and π-cation interactions. These results highlight [Fe₃(btc)₂] as a promising drug delivery system with high loading capacity and stable host-guest interactions.