Inositol polyphosphate multikinase modulates redox signaling through nuclear factor erythroid 2-related factor 2 and glutathione metabolism.

Maintenance of redox balance plays central roles in a plethora of signaling processes. Although physiological levels of reactive oxygen and nitrogen species are crucial for functioning of certain signaling pathways, excessive production of free radicals and oxidants can damage cell components. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade is the key pathway that mediates cellular response to oxidative stress. It is controlled at multiple levels, which serve to maintain redox homeostasis within cells. We show here that inositol polyphosphate multikinase (IPMK) is a modulator of Nrf2 signaling. IPMK binds Nrf2 and attenuates activation and expression of Nrf2 target genes. Furthermore, depletion of IPMK leads to elevated glutathione and cysteine levels, resulting in increased resistance to oxidants. Accordingly, targeting IPMK may restore redox balance under conditions of cysteine and glutathione insufficiency.

Antimicrobial Resistance and Virulence Gene Profile of Clinical Staphylococcus aureus: A Multi-Center Study from Ethiopia.

Background: Staphylococcus aureus causes a wide range of infections from mild skin and soft tissue to severe life-threatening bacteremia. The pathogenicity of S. aureus infections is related to various bacterial surface components and extracellular proteins such as toxic-shock syndrome (TSS) toxin and Panton-Valentine leukocidin (PVL). In this study we determine the antimicrobial resistance of isolated strains and their virulence genes in Ethiopia. Methods: A total of 190 archived S. aureus isolates from four Ethiopia Antimicrobial Resistance (AMR) Surveillance sites were analyzed. The identification of S. aureus was done by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF Biotyper) and antimicrobial susceptibility test (AST) was done using VITEK® 2. Multiplex PCR was used to detect mecA, mecC, pvl and spa genes and super-antigens (sea, seb, sec, seh and sej staphylococcal enterotoxins). Results: A total of 172 isolates were confirmed as S. aureus, 9 (5.23%) were methicillin-resistant S. aureus (MRSA) and 163 (94.76%) were methicillin-susceptible S. aureus (MSSA). AST showed that 152 (88.4%) isolates were resistant to penicillin; 90 (52.32%) resistant to trimethoprim-sulfamethoxazole; and 45 (26.16%) resistant to tetracycline. A total of 66 (38.37%) isolates harbored at least one staphylococcal enterotoxin gene and 31 (46.96%) isolates had more than one. The most frequent enterotoxin gene encountered was seb 28 (16.28%). The TSST-1 gene was detected in 23 (13.37%). Presence of staphylococcal enterotoxin gene showed significant association with antibiotic resistance to cefoxitin, benzylpenicillin, oxacillin, erythromycin, clindamycin, tetracycline and SXT. The pvl gene was detected in 102 (59.3%) of isolates. Isolates from patients below 15 years of age showed significantly high numbers of pvl gene (P = 0.02). Presence of sej (P = 0.011) and TSST-1 (P <0.001) genes were associated with the presence of pvl gene. Conclusion: In this study, isolates were highly resistant to oral antibiotics and the pvl, seb, sea and TSST-1 genes were prevalent.

Clonal diversity of Staphylococcus aureus isolates in clinical specimens from selected health facilities in Ethiopia.

Staphylococcus aureus is among the top three causative agents of nosocomial infection in Ethiopia. The majority of studies in Ethiopia have focused on the epidemiology of S. aureus in hospital settings, with limited molecular genotyping results. Molecular characterization of S. aureus is essential for identification of strains, and contributes to the control and prevention of S. aureus infection. The aim of the current study was to determine the molecular epidemiology of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates recovered from clinical specimens in Ethiopia. A total of 161 MSSA and 9 MRSA isolates were characterized using pulsed-field gel electrophoresis (PFGE) and staphylococcal protein A (spa) typing. Based on the PFGE analysis, MSSA isolates were grouped into eight pulso-types groups (from A to I), while MRSA isolates clustered into three (A, B and C) pulso-types with more than 80% similarity. The spa typing analysis showed diversity of S. aureus with 56 distinct spa types. Spa type t355 was most prevalent (56/170, 32.9%), while eleven new spa types were detected including t20038, t20039, and t20042. The identified spa types were clustered into 15 spa-clonal complexes (spa-CCs) using BURP analysis; novel/unknown spa types were further subjected to MLST analysis. The majority of isolates belonged to spa-CC 152 (62/170, 36.4%), followed by spa-CC 121 (19/170, 11.2%), and spa-CC 005 (18 /170, 10.6%). Of the nine MRSA isolates, 2 (22.2%) were spa-CC 239 with staphylococcal cassette chromosome (SCC)mec III. These findings highlight the diversity of S. aureus strains in Ethiopia, as well as the presence of potentially epidemic strains circulating in the country necessitating further characterization of S. aureus for antimicrobial resistance detection and infection prevention purposes.

Serine Racemase mediates subventricular zone neurogenesis via fatty acid metabolism.

The adult subventricular zone (SVZ) is a neurogenic niche that continuously produces newborn neurons. Here we show that serine racemase (SR), an enzyme that catalyzes the racemization of L-serine to D-serine and vice versa, affects neurogenesis in the adult SVZ by controlling de novo fatty acid synthesis. Germline and conditional deletion of SR (nestin precursor cells) leads to diminished neurogenesis in the SVZ. Nestin-cre+ mice showed reduced expression of fatty acid synthase and its substrate malonyl-CoA, which are involved in de novo fatty acid synthesis. Global lipidomic analyses revealed significant alterations in different lipid subclasses in nestin-cre+ mice. Decrease in fatty acid synthesis was mediated by phospho Acetyl-CoA Carboxylase that was AMP-activated protein kinase independent. Both L- and D-serine supplementation rescued defects in SVZ neurogenesis, proliferation, and levels of malonyl-CoA in vitro. Our work shows that SR affects adult neurogenesis in the SVZ via lipid metabolism.

Loss of PI3k activity of inositol polyphosphate multikinase impairs PDK1-mediated AKT activation, cell migration, and intestinal homeostasis.

Protein kinase B (AKT) is essential for cell survival, proliferation, and migration and has been associated with several diseases. Here, we demonstrate that inositol polyphosphate multikinase (IPMK's) lipid kinase property drives AKT activation via increasing membrane localization and activation of PDK1 (3-Phosphoinositide-dependent kinase 1), largely independent of class I PI3k (cPI3K). Deletion of IPMK impairs cell migration, which is partially associated with the abolition of PDK1-mediated ROCK1 disinhibition and subsequent myosin light chain (MLC) phosphorylation. IPMK is highly expressed in intestinal epithelial cells (IEC). Deleting IPMK in IEC reduced AKT phosphorylation and diminished the number of Paneth cells. Ablation of IPMK impaired IEC regeneration both basally and after chemotherapy-induced damage, suggesting a broad role for IPMK in activating AKT and intestinal tissue regeneration. In conclusion, the PI3k activity of IPMK is necessary for PDK1-mediated AKT activation and intestinal homeostasis.

An Arsenal of Multiple Antimicrobial Resistance, Toxins, and Virulence Factors in Gram-Negative Bacterial Isolates from Food - A Formidable Combination!

Background: Infectious diseases caused by pathogenic members of the family Enterobacteriaceae cause mortality and morbidity in humans. These are mediated mainly via toxins or virulence factors in combination with multiple antimicrobial resistance (MAR) against antimicrobials intended to treat infections. Resistance can be transferred to other bacteria, possibly also in association with other resistance determinants and/or virulence properties. Food-borne bacterial infections are one of the major causes of infections in humans. The level of scientific information about foodborne bacterial infections in Ethiopia is very limited at best. Methods: Bacteria were isolated from commercial dairy foods. These were cultured in appropriate media for identification at the family level (Enterobacteriaceae) based on Gram-negative, catalase-positive, oxidase-negative, and urease-negative phenotypes, followed by testing for the presence of virulence factors and resistance determinants to various antimicrobial classes using phenotypic and molecular tests. Results: Twenty Gram-negative bacteria isolated from the foods were found to be resistant to almost all antimicrobials belonging to the phenicol, aminoglycoside, fluoroquinolone, monobactam, and ß-lactam classes. All of them were multiple-drug-resistant. The resistance to the ß-lactams was due to the production of ß-lactamases and were also mostly resistant to some of the ß-lactam/ß-lactamase inhibitor combinations. Some isolates also contained toxins. Conclusion: This small-scale study demonstrated the presence, in the isolates, of high levels of virulence factors and resistance to major antimicrobials that are in clinical use. Most treatment being empirical, there can be not only a high degree of treatment failure but also the likelihood for further development and dissemination of antimicrobial resistance. Since dairy foods are animal products, there is an urgent need to control animal-food-human transmission mechanisms, restrict antimicrobial use in animal agriculture, and improve clinical treatment from the usual empirical treatment to more targeted and effective treatment.

The pandemic is not the great equalizer: front-line labor and rationing in COVID-19 critical care.

BACKGROUND: Framed as "the great-equalizer," the COVID-19 pandemic has intensified pressure to adapt critical care labor and resulted in rationing by healthcare workers across the world. OBJECTIVE: To critically investigate how hospital intensive care units are critical sites of care labor and examine how rationing highlights key features of healthcare labor and its inequalities. METHODS: A practice-oriented ethnographic study was conducted in a United States academic ICU by a medical anthropologist and medical intensivists with global health expertise. The analysis drew on 57 in-depth interviews and 25 months of participant observation between 2020 and 2021. RESULTS: Embodied labor constitutes sites and practices of shortage or rationing along three domains: equipment and technology, labor, and emotions and energy. The resulting workers' practices of adaptation and resilience point to a potentially more robust global health labor politics based on seeing rationing as work. CONCLUSION: Studies of pandemic rationing practices and critical care labor can disrupt too-simple comparative narratives of Global North/South divides. Further studies and efforts must address the toll of healthcare labor.

CONTEXTE: Présentée comme « le grand égalisateur ¼, la pandémie de COVID-19 a accentué la pression pour adapter le travail des soins intensifs et a entraîné le rationnement des travailleurs de la santé dans le monde entier. OBJECTIF: Étudier de manière critique comment les unités de soins intensifs des hôpitaux sont des sites critiques dans le système de santé et examiner comment le rationnement met en évidence les caractéristiques clés du travail de la santé et ses inégalités. MÉTHODES: Une étude ethnographique axée sur la pratique a été menée dans une unité de soins intensifs universitaire des États-Unis par un anthropologue médical et des médecins intensivistes spécialisés dans la santé mondiale. L'analyse s'est appuyée sur 57 entretiens approfondis et 25 mois d'observation participante entre 2020 et 2021. RÉSULTATS: Le travail incarné constitue des sites et des pratiques de pénurie ou de rationnement le long de trois domaines : équipement et technologie, travail, émotions et énergie. Les pratiques d'adaptation et de résilience des travailleurs qui en résultent indiquent une politique du travail potentiellement plus robuste dans le domaine de la santé mondiale, fondée sur une vision du rationnement en tant que travail. CONCLUSION: Les études sur les pratiques de rationnement en cas de pandémie et sur le travail dans le domaine des soins intensifs peuvent perturber les récits comparatifs trop simples des divisions Nord/Sud. D'autres études et efforts doivent porter sur le coût du travail dans le secteur des soins de santé.

Tuberculosis in individuals who recovered from COVID-19: A systematic review of case reports.

BACKGROUND: The emergence of COVID-19 overwhelmed tuberculosis (TB) prevention and control, resulting in a decrease in TB detection rate and an increase in TB deaths. Furthermore, the temporary immunosuppressive effects, lung inflammation, and the corticosteroids used to treat COVID-19, may play a direct role in immunosuppression, leading to reactivation of either previous infection or latent TB or the development of new TB. Thus, the aim of this study was to review TB incidence in individuals who recovered from COVID-19. METHODS: We conducted a systematic search of available databases for previously published studies that reported TB in COVID-19 survivors. The PRISMA checklist was used to guide the review, and the JBI checklist was used to evaluate the study's quality. The descriptive data were summarized. RESULTS: Data were extracted from 21 studies conducted in 13 countries having 33 cases. The median age was 44 years (range; 13.5-80), and more than half (18, 54.5%) were males. Twelve patients immigrated from TB endemic settings. All 17 patients assessed for HIV were seronegative, and all 11 patients assessed for BCG vaccination status were vaccinated. The majority (20, 69%) of patients had some type of comorbidity with diabetes (12/29) and hypertension (9/29) being the most common. Four patients (30.77%) had a history of TB. Corticosteroids were used to treat COVID-19 in 62.5% (10) of individuals. Dexamethasone, remdesivir, azithromycin, hydroxychloroquine, and enoxaparin were the most commonly used drugs to treat COVID-19. The most common TB symptoms were fever, cough, weight loss, dyspnea, and fatigue. Twenty, eleven, and two patients developed pulmonary, extrapulmonary, and disseminated/miliary TB respectively. It may take up to seven months after COVID-19 recovery to develop tuberculosis. Data on the final treatment outcome was found for 24 patients, and five patients died during the anti-TB treatment period. CONCLUSION: Tuberculosis after recovering from COVID-19 is becoming more common, potentially leading to a TB outbreak in the post-COVID-19 era. The immunosuppressive nature of the disease and its treatment modalities may contribute to post COVID-19 TB. Thus, we recommend a further study with a large sample size. Furthermore, we recommend feasibility studies to assess and treat latent TB in COVID-19 patients residing in TB endemic counties since treatment of latent TB is done only in TB non-endemic countries.

A Novel Stereospecific Bioluminescent Assay for Detection of Endogenous d-Cysteine.

The presence of endogenous d-stereoisomers of amino acids in mammals dispels a long-standing dogma about their existence. d-Serine and d-aspartate function as novel neurotransmitters in mammals. However, the stereoisomer with the fastest, spontaneous in vitro racemization rate, d-cysteine, has not been reported. We utilized a novel, stereospecific, bioluminescent assay to identify endogenous d-cysteine in substantial amounts in the eye, brain, and pancreas of mice. d-Cysteine is enriched in mice embryonic brains at day E9.5 (4.5 mM) and decreases progressively with development (µM levels). d-Cysteine is also present in significantly higher amounts in the human brain white matter compared with gray matter. In the luciferase assay, d-cysteine conjugates with cyano hydroxy benzothiazole in the presence of a base and reducing agent to form d-luciferin. d-Luciferin, subsequently, in the presence of firefly luciferase and ATP, emits bioluminescence proportional to the concentration of d-cysteine. The assay is stereospecific and allows the quantitative estimation of endogenous d-cysteine in tissues in addition to its specificity for d-cysteine. Future efforts aimed at bioluminescent in vivo imaging of d-cysteine may allow a more noninvasive means of its detection, thereby elucidating its function.

Mutant Huntingtin Derails Cysteine Metabolism in Huntington's Disease at Both Transcriptional and Post-Translational Levels.

Cysteine is a semi-essential amino acid that not only plays an essential role as a component of protein synthesis, but also in the generation of numerous sulfur-containing molecules such as the antioxidant glutathione and coenzyme A. We previously showed that the metabolism of cysteine is dysregulated in Huntington's disease (HD), a neurodegenerative disorder triggered by the expansion of polyglutamine repeats in the protein huntingtin. In this study, we showed that cysteine metabolism is compromised at multiple levels in HD, both transcriptional and post-translational. Accordingly, restoring cysteine homeostasis may be beneficial in HD.

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Atroposelective Total Synthesis of Darobactin A.

A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-based macrocyclizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late stage. Requisite unnatural amino acid building blocks are easily prepared in an enantiopure form using C-H activation and decarboxylative cross-coupling tactics.

Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.

Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth-/- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth-/- mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity, the neuronal process of adapting to diverse and variable inputs, depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR-/-) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the N-methyl-d-aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.

A high-affinity cocaine binding site associated with the brain acid soluble protein 1.

Cocaine exerts its stimulant effect by inhibiting dopamine (DA) reuptake, leading to increased dopamine signaling. This action is thought to reflect the binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share cocaine's behavioral actions. Further, recent reports show more potent actions of the drug, implying the existence of a high-affinity receptor for cocaine. We now report high-affinity binding of cocaine associated with the brain acid soluble protein 1 (BASP1) with a dissociation constant (Kd) of 7 nM. Knocking down BASP1 in the striatum inhibits [3H]cocaine binding to striatal synaptosomes. Depleting BASP1 in the nucleus accumbens but not the dorsal striatum diminishes locomotor stimulation in mice. Our findings imply that BASP1 is a pharmacologically relevant receptor for cocaine.

Mammalian D-cysteine: A novel regulator of neural progenitor cell proliferation Mammalian D-cysteine: A novel regulator of neural progenitor cell proliferation Endogenous D-cysteine, the stereoisomer with rapid spontaneous in vitro racemization rate, has major neural roles

D-amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D-cysteine in mammalian brain. D-cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D-cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D-cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D-cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D-cysteine inhibits AKT phosphorylation at Thr 308 and Ser 473 in NPCs. D-cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D-cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D-cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD).

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Pandemic: Are Africa's Prevalence and Mortality Rates Relatively Low?

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease 19 (COVID-19), has been rapidly spreading since December 2019, and within a few months, it turned out to be a global pandemic. The disease affects primarily the lungs, but its pathogenesis spreads to other organs as well. However, its mortality rates vary, and in the majority of infected people, there are no serious consequences. Many factors including advanced age, preexisting health conditions, and genetic predispositions are believed to exacerbate outcomes of COVID-19. The virus contains several structural proteins including the spike (S) protein with subunits for binding, fusion, and internalization into host cells following interaction with host cell receptors and proteases (ACE2 and TMPRSS2, respectively) to cause the subsequent pathology. Although the pandemic has spread into all countries, most of Africa is thought of as having relatively less prevalence and mortality. Several hypotheses have been forwarded as reasons for this and include warmer weather conditions, vaccination with BCG (i.e., trained immunity), and previous malaria infection. From genetics or metabolic points of view, it has been proposed that most African populations could be protected to some degree because they lack some genetic susceptibility risk factors or have low-level expression of allelic variants, such as ACE2 and TMPRSS2 that are thought to be involved in increased infection risk or disease severity. The frequency of occurrence of α-1 antitrypsin (an inhibitor of a tissue-degrading protease, thereby protecting target host tissues including the lung) deficiency is also reported to be low in most African populations. More recently, infections in Africa appear to be on the rise. In general, there are few studies on the epidemiology and pathogenesis of the disease in African contexts, and the overall costs and human life losses due to the pandemic in Africa will be determined by all factors and conditions interacting in complex ways.

Inositol hexakisphosphate kinase-2 non-catalytically regulates mitophagy by attenuating PINK1 signaling.

Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in various cellular functions including neuroprotection. Absence of IP6K2 causes impairment of oxidative phosphorylation regulated by creatine kinase-B. In the present study, we show that IP6K2 is involved in attenuation of PINK1-mediated mitochondrial autophagy (mitophagy) in the brain. Up-regulation of dynamin-related protein (Drp-1), as well as increased expression of mitochondrial biogenesis markers (PGC1-α and NRF-1) in the cerebella of IP6K2-deleted mice (IP6K2-knockout), point to the involvement of IP6K2 in the regulation of mitochondrial fission. Knockdown of IP6K2 also leads to augmented glycolysis, potentially as a compensatory mechanism for decreased mitochondrial respiration. Overexpressing IP6K2 as well as IP6K2-kinase dead mutant in IP6K2-knockdown N2A cells reverses the expression of mitophagy markers, demonstrating that IP6K2-induced mitoprotection is catalytically/kinase independent. IP6K2 supplementation in K2-PINK1 double-knockdown N2A cells fails to reverse the expression of the mitophagic marker, LC3-II, indicating that the mitoprotective effect of IP6K2 is dependent on PINK1. Overall, our study reveals a key neuroprotective role of IP6K2 in the prevention of PINK1-mediated mitophagy in the brain.

Exploring the patterns of multisectoral approach in fighting COVID-19 Pandemic in SNNPR, Ethiopia: A qualitative case study approach.

BACKGROUND: Since COVID-19 has been declared as a global pandemic, South Nations, Nationalities People's Region, Ethiopia, has been responding by establishing strong structure. The response against the disease requires consolidated efforts, However, there is paucity of information about the patterns of multisectoral collaboration actions in the region. Therefore, this study was conducted with the aim of exploring the patterns of multisectoral collaboration against the COVID-19 using a qualitative case study design. Data were collected by key informant interview and document review and analyzed using a content analysis framework focused on case study data analysis. RESULT: The study has indicated a unique perspective in establishing functional multisectoral approach with strong courage and motivation of most involved stakeholder. Almost all stakeholders have shown clear understanding about the multidimensional burdens the disease could cause and the necessities for joint efforts to tackle the multidimensional problems. The study further elucidated that despite the encouraging beginning, the eventual slowdown undertakings in the joint actions. This included failure to meet regularly to monitor and evaluate as stated earlier and societies' reluctances despite consistent information dissemination. CONCLUSION: A firm understanding about multidimensional impacts of COVID-19 by all stakeholders was revealed in the region. Remarkable achievements were observed at the early stage of disease prevention and control responses with encouraging multisectoral approach as guided by the convergence model. However, several setbacks were observed in the process of multisectoral approach intervention as indicated by the conceptual framework. Hence, to ensure sustainable MSA, revitalization of the initial commitment of all stakeholders and strengthening MSA considering end-to end approach of the convergence frame is crucial; subsequent quantitative study recommended to establish wider determinants on success of MSA.

Cost-effectiveness of pulse oximetry and integrated management of childhood illness for diagnosing severe pneumonia.

Pneumonia is a major killer of children younger than five years old. In resource constrained health facilities, the capacity to diagnose severe pneumonia is low. Therefore, it is important to identify technologies that improve the diagnosis of severe pneumonia at the lowest incremental cost. The objective of this study was to conduct a health economic evaluation of standard integrated management of childhood illnesses (IMCI) guideline alone and combined use of standard IMCI guideline and pulse oximetry in diagnosing childhood pneumonia. This is a cluster-randomized controlled trial conducted in health centres in southern Ethiopia. Two methods of diagnosing pneumonia in children younger than five years old at 24 health centres are analysed. In the intervention arm, combined use of the pulse oximetry and standard IMCI guideline was used. In the control arm, the standard IMCI guideline alone was used. The primary outcome was cases of diagnosed severe pneumonia. Provider and patient costs were collected. A probabilistic decision tree was used in analysis of primary trial data to get incremental cost per case of diagnosed severe pneumonia. The proportion of children diagnosed with severe pneumonia was 148/928 (16.0%) in the intervention arm and 34/876 (4.0%) in the control arm. The average cost per diagnosed severe pneumonia case was USD 25.74 for combined use of pulse oximetry and standard IMCI guideline and USD 17.98 for standard IMCI guideline alone. The incremental cost of combined use of IMCI and pulse oximetry was USD 29 per extra diagnosed severe pneumonia case compared to standard IMCI guideline alone. Adding pulse oximetry to the diagnostic toolkit in the standard IMCI guideline could detect and treat one more child with severe pneumonia for an additional investment of USD 29. Better diagnostic tools for lower respiratory infections are important in resource-constrained settings, especially now during the COVID-19 pandemic.