Cost analysis of establishing and operating the first human milk bank at Da Nang Hospital for Women and Children in Vietnam: an activity-based costing ingredients study.

BACKGROUND: Breastfeeding is the biological norm for feeding infants and young children. When mothers' breastmilk is unavailable, donor human milk (DHM) from a human milk bank (HMB) becomes the next option for small vulnerable newborns. A comprehensive cost analysis is essential for understanding the investments needed to establish, operate, and scale up HMBs. This study aims to estimate and analyze such costs at the first facility established in Vietnam. METHODS: An activity-based costing ingredients (ABC-I) approach was employed, with the cost perspective from service provision agencies (specifically, the project conducted at Da Nang Hospital for Women and Children and Development Partners). Estimated financial costs, based on actual expenditures, were measured in 2023 local currency and then converted to 2023 US dollars (USD). We examined three scenarios: 1) direct start-up costs + indirect start-up costs + implementation costs, 2) direct start-up costs + implementation costs, and 3) capital costs + implementation costs over the 6.5 years of operation. RESULTS: The total start-up cost was USD 616,263, with total expenditure on direct activities at USD 228,131 and indirect activities at USD 388,132. Investment in equipment accounted for the largest proportion (USD 84,213). The monthly costs of Da Nang HMB were USD 25,217, 14,565, and 9,326, corresponding to scenarios 1, 2, and 3, respectively. Over HMB's 6.5 years of operation, on average, the unit costs were USD 166, USD 96, and USD 62 for DHM received and USD 201, USD 116, and USD 74 for pasteurized DHM meeting specified criteria in the corresponding scenarios. Unit costs were highest in the initial six months, decreased, and reached their lowest levels after a year. Then, the unit costs experienced an increase in late 2020 and early 2021. CONCLUSION: Although the unit cost of DHM in Da Nang HMB is comparable to that in certain neighboring countries, intentional measures to reduce disposal rates, improve HMB efficiency, motivate more community-based donors, and establish an HMB service network should be implemented to lower costs.

Discussion of an approach to starting a JEDI inventory in a College of Pharmacy.

Problem description\The University of Nebraska College of Pharmacy is interested in conducting and learning from an inventory of Justice, Equity, Diversity, and Inclusion (JEDI) within the college. QUALITY IMPROVEMENT METHODS: An extensive literature review was undertaken to define the terms included in JEDI and to craft a listing of ideal inventory components. RESULTS OF CQI INQUIRY: The terms used in JEDI were defined and a list of 148 ideal inventory components was created. This list is further segmented by the JEDI components themselves and by five assessment factors including: representation, curriculum & education, policies & procedures, support & resources, and college climate. INTERPRETATION AND DISCUSSION: The attempt to create an ideal listing of JEDI inventory components resulted in an unusably large number of potential items. This occurred intentionally to allow the next steps in the longitudinal creation of a workable, quantifiable, and evaluative JEDI inventory process. Describing these preliminary efforts are important in the ultimate acceptance of the results of the JEDI inventory. CONCLUSION: Deliberate and extensive listing of initial aspirations for a JEDI inventory of a College of Pharmacy or any institution allows for sufficient input and breadth to help assure that no significant factor is overlooked as the process is refined.

Uncertainty-aware deep-learning model for prediction of supratentorial hematoma expansion from admission non-contrast head computed tomography scan.

Hematoma expansion (HE) is a modifiable risk factor and a potential treatment target in patients with intracerebral hemorrhage (ICH). We aimed to train and validate deep-learning models for high-confidence prediction of supratentorial ICH expansion, based on admission non-contrast head Computed Tomography (CT). Applying Monte Carlo dropout and entropy of deep-learning model predictions, we estimated the model uncertainty and identified patients at high risk of HE with high confidence. Using the receiver operating characteristics area under the curve (AUC), we compared the deep-learning model prediction performance with multivariable models based on visual markers of HE determined by expert reviewers. We randomly split a multicentric dataset of patients (4-to-1) into training/cross-validation (n = 634) versus test (n = 159) cohorts. We trained and tested separate models for prediction of ≥6 mL and ≥3 mL ICH expansion. The deep-learning models achieved an AUC = 0.81 for high-confidence prediction of HE≥6 mL and AUC = 0.80 for prediction of HE≥3 mL, which were higher than visual maker models AUC = 0.69 for HE≥6 mL (p = 0.036) and AUC = 0.68 for HE≥3 mL (p = 0.043). Our results show that fully automated deep-learning models can identify patients at risk of supratentorial ICH expansion based on admission non-contrast head CT, with high confidence, and more accurately than benchmark visual markers.

Preventing Static Biofilm Formation of Staphylococcus aureus on Different Types of Surfaces Using Microbubbles.

Bacterial fouling and biofilm formation on surfaces have been ongoing problems in real life as well as in the medical field. Different approaches have been taken to tackle the issues, from costly surface modification to antibiotic-delivering strategies. In this study, we examined the potential of using stabilized microbubbles (MBs) to shield against bacterial adhesion. Three types of surfaces were tested: hydrophilic glass (hydrophilic surface), neutral hydrophobic polystyrene (PS)-coated surfaces, and negatively charged hydrophobic octadecyltrichlorosilane (OTS)-coated surfaces. By evaluating the colony-forming unit (CFU) values from each surface, MBs stabilized by 0.05 mM SDS were shown to only produce significant reduction of Staphylococcus aureus adhesion on PS surfaces, up to 60.29 and 82.32% compared to no-MB PS surfaces, and no-MB uncoated surfaces, correspondingly, due to the appropriate size, stability, and negative charges of the MB shielding layer. On the other hand, OTS coatings had an intrinsic antiadhesion effect (69.83% compared to uncoated surface), given that the negatively charged OTS-aqueous interface or surface porosity nature of the coating prohibited the attachment of MBs, leading to the elimination of the antifouling effect of MBs. Ultimately, MBs gave better shielding results than surface modification when compared to uncoated surfaces and hence can be applied more widely.

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage.

INTRODUCTION: Perihematomal edema (PHE) represents secondary brain injury and a potential treatment target in intracerebral hemorrhage (ICH). However, studies differ on optimal PHE volume metrics as prognostic factor(s) after spontaneous, non-traumatic ICH. This study examines associations of baseline and 24-h PHE shape features with 3-month outcomes. PATIENTS AND METHODS: We included 796 patients from a multicentric trial dataset and manually segmented ICH and PHE on baseline and follow-up CTs, extracting 14 shape features. We explored the association of baseline, follow-up, difference (baseline/follow-up) and temporal rate (difference/time gap) of PHE shape changes with 3-month modified Rankin Score (mRS) - using Spearman correlation. Then, using multivariable analysis, we determined if PHE shape features independently predict outcome adjusting for patients' age, sex, NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), and hematoma volume. RESULTS: Baseline PHE maximum diameters across various planes, main axes, volume, surface, and sphericity correlated with 3-month mRS adjusting for multiple comparisons. The 24-h difference and temporal change rates of these features had significant association with outcome - but not the 24-h absolute values. In multivariable regression, baseline PHE shape sphericity (OR = 2.04, CI = 1.71-2.43) and volume (OR = 0.99, CI = 0. 98-1.0), alongside admission NIHSS (OR = 0.86, CI = 0.83-0.88), hematoma volume (OR = 0.99, CI = 0. 99-1.0), and age (OR = 0.96, CI = 0.95-0.97) were independent predictors of favorable outcomes. CONCLUSION: In acute ICH patients, PHE shape sphericity at baseline emerged as an independent prognostic factor, with a less spherical (more irregular) shape associated with worse outcome. The PHE shape features absolute values over the first 24 h provide no added prognostic value to baseline metrics.

Arsenal of nanobodies shows broad-spectrum neutralization against SARS-CoV-2 variants of concern in vitro and in vivo in hamster models.

Nanobodies offer several potential advantages over mAbs for the control of SARS-CoV-2. Their ability to access cryptic epitopes conserved across SARS-CoV-2 variants of concern (VoCs) and feasibility to engineer modular, multimeric designs, make these antibody fragments ideal candidates for developing broad-spectrum therapeutics against current and continually emerging SARS-CoV-2 VoCs. Here we describe a diverse collection of 37 anti-SARS-CoV-2 spike glycoprotein nanobodies extensively characterized as both monovalent and IgG Fc-fused bivalent modalities. The nanobodies were collectively shown to have high intrinsic affinity; high thermal, thermodynamic and aerosolization stability; broad subunit/domain specificity and cross-reactivity across existing VoCs; wide-ranging epitopic and mechanistic diversity and high and broad in vitro neutralization potencies. A select set of Fc-fused nanobodies showed high neutralization efficacies in hamster models of SARS-CoV-2 infection, reducing viral burden by up to six orders of magnitude to below detectable levels. In vivo protection was demonstrated with anti-RBD and previously unreported anti-NTD and anti-S2 nanobodies. This collection of nanobodies provides a potential therapeutic toolbox from which various cocktails or multi-paratopic formats could be built to combat multiple SARS-CoV-2 variants.

High prevalence and significant ethnic differences in actionable HbA1C after gestational diabetes mellitus in women living in Norway.

BACKGROUND: The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. METHODS: This cross-sectional study, enrolling South Asian and Nordic women 1-3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1-6.9 mmol/L, FPG 6.1-6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6-6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ2 (Pearson) tests and logistic regression models. RESULTS: We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. CONCLUSIONS: In women with GDM 1-3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening-preferably with HbA1c measurements-to facilitate early intervention after GDM.

Plastic waste as a valuable resource: strategy to remove heavy metals from wastewater in bench scale application.

Single-use plastic waste is gradually considered a potential material for circular economy. Ion exchange resin obtained from polystyrene waste by sulfonating with H2SO4 was used for heavy metal removal from electroplating wastewater. Batch mode experiments of Cu2+, Zn2+, and Cd2+ were carried out to determine effect of pH, initial concentration, equilibrium time, and the isotherm and kinetic parameters; the stability of the resin in continuous operation was then evaluated. Finally, the longevity of the resin after being exhausted was explored. The results indicated that at pH 6, a pseudo-second-order kinetic model was applicable to describe adsorption of studied heavy metals by sulfonated polystyrene with adsorption capacities of 7.48 mg Cu2+/g, 7.23 mg Zn2+/g, and 6.50 mg Cd2+/g, respectively. Moreover, the ion exchange process between sulfonated polystyrene resin and Cu2+, Zn2+, Cd2+ ions followed the Langmuir isotherm adsorption model with R2 higher than 96%. The continuous fixed-bed column in conditions of a sulfonated polystyrene mass of 500 g, and a flow rate of 2.2 L/h was investigated for an influent solution with known initial concentration of 20 mg/L. Thomas and Yoon-Nelson models were tested with regression analysis. When being exhausted, the sulfonated polystyrene was regenerated by NaCl in 10 min with ratio 5 mL of NaCl 2 M per 1 g saturated resins. After 4 times regeneration, the heavy metal removal efficiency of sulfonated polystyrene was reduced to 50%. These aforementioned results can figure out that by sulfonating polystyrene waste to synthesize ion exchanging materials, this method is technically efficient and environmentally friendly to achieve sustainability.

Adherence to hypertension and dyslipidemia treatment and its implication on control of cardiovascular disease in Vietnam: A semi-systematic review.

BACKGROUND: To understand the prevalent issues and challenges in the provision of care for dyslipidemia and hypertension in Vietnamese adults, quantification of patient journey stages (awareness, screening, diagnosis, treatment, adherence, and control) was performed in this semi-systematic review. METHODS: The EMBASE and MEDLINE databases were searched for English articles published between 2010 and 2019. Thesis abstracts, letters to the editor, editorials, case studies, and studies on patient subgroups or nationally unrepresentative studies, were excluded. Articles from Google, the Incidence and Prevalence Database, the World Health Organization, Vietnam's Ministry of Health, and those suggested by the authors were also included. The last search was run on December 10, 2019 for dyslipidemia and hypertension. RESULTS: A reviewer independently screened 586 retrievals for dyslipidemia and 177 retrievals for hypertension, and extracted data from 2 articles on dyslipidemia and 6 articles on hypertension that were included in the final synthesis. CONCLUSION: The data generated in this review will help overcome these issues and barriers to patient care in populations with these 2 conditions.

Understanding mechanisms behind unwanted health behaviours in Nordic and South Asian women and how they affect their gestational diabetes follow-ups: A qualitative study.

AIMS: The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow-up in the Nordic and South Asian women with previous GDM by comparing (1) their experiences, (2) health and disease perceptions and (3) barriers to and facilitators of health-promoting behaviours. METHODS: This qualitative study was conducted in three hospital outpatient clinics in Norway, comprising six focus group interviews with 28 women 1-3 years after a pregnancy with GDM. The participants were purposively sampled and grouped according to their ethnicity. The data were analysed using thematic analysis, and a theoretical approach was applied to support the analysis and discuss the study's findings. RESULTS: Five main themes were identified: lack of resilience, emotional distress, 'caught between a rock and a hard place', postpartum abandonment and insufficient guidance. The key determinants of the maintenance of unwanted health behaviours after GDM were consistent across the ethnic groups. Although the importance of a culturally sensitive approach was emphasised, it appeared secondary to the need for a more organised public healthcare during and after GDM. CONCLUSIONS: Women's real-life constraints, combined with the inadequate healthcare-service implementation, could explain the non-adherence to the lifestyle-changes guidelines essential for preventing diabetes post-GDM. We suggest promoting specific coping strategies and changing the healthcare service approach rather than relying on women's capacity to initiate the necessary changes.

Use of Korean dramas to facilitate precision mental health understanding and discussion for Asian Americans.

Precision mental health holds great potential for revolutionizing care and reducing the burden of mental illness. All races and ethnicities such as Asian Americans, the fastest growing racial group in the United States (U.S.), need to be engaged in precision mental health research. Owing to its global popularity, Korean drama ('K-drama') television shows may be an effective educational tool to increase precision mental health knowledge, attitudes and behaviors among Asian Americans. This qualitative study examined the participants' perspectives about and acceptance of using K-dramas to educate and engage Asian Americans about precision mental health. Twelve workshops were conducted in English, Vietnamese and Korean with a convenience sample in the San Francisco Bay Area in the U.S. (n = 122). Discussions were coded for themes. Findings revealed that all language groups reported positive reactions to using K-dramas to learn about precision health, genetics and mental health. Overall, participants shared that they learned about topics that are not generally talked about (e.g. precision health; genetic testing; mental health), from other people's perspectives, and the importance of mental health. Participants expressed how much they enjoyed the workshop, how they felt relieved due to the workshop, thought the workshop was interesting, and had an opportunity for self-reflection/healing. This pilot test demonstrated that K-dramas has promise to be used as a health educational tool in a workshop format focused on mental health among a diverse group of Asian Americans. Given the widespread access to K-dramas, they present a scalable opportunity for increasing awareness about specific health topics.

Factors associated with potential over- and undertreatment of hyperglycaemia and annual measurement of HbA1c in type 2 diabetes in norwegian general practice.

AIMS: To identify individual and general practitioner (GP) characteristics associated with potential over- and undertreatment of hyperglycaemia in type 2 diabetes and with HbA1c not being measured. METHODS: A cross-sectional study that included 10233 individuals with type 2 diabetes attending 282 GPs. Individuals with an HbA1c measurement during the last 15 months were categorized as potentially overtreated if they were prescribed a sulphonylurea and/or insulin when the HbA1c was less than 53 mmol/mol (7%) when aged over 75 years or less than 48 mmol/mol (6.5%) when aged between 65 and 75 years. Potential undertreatment was defined as age less than 60 years and HbA1c > 64 mmol/mol (8.0%) or HbA1c > 69 mmol/mol (8.5%) and treated with lifestyle modification and/or monotherapy. We used multilevel binary and multinominal logistic regression models to examine associations. RESULTS: Overall, 4.1% were potentially overtreated, 7.8% were potentially undertreated and 11% did not have HbA1c measured. Characteristics associated with potential overtreatment were as follows: long diabetes duration, prescribed antihypertensive medication, cardiovascular disease and renal failure. Potential undertreatment was associated with male gender, non-western origin and low educational level. Characteristics associated with not having an HbA1c measurement performed were male gender, age < 50 years and cardiovascular diseases. GP specialist status and GPs' use of a Noklus diabetes application reduced the risk of not having an HbA1c measurement performed. CONCLUSION: Potential overtreatment in elderly individuals with type 2 diabetes was relatively low. Nevertheless, appropriate de-intensification or intensification of treatment and regular HbA1c measurement in identified subgroups is warranted.

Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

Interleukin-6 inhibition in the management of non-infectious uveitis and beyond.

BACKGROUND: Uveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis. MAIN BODY: Pan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor. CONCLUSION: Studies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.

Probiotic Beverage From Pineapple Juice Fermented With Lactobacillus and Bifidobacterium Strains.

Pineapple is an economically significant plant and the third most important fruit crop in the tropical and subtropical regions of the world. In this study, fermentation of pineapple juice with probiotic bacteria Lactobacillus and Bifidobacterium strains as well as changes of some properties in the beverage during storage were investigated. All tested strains exhibited good growth properties on pineapple juice without supplementation of any nutrient compounds. After 24 h fermentation, the cell counts of lactobacilli passed the level of 5*109 cfu/ml, while the cell number of bifidobacteria reached a level of 109 cfu/ml. The highest volumetric productivity (3.5*108 cfu/ml*h) was observed in L. plantarum 299V. The ratios of lactic acids to acetic acids in the cases of L. plantarum 299V and L. acidophilus La5 were 5.37 and 9.91, respectively. In the case of B. lactis Bb-12, the concentrations of lactic acid and acetic acid were 6 mM and 23 mM in natural juices, and 15 and 21 mM in the case of supplementation with prebiotics at the 16th h of fermentation, respectively. Additionally, supplementation with prebiotics at the initiation of fermentation resulted 7 mM lactic acid and 23 mM acetic acid at the end of fermentation. Fructose was the most preferred sugar for both lactobacilli and bifidobacteria. Both total phenolic content and antioxidant capacity increased slightly during fermentation and dropped during the storage period. The microbial population did not change significantly during the first month of storage. After the storage period (2 months), the probiotic bacteria lost about 0.11 log cfu/ml viability after treatment with 0.3% pepsin for 135 min, and a further 0.1 log cfu/ml after treatment with 0.6% bile salts. These values were 10 times higher than data from the fresh fermented pineapple juice. Our results are very promising and may serve as a good base for developing probiotic pineapple juice.

MiR-35 buffers apoptosis thresholds in the C. elegans germline by antagonizing both MAPK and core apoptosis pathways.

Apoptosis is a genetically programmed cell death process with profound roles in development and disease. MicroRNAs modulate the expression of many proteins and are often deregulated in human diseases, such as cancer. C. elegans germ cells undergo apoptosis in response to genotoxic stress by the combined activities of the core apoptosis and MAPK pathways, but how their signalling thresholds are buffered is an open question. Here we show mir-35-42 miRNA family play a dual role in antagonizing both NDK-1, a positive regulator of MAPK signalling, and the BH3-only pro-apoptotic protein EGL-1 to regulate the magnitude of DNA damage-induced apoptosis in the C. elegans germline. We show that while miR-35 represses EGL-1 by promoting transcript degradation, repression of NDK-1 may be through sequestration of the transcript to inhibit translation. Importantly, dramatic increase in NDK-1 expression was observed in cells about to die. In the absence of miR-35, increased NDK-1 activity enhanced MAPK signalling that lead to significant increases in germ cell death. Our findings demonstrate that NDK-1 acts upstream of (or in parallel to) EGL-1, and that miR-35 targets both egl-1 and ndk-1 to fine-tune cell killing in response to genotoxic stress.

Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4+ T Cell Immunity.

T cell antigen-presenting cell (APC) interactions early during chronic viral infection are crucial for determining viral set point and disease outcome, but how and when different APC subtypes contribute to these outcomes is unclear. The TNF receptor superfamily (TNFRSF) member GITR is important for CD4+ T cell accumulation and control of chronic lymphocytic choriomeningitis virus (LCMV). We found that type I interferon (IFN-I) induced TNFSF ligands GITRL, 4-1BBL, OX40L, and CD70 predominantly on monocyte-derived APCs and CD80 and CD86 predominantly on classical dendritic cells (cDCs). Mice with hypofunctional GITRL in Lyz2+ cells had decreased LCMV-specific CD4+ T cell accumulation and increased viral load. GITR signals in CD4+ T cells occurred after priming to upregulate OX40, CD25, and chemokine receptor CX3CR1. Thus IFN-I (signal 3) induced a post-priming checkpoint (signal 4) for CD4+ T cell accumulation, revealing a division of labor between cDCs and monocyte-derived APCs in regulating T cell expansion.

Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of Azacycles.

The development of new and practical 3-pentoxythiocarbonyl auxiliaries for IrI -catalyzed C-H alkylation of azacycles is described. This method allows for the α-C-H alkylation of a variety of substituted pyrrolidines, piperidines, and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries is underscored by the ease of installation and removal, the method's utility is demonstrated in its ability to functionalize biologically relevant l-proline and l-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogues that are not accessible by other C-H functionalization methods.

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

ß-C(sp(3))-H Arylation of α-Hydroxy Acid Derivatives Utilizing Amino Acid as a Directing Group.

The Pd(II)-catalyzed arylation of unactivated ß-C(sp(3))-H bonds in α-hydroxy aliphatic acid with a variety of aryl iodides was developed utilizing an amino acid auxiliary as a directing group. This protocol provides access to biologically active ß-arylated-α-hydroxy acid derivatives.