Systematic review to evaluate a potential association between helminth infection and physical stunting in children.

BACKGROUND: Despite considerable public health efforts over the past 20 years, childhood stunting (physical and/or cognitive) levels globally remain unacceptably high-at 22% amongst children under 5 years old in 2020. The aetiology of stunting is complex and still largely unknown. Helminths can cause significant mortality and morbidity and have often been cited as major causative agents for stunting, although their actual role in childhood stunting remains unclear. Our aim was to systematically review the current evidence to help support or refute the hypothesis that helminths cause physical stunting in children. METHODS: Inclusion criteria were as follows: infected with (and/or exposed to) helminths (soil-transmitted helminths, schistosomes or food-borne trematodes), children, pregnant or breastfeeding women as study participants (children included infants 0-1 year old, preschool-age children 1-5 years and school-age children > 5 years old), anthelmintic treatment intervention, stunting-related variables reported (e.g. height, height-for-age z-score, birth weight), helminth infection reported in relation to stunting, any geographic location, any date, peer-reviewed literature only. Exclusion criteria were: non-primary research, study protocols, studies with no new data, non-English language papers and animal (non-human) helminth studies. Seven databases were searched on 28 May 2021. Risk of bias was assessed for included studies and GRADE was used for studies included in RCT subgroup meta-analyses (in preschool-age children and pregnant women). This systematic review was registered with PROSPERO (CRD42021256201). RESULTS: Eighty studies were included in the analyses. No significant overall evidence was found in support of the hypothesis that helminths cause physical stunting in children, although there was some association with wasting. CONCLUSIONS: Whilst analyses of the available literature to date failed to support a direct association between helminth infection and childhood stunting, there was significant heterogeneity between studies, and many had follow-up periods which may have been too short to detect impacts on growth. Most apparent was a lack of available data from key demographic groups wherein one may predict the greatest association of helminth infection with stunting-notably that of infants, preschool-age children, and pregnant or nursing women. Thus this review highlights the urgent need for further targeted empirical research amongst these potentially most vulnerable demographic groups.

Nitrate sources and mixing in the Danube watershed: implications for transboundary river basin monitoring and management.

Dispersed and unknown pollution sources complicate water management in large transboundary watersheds. We applied stable isotopes of water and nitrate together with contaminants of emerging concern (CECs: carbamazepine, caffeine, sulfamethoxazole, perfluorooctanoic acid and 2,4-dinitrophenol) to evaluate mixing and inputs of water and contaminants from tributaries into the mainstem of the transboundary Danube River. Stable isotope (δ18O, δ2H) variations from low values (- 13.3 ‰, - 95.1 ‰) in the Upper Danube after the Inn River confluence to high values (- 9.9 ‰, - 69.7 ‰) at the Danube River mouth revealed snowmelt dominated tributary mixing (~ 70%) in the mainstem. Stable isotopes of nitrate (δ15N-NO3) in the Danube River varied from lower values (+ 6.7 ‰) in the Upper Danube to higher values after the mixing with Morava River (+ 10.5 ‰) and showed that cold snowmelt can reduce biological activity and controls nitrate biotransformation processes in the mainstem up to 1000 km downstream. Data on emerging contaminants affirmed the low biodegradation potential of organic compounds transferred into the mainstem by tributaries. We found pollutant source tracing in large rivers is complicated by mixing of multiple sources with overlapping isotopic signatures, but additional tracers such as CECs improve the interpretation of hydrological processes (e.g., water transit time) and support tracing of nitrate pollution sources, and biogeochemical processes. Our approach can be applied to other watersheds to improve the understanding of dilution and mixing processes. Moreover, it provides directions for improving national and transboundary water quality monitoring networks.

CEP290 gene transfer rescues Leber congenital amaurosis cellular phenotype.

Mutations in CEP290 are the most common cause of Leber congenital amaurosis (LCA), a severe inherited retinal degenerative disease for which there is currently no cure. Autosomal recessive CEP290-associated LCA is a good candidate for gene replacement therapy, and cells derived from affected individuals give researchers the ability to study human disease and therapeutic gene correction in vitro. Here we report the development of lentiviral vectors carrying full-length CEP290 for the purpose of correcting the CEP290 disease-specific phenotype in human cells. A lentiviral vector containing CMV-driven human full-length CEP290 was constructed. Following transduction of patient-specific, iPSC-derived, photoreceptor precursor cells, reverse transcriptase-PCR analysis and western blotting revealed vector-derived expression. As CEP290 is important in ciliogenesis, the ability of fibroblast cultures from CEP290-associated LCA patients to form cilia was investigated. In cultures derived from these patients, fewer cells formed cilia compared with unaffected controls. Cilia that were formed were shorter in patient-derived cells than in cells from unaffected individuals. Importantly, lentiviral delivery of CEP290 rescued the ciliogenesis defect. The successful construction and viral transfer of full-length CEP290 brings us closer to the goal of providing gene- and cell-based therapies for patients affected with this common form of LCA.

ATP11B mediates platinum resistance in ovarian cancer.

Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.

Regulation of chemokine receptor CCR5 and production of RANTES and MIP-1alpha by interferon-beta.

Trafficking of inflammatory T cells into the brain is associated with interactions of certain chemokines with their receptors, which plays an important role in the pathogenesis of multiple sclerosis (MS). We examined whether interferon-beta (IFN-beta) had the ability to regulate the production of chemokines and the expression of their receptors in T cells derived from patients with MS. It was demonstrated for the first time that in vitro exposure of T cells to IFN-beta-1a selectively inhibited mRNA expression for RANTES and MIP-1alpha and their receptor CCR5. T cell surface expression of CCR5 was significantly reduced in MS patients treated with IFN-beta, correlating with decreased T cell transmigration toward RANTES and MIP-1alpha. The study provides new evidence suggesting that IFN-beta treatment impairs chemokine-induced T cell trafficking by reducing the production of RANTES and MIP-1alpha and the expression of their receptors CCR5.

Aberrant T cell migration toward RANTES and MIP-1 alpha in patients with multiple sclerosis. Overexpression of chemokine receptor CCR5.

Trafficking of inflammatory T cells into the central nervous system (CNS) plays an important role in the pathogenesis of multiple sclerosis. The directional migratory ability of peripheral T cells is associated with interactions of chemokines with their receptors expressed on T cells. In this study, transmigration of peripheral T cells toward a panel of chemokines was examined in patients with multiple sclerosis and healthy individuals using Boyden chemotactic transwells. A significantly increased migratory rate preferentially toward RANTES and MIP-1alpha, but not other chemokines, was found in T cells obtained from multiple sclerosis patients as opposed to healthy individuals (P: < 0.001). The migratory T-cell populations represented predominantly Th1/Th0 cells while non-migratory T cells were enriched for Th2-like cells. The study demonstrated further that aberrant migration of multiple sclerosis-derived T cells toward RANTES and MIP-1 alpha resulted from overexpression of their receptors (CCR5) and could be blocked by anti-CCR5 antibodies. These findings have important implications for our understanding of the mechanism underlying aberrant T cell trafficking in multiple sclerosis.

Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta.

Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17beta (E(2)) and its catechol metabolite 4-hydroxy-E(2) (4OHE(2)) can modulate uterine gene expression in ERalpha(-/-) mice. Whereas administration of E(2) or 4OHE(2) rapidly up-regulated (4-8-fold) the expression of immunoglobulin heavy chain binding protein (Bip), calpactin I (CalP), calmodulin (CalM), and Sik similar protein (Sik-SP) genes in ovariectomized wild-type or ERalpha(-/-) mice, the expression of secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions. Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ERalpha, ERbeta, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ERalpha(-/-) uteri. Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.

Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation.

The mechanism(s) by which localized vascular permeability and angiogenesis occur at the sites of implantation is not clearly understood. Vascular endothelial growth factor (VEGF) is a key regulator of vasculogenesis during embryogenesis and angiogenesis in adult tissues. VEGF is also a vascular permeability factor. VEGF acts via two tyrosine kinase family receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). Recent evidence suggests that neuropilin-1 (NRP1), a receptor involved in neuronal cell guidance, is expressed in endothelial cells, binds to VEGF(165) and enhances the binding of VEGF(165) to VEGFR2. We examined the spatiotemporal expression of vegf isoforms, nrp1 and vegfr2 as well as their interactions in the periimplantation mouse uterus. We observed that vegf(164) is the predominant isoform in the mouse uterus. vegf(164) mRNA accumulation primarily occurred in epithelial cells on days 1 and 2 of pregnancy. On days 3 and 4, the subepithelial stroma in addition to epithelial cells exhibited accumulation of this mRNA. After the initial attachment reaction on day 5, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited distinct accumulation of vegf(164) mRNA. On days 6-8, the accumulation of this mRNA occurred in both mesometrial and antimesometrial decidual cells. These results suggest that VEGF(164) is available in mediating vascular changes and angiogenesis in the uterus during implantation and decidualization. This is consistent with coordinate expression of vegfr2, and nrp1, a VEGF(164)-specific receptor, in uterine endothelial cells. Their expression was low during the first 2 days of pregnancy followed by increases thereafter. With the initiation and progression of implantation (days 5-8), these genes were distinctly expressed in endothelial cells of the decidualizing stroma. Expression was more intense on days 6-8 at the mesometrial pole, the presumptive site of heightened angiogenesis and placentation. However, the expression was absent in the avascular primary decidual zone immediately surrounding the implanting embryo. Crosslinking experiments showed that (125)I-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells. These results suggest that VEGF(164), NRP1 and VEGFR2 play a role in VEGF-induced vascular permeability and angiogenesis in the uterus required for implantation. genesis 26:213-224, 2000.

Protective role of black tea against oxidative damage of human red blood cells.

The purpose of our study was to explore the possible scavenging property of black tea and catechins, the major flavonols of tea-leaf, against damage by oxidative stress. For this purpose, human red blood cell (rbc) was taken as the model and the oxidative damage was induced by a variety of inducers, e.g. phenylhydrazine (PHX), Cu(2+)-ascorbic acid, and xanthine/xanthine oxidase systems. Lipid peroxidation of pure erythrocyte membrane and of whole red blood cell could be completely prevented by black tea extract. Similarly, black tea provided total protection against degradation of membrane proteins. Finally, membrane fluidity studies as monitored by the fluorescent probe 1,6 diphenyl hexa 1,3,5-triene (DPH) showed considerable disorganization of its architecture that could be restored back to normal on addition of black tea or free catechins. Black tea extract in comparison to free catechins seemed to be a better protecting agent against various types of oxidative stress. Apparently, conversion of catechins to partially polymerized products such as theaflavin or thearubigin during 'fermentation' process for making black tea has no deleterious effect on its scavenging properties.

The product of maize streak virus ORF V1 is associated with secondary plasmodesmata and is first detected with the onset of viral lesions.

We have used a polyclonal antiserum derived from a bacterially expressed viral fusion protein to investigate the expression and subcellular localisation of the maize streak virus V1 product (PV1). Western blot analysis of agroinfected tissue showed that PV1 was detectable from 10 days postinoculation, coinciding with the first appearance of chlorotic viral lesions. The viral protein was only detectable in cell wall fractions of plant protein extracts. PV1 migrated with an apparent size of 14 kDa on SDS-PAGE, larger than the 10.9 kDa predicted from the amino acid sequence and therefore suggestive of posttranslational modification. Immunogold labelling located PV1 to the cell walls within lesion tissue and demonstrated a close association between the viral protein and secondary plasmodesmata. These results are consistent with the V1 product of MSV playing a role in the cell-to-cell movement of the virus in infected plants.

Inhibition of electron flow through complex I of the mitochondrial respiratory chain of Ehrlich ascites carcinoma cells by methylglyoxal.

The effect of methylglyoxal on the oxygen consumption of Ehrlich-ascites-carcinoma (EAC)-cell mitochondria was tested by using different respiratory substrates, electron donors at different segments of the mitochondrial respiratory chain and site-specific inhibitors to identify the specific respiratory complex which might be involved in the inhibitory effect of methylglyoxal on the oxygen consumption by these cells. The results indicate that methylglyoxal strongly inhibits ADP-stimulated alpha-oxo-glutarate and malate plus pyruvate-dependent respiration, whereas, at a much higher concentration, methylglyoxal fails to inhibit succinate-dependent respiration. Methylglyoxal also fails to inhibit respiration which is initiated by duroquinol, an artificial electron donor. Moreover, methylglyoxal cannot inhibit oxygen consumption when the NNN'N'-tetramethyl-p-phenylenediamine by-pass is used. The inhibitory effect of methylglyoxal is identical on both ADP-stimulated and uncoupler-stimulated respiration. Lactaldehyde, a catabolite of methylglyoxal, can exert a protective effect on the inhibition of EAC-cell mitochondrial respiration by methylglyoxal. We suggest that methylglyoxal possibly inhibits the electron flow through complex I of the EAC-cell mitochondrial respiratory chain.

Inhibition of glycolysis and mitochondrial respiration of Ehrlich ascites carcinoma cells by methylglyoxal.

The effect of methylglyoxal (MG) on the aerobic glycolysis of Ehrlich ascites carcinoma (EAC) cells has been tested. Methylglyoxal inhibited glucose utilization and glucose 6-phosphate (G6P) and L-lactate formation in whole EAC cells. Methylglyoxal strongly inactivated glyceraldehyde 3-phosphate dehydrogenase (GA3PD) of the malignant cells, whereas MG has little inactivating effect on this enzyme from several normal sources. Methylglyoxal also inactivated only the particulate hexominase of the EAC cells, but this inactivation was less pronounced than the effect on GA3PD. Methylglyoxal has little inactivating effect on glucose 6-phosphate dehydrogenase (G6PD), and no effect on L-lactate dehydrogenase (LDH) of the malignant cells. Glucose-dependent L-lactic acid formation of EAC-cell-free homogenate was strongly inhibited by MG, but when GA3PD of normal cells was added to this homogenate, significant lactate formation was observed even in the presence of MG. Methylglyoxal also inhibited the respiration of EAC-cell mitochondria. Respiration of mitochondria isolated from liver and kidney of normal mice, however, remained unaffected. As a consequence of the inhibition of glycolysis and mitochondrial respiration, the ATP level of the EAC cells was drastically reduced. Studies reported herein strongly suggest that the tumoricidal effect of MG is mediated at least in part through the inhibition of mitochondrial respiration and inactivation of GA3PD, and this enzyme may play an important role in the high glycolytic capacity of the malignant cells.

Inhibition of respiration of tumor cells by methylglyoxal and protection of inhibition by lactaldehyde.

The effect of methylglyoxal (MG), ascorbic acid and lactaldehyde has been tested on the in vitro respiration of Ehrlich ascites carcinoma (EAC) cells and several normal and malignant human tissues. Methylglyoxal inhibited the respiration of each type of malignant cell and tissue tested, but it had practically no inhibitory effect on the respiration of any of the normal cells and tissues. Ascorbic acid exhibited a synergistic effect with MG in inhibiting the respiration of all the neoplastic cells. In the presence of lactaldehyde, a catabolite of MG, the inhibitory effect of MG on the respiration of tumor cells was significantly reduced. Lactaldehyde can exert a similar protective effect on the loss of viability and transplantability of MG-treated EAC cells.