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Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Published version The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272.

Background and aim Plantago major has long been used for medical purposes in Indonesia. However, reports on the anti-arthritic activities of P. major are limited. Experimental procedure The anti-arthritic properties of an n-hexane-insoluble fraction of dichloromethane extracts of P. major (IPM) were evaluated using Complete Freund's Adjuvant (CFA)-induced arthritis induced in female Wistar rat by CFA. Diclofenac was used as a positive control. The volume of paw oedema, white blood cell count, lymphocytes, neutrophils, expression of TNF-α and Interleukin-6 and the histopathological features of the joint tissues were assessed to characterise IPM activity. Results The IPM extract at doses of 280 and 420 mg/kg BW and diclofenac inhibited paw oedema by 15.70 %, 15.94 % and 19.71 % respectively. IPM also reduced the incidence of arthritis and arthritic index. Unlike untreated rats, animals treated with IPM showed a significant decrease in the number of neutrophils and decreased expression of TNF-α and Interleukin-6. Histopathological examination showed a reduction in the number of inflammatory cells and hyperplasia of the synovium after IPM treatment. Conclusion This study showed that P. major displays anti-rheumatoid arthritis activity.

The purpose of this study was to determine the antioxidant activity of crude extract and their fractions, the content of secondary metabolite types of crude extract, and the chemical content and toxicity of the most active fractions as antioxidants from the stem bark of Artocarpus anisophyllus Miq. (Mentawa). The methods used are phytochemical screening, toxicity tests against Artemia salina by the Brine Shrimp Lethality Test (BSLT), antioxidant activity assay with DPPH radical reduction method, and determination of chemical compound by GC-MS analysis. Phytochemical test results showed that crude extract containing alkaloids, triterpenoids, phenolics and flavonoids. The results of the antioxidant activity of the n-hexane, ethyl acetate and methanol fractions obtained IC50 values of 127.69, 28.65 and 79.43ppm, respectively. Ethyl acetate (as the most active fraction) was then fractionated using a vacuum chromatography column and the fractions obtained were E1 (268.8mg), E2 (337.1), E3 (234.3mg) and E4 (431.2mg). The antioxidant activity test showed that E2 was the most active compared to other fractions with an IC50 value of 37.24ppm. While the toxicity test results showed that E2 was very active with an LC50 value of 6.23ppm indicating that E2 was also potentially developed as an anticancer drug. Based on GC-MS spectrum analysis, of the several main compounds, four of which are aromatic compounds that have the potential to be developed as antioxidants, namely 2- (Benzyloxy) phenol (phenolic compound) (3.96%) (51),), 1, 2- Benzenedicarboxylic acid, dinonyl ester (2.44%) (52), Linderazulene (2.43%) (30), p-Nonylphenol (2.36%). Some other aromatic minor compounds can also be active as antioxidants.

In order to assess the risk of SARS-CoV-2 infection, transmission and reservoir development in swine, we combined results of an experimental and two observational studies. First, intranasal and intratracheal challenge of eight pigs did not result in infection, based on clinical signs and PCR on swab and lung tissue samples. Two serum samples returned a low positive result in virus neutralization, in line with findings in other infection experiments in pigs. Next, a retrospective observational study was performed in the Netherlands in the spring of 2020. Serum samples (N =417) obtained at slaughter from 17 farms located in a region with a high human case incidence in the first wave of the pandemic. Samples were tested with protein micro array, plaque reduction neutralization test and receptor-binding-domain ELISA. None of the serum samples was positive in all three assays, although six samples from one farm returned a low positive result in PRNT (titers 40-80). Therefore we conclude that serological evidence for large scale transmission was not observed. Finally, an outbreak of respiratory disease in pigs on one farm, coinciding with recent exposure to SARS-CoV-2 infected animal caretakers, was investigated. Tonsil swabs and paired serum samples were tested. No evidence for infection with SARS-CoV-2 was found. In conclusion, Although in both the experimental and the observational study few samples returned low antibody titer results in PRNT infection with SARS-CoV-2 was not confirmed. It was concluded that sporadic infections in the field cannot be excluded, but large-scale SARS-CoV-2 transmission among pigs is unlikely. info:eu-repo/semantics/publishedVersion

Purpose: Standard automated perimetry is the gold standard to monitor visual field ( VF) loss in glaucoma management, but it is prone to intrasubject variability. We trained and validated a customized deep learning (DL) regression model with Xception backbone that estimates pointwise and overall VF sensitivity fromunsegmented optical coherence tomography (OCT) scans. Methods: DL regression models have been trained with four imaging modalities (circumpapillary OCT at 3.5 mm, 4.1 mm, and 4.7 mm diameter) and scanning laser ophthalmoscopy en face images to estimate mean deviation (MD) and 52 threshold values. This retrospective study used data from patients who underwent a complete glaucoma examination, including a reliable Humphrey Field Analyzer (HFA) 24-2 SITA Standard (SS) VF exam and a SPECTRALIS OCT. Results: For MD estimation, weighted prediction averaging of all four individuals yielded a mean absolute error (MAE) of 2.89 dB (2.50-3.30) on 186 test images, reducing the baseline by 54% (MAEdecr%). For 52 VF threshold values' estimation, the weighted ensemble model resulted in anMAE of 4.82 dB (4.45-5.22), representing anMAEdecr% of 38% from baseline when predicting the pointwise mean value. DL managed to explain 75% and 58% of the variance (R-2) in MD and pointwise sensitivity estimation, respectively. Conclusions: Deep learning can estimate global and pointwise VF sensitivities that fall almost entirely within the 90% test-retest confidence intervals of the 24-2 SS test. Translational Relevance: Fast and consistent VF prediction from unsegmented OCT scans could become a solution for visual function estimation in patients unable to perform reliable VF exams. Supported by the Research Group Ophthalmology, KU Leuven and VITO NV (to RH) and the Flemish Government under the “Onderzoeksprogramma Artificiële Intelligentie (AI) Vlaanderen” program. No outside entities have been involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. This article was presented at the Association for Research in Vision and Ophthalmology Annual Meeting (ARVO2021) virtual conference, May 1st to May 7th, 2021.

The function of the skin as a barrier against a dry environment evolved in a common ancestor of terrestrial vertebrates such as mammals and birds. However, it is unknown which elements of the genetic program of skin barrier formation are evolutionarily ancient and conserved. In this study, we determined the transcriptomes of chicken keratinocytes (KCs) grown in monolayer culture and in an organotypic model of avian skin. The differentiation-associated changes in global gene expression were compared with previously published transcriptome changes of human KCs cultured under equivalent conditions. We found that specific keratins and genes of the epidermal differentiation complex were upregulated during the differentiation of both chicken and human KCs. Likewise, the transcriptional upregulation of genes that control the synthesis and transport of lipids, anti-inflammatory cytokines of the IL-1 family, protease inhibitors, and other regulators of tissue homeostasis was conserved in the KCs of both species. However, some avian KC differentiation-associated transcripts lack homologs in mammals and vice versa, indicating a genetic basis for taxon-specific skin features. The results of this study reveal an evolutionarily ancient program in which dynamic gene transcription controls the metabolism and transport of lipids as well as other core processes during terrestrial skin barrier formation.

The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallett et al., 2015) reported that AMPK in yeast, that is Snf1, prevents the transient TORC1 reactivation during the early phase following acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 temporally maintains TORC1 inactive in glucose-starved cells primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells. ispartof: Elife vol:12 pages:e84319- ispartof: location:England status: Published online

Goat farming has been severely affected by Desertification, limiting their water and food resources and inducing physiological heat stress that reduces the doe milk yield. Does well adapted to heat stress would be a possible solution, but creole or indigenous goats from desert or arid areas produce between 0.5 to 1.5 L of milk per day, which is lower than the 3 L of milk per day produced by dairy goats like the Saanen breed. Nevertheless, in this chapter, we will discuss the disadvantages of introducing common dairy goats in dry places. Instead, we propose the introduction of desert goats from the Middle East or India, because they produce high-quality milk with low feed intake, making a profitable goat farming activity, and an opportunity to include crossbreeding strategies to improve the herd milk yield. Creole goats, on other hand, has been an underestimated livestock animal with a rich and unveil genetic patrimony that migth improve the herd milk yield. The effect of improved diets and extensive husbandry conditions remains unexplored in desert creole goats, and the use of advanced knowledge in goat genomics, genetic expression, and a wide variety of molecular markers can improve the studies on creole goats for crossbreeding strategies identifying the best traits involved in high-quality milk production and adaptation to dry environments. In this way, the synergy between goat type selection and molecular markers should boost goat farming in recently new desert or arid zones, counteracting the detrimental effects produced by the desertification.

Cassia alata L. (Gelinggang) one of the plants known as medicinal plants, especially for the treatment of skin diseases. The purpose of this study was to determine the type of secondary metabolites using phytochemical tests, toxicity with the BSLT method and antioxidant properties against DPPH radicals from the extract of the Gelinggang leaves. The results of the study showed extracts of Gelinggang leaves containing alkaloids, triterpenoids, steroids, and quinones. Based on the results of toxicity and antioxidant tests showed that Gelinggang leaves extract was very toxic to Artemia salina shrimp and it was a strong antioxidant against DPPH radicals with LC50 and IC50 were 28.84 ppm and 73.57 ppm, respectively. Keywords: Gelinggang, Cassia alata L., toxicity, antioxidants, DPPH

In the Miocene era about 20 million years ago, the South Coast of West Java was a sea and habitat for marine organisms including giant sharks Megalodon measuring about 18 meters long. This study aimed to model the habitat preference of the prehistoric gigantic shark Otodus megalodon population based on the fossil record. From fossil teeth, it revealed that the rock layer where the teeth found was Bentang formation from Miocene era. Many fossils of Megalodon had been unearthed from Bentang formation which is part of the South Coast of West Java. The habitat model was developed using the Sea Level Rise Inundation Tool of ArcGIS to estimate the sea depth and Megalodon’s habitat during the Miocene. The length of the teeth of O. megalodon found was ranged from 13 to 19 cm, indicating the presence of juvenile and adult O. megalodon. Based on the model, in the Miocene era, half of West Java was a sea with a depth ranging from 0 to 200 meters. At that time, it was estimated that juvenile O. megalodon occupied waters with a depth of 0-40 meters with an area of 1365 km2. Meanwhile, adult O. megalodon prefers a depth of 80-160 m and the frequency of habitat use increases at a depth of 200 m. The declining population of O. megalodon is associated with climate change and declining prey populations.

The interaction of ectoparasite in correlation to its host’s skin is important. The extent of interaction somewhat makes these parasites able to survive in the harsh conditon of the host’s skin. Their existence mostly in the context of gaining their nutrition and perhaps continue its regeneration. Because these diseases caused by ectoparasite are easility transmitted, widespread, and the state of polyparasitism is often took place in a single vulnerable host, and significant primary and secondary morbidity and or complication occurs, which can worsen the course of the inital disease. This minireview aim to discuss about the interlinkage of some EPSD agents in correlation to its host’s skin, their interaction and what makes these endoparasites able to survive in the skin in the context of gaining their nutrition.

Heather, Calluna vulgaris, is a key species of European dry heath and central determinant of its conservation status. The established Calluna life cycle concept describes four phases—pioneer, building, mature, and degeneration—distinguishable by growth and vitality characteristics of undisturbed plants grown from seeds. However, little is known about the life cycle and ageing of plants subjected to severe disturbance, although measures to this effect (burning, mowing) are common in heathland management. We studied the vitality of over 400 heather plants by examining multiple morphological (plant height, long shoot and inflorescence lengths, flowering activity), anatomical (growth rings) and environmental (management, nitrogen deposition, climate) attributes. We found Calluna vitality to be mainly determined by the aboveground stem age, and that severe disturbances promote vigorous vegetative regeneration. Ageing-related shifts in the habit and vitality of plants resprouting from stem-base buds is similar to that of seed-based plants, but the former revealed higher vitality when young, at the cost of a shorter life span. In contrast, plants originating from decumbent stems resemble building-stage plants but apparently lack the capacity to re-enter a cycle including stages other than degeneration-type. As a consequence, we supplemented the established heather life cycle concept with a post-disturbance regeneration cycle of plants derived from resprouting. We conclude that management of dry lowland heathlands should include rotational small-scale severe disturbance to support both seed germination and seedling establishment as well as vegetative regeneration chiefly of young heather plants capable of resprouting from buds near rootstock.

Condition indices are key predictors of health and fitness in wild fish populations. Variation in body condition, therefore, can be used to identify stressful conditions that may impact endangered species, such as California’s endemic Delta Smelt (Hypomesus transpacificus McAllister, 1963). Here, we examined spatiotemporal variation in the condition indices of > 1600 Delta Smelt collected over nine years (2011–2019), a period characterized by tremendous variability in hydrodynamic and water quality conditions. The population exhibited low hepatosomatic index (HSI) and condition factor (CF) during September/October/November (fall), and both condition indices declined over the nine-year study during fall. HSI was positively correlated with indicators of pelagic productivity (e.g., Chlorophyll a, zooplankton biomass, and proximity to tidal wetlands), whereas CF was negatively correlated with temperature, peaking at a relatively cool 10–13°C. In sum, seasonal and interannual variation in body condition corresponded most strongly with pelagic productivity and water temperature, with little correlation to freshwater outflow. Management actions that increase pelagic productivity, restore and freshen productive wetlands during late summer-fall, and reduce water temperatures overall are likely to benefit condition indices and, therefore, fitness of the Delta Smelt population.

Picralima nitida is widely used in herbal medicine due to its numerous health benefits. We investigated the effects of extracts of P. nitida in alloxan-induced diabetic rats. Thirty Wistar rats were randomized into 6 groups of 5 rats each and treated as follows; Group I — normal control rats, Group II — diabetic rats treated with glibenclamide, Group III — diabetic rats not treated, Group IV — diabetic rats treated with methanol extract of P. nitida leaf, Group V — diabetic rats treated with methanol extract of P. nitida seed, Group VI — diabetic rats treated with methanol extract of P. nitida root. Phytochemical analysis of the methanol extracts of P. nitida revealed significantly (p

Background Combination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)V600–mutated melanoma (IMMU-TARGET, NCT02902042 ). Methods The dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1 and 200 mg QD and 30 mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose of the triplet combination, DLT and safety. As per the sponsor's decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD, NCT04657991 ). Results Fifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n = 1) and gamma glutamyl transferase (GGT) increase (n = 1). No DLT was observed in further 3 + 3 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III–IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12–45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35–87). At a median follow-up of 25 months (IQR, 9–28), progression-free survival at 12 months was 41% (95% CI, 13–68). Conclusions Triplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control.

NOD-like receptors (NLRs) are sensors of pathogen-associated molecular patterns with critical roles in the control of immune responses and programmed cell death. Recent studies have revealed inter-species differences in mammalian innate immune genes and a particular degeneration of nucleic acid sensing pathways in pangolins, which are currently investigated as potential hosts for zoonotic pathogens. Here, we used comparative genomics to determine which NLR genes are conserved or lost in pangolins and related mammals. We show that NOD2, which is implicated in sensing bacterial muramyl dipeptide and viral RNA, is a pseudogene in pangolins, but not in any other mammalian species investigated. NLRC4 and NAIP are absent in pangolins and canine carnivorans, suggesting convergent loss of cytoplasmic sensing of bacterial flagellin in these taxa. Among NLR family pyrin domain containing proteins (NLRPs), skin barrier-related NLRP10 has been lost in pangolins after the evolutionary divergence from Carnivora. Strikingly, pangolins lack all NLRPs associated with reproduction (germ cells and embryonic development) in other mammals, i.e., NLRP2, 4, 5, 7, 8, 9, 11, 13, and 14. Taken together, our study shows a massive degeneration of NLR genes in pangolins and suggests that these endangered mammals may have unique adaptations of innate immunity and reproductive cell biology.

Background: Atrial fibrillation is one of the factors forming thromboembolism. The thromboembolism can be prevented with warfarin. A side effect of warfarin is increasing the occurrence of bleeding, these therapy requires an evaluation of its usage. These evaluations can be seen in the Time in Therapeutic Range (TTR) patients. TTR is the duration in which the International Normalized Ratio (INR) patients in referral value are 2.0-3.0. TTR > 70% can prevent bleeding on FA patients with warfarin therapy.Aim: To determine TTR in patients receiving warfarin with atrial fibrillation.Methods: This study was descriptive with a cross-sectional design for six months at Dr. Kariadi Hospital Semarang. TTR was calculated using Rosendaal's Methods after collecting three INRs and patients' demographics.Results: Total subject was 111 patients with an average age of 52,63 and the TTR average is 53,75. TTR in this study was divided into two groups, that groups were poor TTR (TTR < 70%) with 82 patients (73.88%) and good TTR (≥70%) with 29 patients (26.12%).Conclusions: The average TTR in FA patients with warfarin therapy was 53,75%.

Despite recent advances in understanding skin scarring, mechanisms triggering hypertrophic scar formation are still poorly understood. In the present study, we investigate mature human hypertrophic scars and developing scars in mice at single cell resolution. Compared to normal skin, we find significant differences in gene expression in most cell types present in scar tissue. Fibroblasts show the most prominent alterations in gene expression, displaying a distinct fibrotic signature. By comparing genes upregulated in murine fibroblasts during scar development with genes highly expressed in mature human hypertrophic scars, we identify a group of serine proteases, tentatively involved in scar formation. Two of them, dipeptidyl-peptidase 4 (DPP4) and urokinase (PLAU), are further analyzed in functional assays, revealing a role in TGFβ1-mediated myofibroblast differentiation and over-production of components of the extracellular matrix in vitro. Topical treatment with inhibitors of DPP4 and PLAU during scar formation in vivo shows anti-fibrotic activity and improvement of scar quality, most prominently after application of the PLAU inhibitor BC-11. In this study, we delineate the genetic landscape of hypertrophic scars and present insights into mechanisms involved in hypertrophic scar formation. Our data suggest the use of serine protease inhibitors for the treatment of skin fibrosis., Mechanisms triggering hypertrophic scar formation remain poorly understood. Here the authors perform scRNA-seq on mature human hypertrophic scars and developing scars in mice to identify the serine proteases dipeptidyl-peptidase 4 and urokinase as key molecules in this process.

Aims Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA‐34a (miR‐34a) among the most upregulated miRs in tubers. Here, we characterised miR‐34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR‐34a. Methods We analysed the expression of miR‐34a in resected cortical tubers (n = 37) compared with autopsy‐derived control tissue (n = 27). The effect of miR‐34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH‐SY5Y cells following miR‐34a transfection. Results The peak of miR‐34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR‐34a was also strongly expressed in foetal TSC cortex. Overexpression of miR‐34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR‐34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. Conclusions MicroRNA‐34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR‐34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC., MicroRNA‐34a (MiR‐34a) is overexpressed in cortical tubers from children with tuberous sclerosis complex with a peak during infancy. MiR‐34a negatively regulates constitutively activated mechanistic target of rapamycin complex 1 in human astrocytes. MiR‐34a overexpression impairs corticogenesis in the embryonic mouse brain, potentially through targeting genes involved in neuronal migration.

Bacterial infections are a major cause of chronic infections and mortality that continues to threaten public health worldwide. Various medicinal plants used in folk medicine have demonstrated wound healing and antibacterial properties. The aims of the study are investigation phytochemical and antibacterial activity of ethyl acetate fraction from jarak pagar roots ( Jatropha curcas Linn.). The roots were treated with maceration method using ethanol 70% and subsequently fractioned to ethyl acetate fraction. The fractions were used for phytochemical screening and antibacterial assay using Kirby and Bauer agar difussion method. The results showed that ethyl acetate fraction jarak pagar roots contained alkaloid, flavonoids, saponins, steroids, poliphenol dan tannins. The antibacterial activity of jarak pagar roots againts Staphylococcus aureus and Escherichia coli shows that the activity of this fraction with concentration 8 mg/mL has strong inhibitory potency against the growth S. a ureus with inhibitory zone is 14,3 mm and has moderate inhibitory potency against E. c oli with inhibitory zone is 9 mm. The increase concentrations of ethyl asetate fraction jarak pagar roots shows high inhibition diameter of bacterial growth.

Constraining patterns of growth using directly observable and quantifiable characteristics can reveal a wealth of information regarding the biology of the Ediacara biota—the oldest macroscopic, complex community-forming organisms in the fossil record. However, these rely on individuals captured at an instant in time at various growth stages, and so different interpretations can be derived from the same material. Here we leverage newly discovered and well-preserved Dickinsonia costata Sprigg, 1947 from South Australia, combined with hundreds of previously described specimens, to test competing hypotheses for the location of module addition. We find considerable variation in the relationship between the total number of modules and body size that cannot be explained solely by expansion and contraction of individuals. Patterns derived assuming new modules differentiated at the anterior result in numerous examples in which the oldest module(s) must decrease in size with overall growth, potentially falsifying this hypothesis. Observed polarity as well as the consistent posterior location of defects and indentations support module formation at this end in D. costata. Regardless, changes in repeated units with growth share similarities with those regulated by morphogen gradients in metazoans today, suggesting that these genetic pathways were operating in Ediacaran animals.

Malaria is a potentially fatal disease caused by Plasmodium spp. Transmission occurs via the bite of female mosquito, Anopheles spp. Epidemiologically, global number of malaria patient are located in Southeast Asia and Africa. Until nowadays, millions of people still living in endemic area, with children and pregnant women are among the most vulnerable group in the population. Although there have been many advances in treatment and management, but the potential for harm remains; one of the example is lung involvement in patients with severe malaria. This paper aim to discuss briefly about lung derangement in the severe malaria and the inflammatory response related to the lung dysfunction. The severity of pulmonary impairment due to complications of malaria is determined not only by the initiation of antimalarial treatment but also by the hosts associated immune response Keywords: Blood protozoan; obligate intracellular; complication; ARDS; pulmonary vascular occlusion; inflammation.

Preputial glands are large lipid and hormone secreting sebaceous organs of mice, and present a convenient model for the investigation of biological processes in sebocytes. Suppression of ATG7-dependent macroautophagy/autophagy in epithelial cells of murine skin causes enlargement of hair follicle-associated sebaceous glands and alters the lipid profile of sebum. We have now extended these studies to the preputial glands and find that autophagy significantly delays the onset of age-related ductal ectasia, influences lipid droplet morphology and contributes to the complete dissolution of the mature sebocytes during holocrine secretion. Single cell RNA sequencing showed that many genes involved in lipid metabolism and oxidative stress response were downregulated in immature and mature epithelial cells of ATG7-deficient glands. When analyzing the lipid composition of control and mutant glands, we found that levels of all phospholipid classes, except choline plasmalogen, were decreased in the mutant glands, with a concomitant accumulation of diacyl glycerides. Mass spectrometric imaging (MSI) demonstrated that phospholipid species, specifically the dominant phosphatidylcholine (PC 34:1), were decreased in immature and mature sebocytes. In addition, we found a strong reduction in the amounts of the pheromone, palmityl acetate. Thus, autophagy in the preputial gland is not only important for homeostasis of the gland as a whole and an orderly breakdown of cells during holocrine secretion, but also regulates phospholipid and fatty acid metabolism, as well as pheromone production. ABBREVIATIONS: ATG7: autophagy related 7; BODIPY: boron dipyrromethene; DAG: diacyl glycerides; DBI: diazepam binding inhibitor; GFP: green fluorescent protein; KRT14: keratin 14; HPLC-MS: high performance liquid chromatography-mass spectrometry; LD: lipid droplet; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MSI: mass spectrometric imaging; ORO: Oil Red O; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PG: preputial gland; PLIN2: perilipin 2; PtdIns: phosphatidylinositol; PL: phospholipids; POPC: 1-palmitoyl-2-oleoyl-PC; PS: phosphatidylserine; qRT-PCR: quantitative reverse transcribed PCR; SG: sebaceous gland; scRNAseq: single-cell RNA sequencing; TAG: triacylglycerides; TLC: thin layer chromatography.

Cellulose from Pennisetum purpureum has been used as the main ingredient in the synthesis of carboxymethyl cellulose (CMC). The purpose of CMC synthesis from the cellulose of Pennisetum purpureum is to obtain CMC compounds with the best degree of substitution (DS) value and the highest yield. The study was conducted using a completely randomized design with a factorial pattern consisting of two independent variables, namely the concentration of trichloroacetic acid (10%, 20%, and 30%) and reaction time (3 and 4 hours). The results showed that the CMC with the highest DS value (0.839) was obtained using 20% trichloroacetic acid with a reaction time of 3 hours. The highest CMC yield was 30.15% which was obtained using 30% trichloroacetic acid with a reaction time of 4 hours. Keywords: Pennisetum purpureum, carboxymethyl cellulose, substitution degree.

Centro de Investigación en Sanidad Animal (CISA), African swine fever (ASF) is currently the major concern of the global swine industry, as a consequence of which a reconsideration of the containment and prevention measures taken to date is urgently required. A great interest in developing an effective and safe vaccine against ASF virus (ASFV) infection has, therefore, recently appeared. The objective of the present study is to test an inactivated ASFV preparation under a vaccination strategy that has not previously been tested in order to improve its protective effect. The following have been considered: (i) virus inactivation by using a low binary ethyleneimine (BEI) concentration at a low temperature, (ii) the use of new and strong adjuvants; (iii) the use of very high doses (6 × 109 haemadsorption in 50% of infected cultures (HAD50)), and (iv) simultaneous double inoculation by two different routes of administration: intradermal and intramuscular. Five groups of pigs were, therefore, inoculated with BEI- Pol16/DP/OUT21 in different adjuvant formulations, twice with a 4-week interval. Six weeks later, all groups were intramuscularly challenged with 10 HAD50 of the virulent Pol16/DP/OUT21 ASFV isolate. All the animals had clinical signs and pathological findings consistent with ASF. This lack of effectiveness supports the claim that an inactivated virus strategy may not be a viable vaccine option with which to fight ASF., This research was funded by Intervet International B.V. (50–2019). E.C.-F. is a recipient of a Spanish Government-funded PhD fellowship for the Training of Future Scholars (FPU) provided by the Spanish Ministry of Education, Culture and Sports., 14 Pág.

In classical viral infections, the avidity of immunoglobulin G (IgG) is low during acute infection and high a few months later. As recently reported, SARS-CoV-2 infections are not following this scheme, but they are rather characterized by incomplete avidity maturation. This study was performed to clarify whether infection with seasonal coronaviruses also leads to incomplete avidity maturation. The avidity of IgG toward the nucleoprotein (NP) of the seasonal coronaviruses 229E, NL63, OC43, HKU1 and of SARS-CoV-2 was determined in the sera from 88 healthy, SARS-CoV-2-negative subjects and in the sera from 70 COVID-19 outpatients, using the recomLine SARS-CoV-2 assay with recombinant antigens. In the sera from SARS-CoV-2-negative subjects, incomplete avidity maturation (persistent low and intermediate avidity indices) was the lowest for infections with the alpha-coronaviruses 229E (33.3%) and NL63 (61.3%), and the highest for the beta-coronaviruses OC43 (77.5%) and HKU1 (71.4%). In the sera from COVID-19 patients, the degree of incomplete avidity maturation of IgG toward NP of 223E, OC43, and HKU1 was not significantly different from that found in SARS-CoV-2-negative subjects, but a significant increase in avidity was observed for IgG toward NP of NL63. Though there was no cross-reaction between SARS-CoV-2 and seasonal coronaviruses, higher concentrations of IgG directed toward seasonal coronaviruses seemed to indirectly increase avidity maturation of IgG directed toward SARS-CoV-2. Our data show that incomplete IgG avidity maturation represents a characteristic consequence of coronavirus infections. This raises problems for the serological differentiation between acute and past infections and may be important for the biology of coronaviruses.

Avidity is defined as the binding strength of immunoglobulin G (IgG) toward its target epitope. Avidity is directly related to affinity, as both processes are determined by the best fit of IgG to epitopes. We confirm and extend data on incomplete avidity maturation of IgG toward severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleoprotein (NP), spike protein‐1 (S1), and its receptor‐binding domain (RBD) in coronavirus disease 2019 (COVID‐19) patients. In SARS‐CoV‐2‐infected individuals, an initial rise in avidity maturation was ending abruptly, leading to IgG of persistently low or intermediate avidity. Incomplete avidity maturation might facilitate secondary SARS‐CoV‐2 infections and thus prevent the establishment of herd immunity. Incomplete avidity maturation after infection with SARS‐CoV‐2 (with only 11.8% of cases showing finally IgG of high avidity, that is, an avidity index > 0.6) was contrasted by regular and rapid establishment of high avidity in SARS‐CoV‐2 naïve individuals after two vaccination steps with the BioNTech messenger RNA (mRNA) Vaccine (78% of cases with high avidity). One vaccination step was not sufficient for induction of complete avidity maturation in vaccinated SARS‐CoV‐2 naïve individuals, as it induced high avidity only in 2.9% of cases within 3 weeks. However, one vaccination step was sufficient to induce high avidity in individuals with previous SARS‐CoV‐2 infection., Highlights After severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, immunoglobulin G (IgG) toward viral nucleoprotein (NP), receptor‐binding domain (RBD), and spike protein‐1 (S1) shows immature avidity.The breakpoint of avidity maturation correlates with that of IgG production.Patients with more severe clinical symptoms show increased avidity maturation.Two vaccination steps lead to complete avidity maturation.Therefore, vaccination seems to induce protective immunity toward SARS‐CoV‐2 and coronavirus disease 2019 (COVID‐19).Preceding SARS‐CoV‐2 infections enhance avidity maturation after subsequent vaccination.

Objective: Hypertension is a major risk factor for cardiovascular disease, kidney disease, and premature death. Increased levels of creatine kinase are associated with development of hypertension. However, it is unknown if creatine, a substrate of CK, is associated with the development of hypertension. We therefore, aimed to investigate the association between plasma creatine concentration and incident hypertension. Methods: We measured fasting plasma creatine concentrations by nuclear magnetic resonance spectroscopy in participants of the population-based PREVEND study. The study outcome was incident hypertension, defined as either a SBP of at least 140mmHg, a DBP of at least 90mmHg, or the new usage of antihypertensive drugs. Participants with hypertension at baseline were excluded. Results: We included 3135 participants (46% men) aged 49=10years. Mean plasma creatine concentrations were 36.2=17.5mmol/l, with higher concentrations in women than in men (42.2=17.6 versus 29.2=17.6mmol/l; P, Journal of Hypertension, 40 (2)

Infections with Mycobacterium microti, a member of the M. tuberculosis complex, have been increasingly reported in humans and in domestic and free-ranging wild animals. At postmortem examination, infected animals may display histopathologic lesions indistinguishable from those caused by M. bovis or M. caprae, potentially leading to misidentification of bovine tuberculosis. We report 3 cases of M. microti infections in free-ranging red deer (Cervus elaphus) from western Austria and southern Germany. One diseased animal displayed severe pyogranulomatous pleuropneumonia and multifocal granulomas on the surface of the pericardium. Two other animals showed alterations of the lungs and associated lymph nodes compatible with parasitic infestation. Results of the phylogenetic analysis including multiple animal strains from the study area showed independent infection events, but no host-adapted genotype. Personnel involved in bovine tuberculosis–monitoring programs should be aware of the fastidious nature of M. microti, its pathogenicity in wildlife, and zoonotic potential.

Background Epigenetic changes have been described in trauma patients in the form of histone acetylation events, but whether DNA-methylation occurs remains unknown. We hypothesized that the combination of hemorrhage and saline resuscitation would alter DNA-methylation and associated proteomic profiles in the rat lung. Methods Ten rats were subjected to a pressure-controlled hemorrhage and resuscitation model consisting of hemorrhage to a mean arterial pressure (MAP) of 35mmHg for 90 minutes, followed by saline resuscitation to a MAP >70mmHg for 90 minutes (n=5) or sham (only anesthesia and cannulation). Lungs were harvested and subjected to reduced genome wide DNA-methylation analysis through bisulphite sequencing as well as proteomics analysis. Data was analyzed for differentially methylated regions and associated alterations in proteomic networks through a weighted correlation network analysis (WCNA). Pathway analysis was used to establish biological relevance of findings. Results Hemorrhage and saline resuscitation were associated with differential methylation of 353 sites across the genome compared to the sham group. Of these, 30 were localized to gene promoter regions, 31 to exon regions and 87 to intron regions. Network analysis identified an association between hemorrhage/resuscitation and DNA-methylation events located to genes involved in areas of endothelial and immune response signaling. The associated proteomic response was characterized by activations of mRNA processing as well as endothelial Nitric Oxide Synthase (eNOS) metabolism. Conclusion We demonstrated an association between DNA-methylation and hemorrhage/saline resuscitation. These results suggest a potential role of DNA-methylation in the host response to injury.

Rats can transmit Streptobacillus moniliformis, which may cause rat-bite fever (RBF), a rare and potentially lethal zoonosis. Fastidious in vitro growth and unspecific symptoms, including fever, arthralgia, and polymorphous skin lesions, complicate the diagnosis. Rat-bite fever follows exposure to contaminated bodily fluids of infected rodents; however, reports on Streptobacillus moniliformis-related infections are few so far. A female patient presented with painful hemorrhagic pustules and purpuric lesions on hands and feet. She developed fever and migratory polyarthralgia. Blood culture yielded growth with Streptobacillus moniliformis. The patient owned rats and handled contaminated rat feces and urine, making this the most likely etiology of infection. We report a case of RBF due to Streptobacillus moniliformis in a rat handling-patient. Difficulties in clinical and microbiological diagnosis highlight the need for a thorough and complete history-taking and a greater understanding of this rare infectious disease.

Background and Aim: Brugia malayi is known to be zoonotically important because it can be transmitted from animals (mammals and primates) to humans or from humans to humans through mosquito vectors. This study was conducted to explore the fauna associated with Malayan filariasis transmission in Sedang village, Suak Tapeh District, Banyuasin Regency, South Sumatra Province, Indonesia. Materials and Methods: A cross-sectional research design with an observational and analytical approach was applied in this study, and it was conducted in May 2018. Mosquitoes were collected twice using human bait both inside and outside the house from 6:00 p.m. to 6:00 a.m. The presence of competitors, predators, and reservoir hosts in the areas of five breeding habitats of Mansonia spp. was observed. The presence of microfilaria was confirmed under a microscope in night blood samples of inhabitants and cats. The presence of infective larvae (L3) of B. malayi was identified microscopically and based on the polymerase chain reaction method in female Mansonia mosquitoes. Results: A total of 12 mosquito species were found, among which Mansonia uniformis was the dominant mosquito, and the predominant competitor was Mansonia annulifera. Dragonflies, as predators were found in two breeding habitats and fish were found in one breeding habitat. The L3 of B. malayi were not identified in the mosquitoes, and the microfilariae of B. malayi were not found in the blood samples of inhabitants and cats. Conclusion: Although Mansonia mosquito population was abundant in Banyuasin Regency, the mosquito was not confirmed as an intermediate host of B. malayi, and the cat was not confirmed as a reservoir of B. malayi in the location.

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE. Magnetic susceptibility of the presumed seizure-onset zone from three patients with focal epilepsy was compared during and after seizure activity. Finally, the cellular effects of iron overload were studied in vitro using an acute mouse hippocampal slice preparation and cultured human fetal astrocytes. While iron-accumulating neurons had a pyknotic morphology, astrocytes appeared to acquire iron-sequestrating capacity as indicated by prominent ferritin expression and iron retention in the hippocampus of patients with SE or TLE. Interictal to postictal comparison revealed increased magnetic susceptibility in the seizure-onset zone of epilepsy patients. Post-SE rats had consistently higher hippocampal iron levels during the acute and chronic phase (when spontaneous recurrent seizures are evident). In vitro, in acute slices that were exposed to iron, neurons readily took up iron, which was exacerbated by induced epileptiform activity. Human astrocyte cultures challenged with iron and ROS increased their antioxidant and iron-binding capacity, but simultaneously developed a pro-inflammatory phenotype upon chronic exposure. These data suggest that seizure-mediated, chronic neuronal iron uptake might play a role in neuronal dysfunction/loss in TLE-HS. On the other hand, astrocytes sequester iron, specifically in chronic epilepsy. This function might transform astrocytes into a highly resistant, pro-inflammatory phenotype potentially contributing to pro-epileptogenic inflammatory processes. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02348-6.

Food modification is still quite common in the community, especially the processing of candy, jelly drinks and dawet. The manufacture of candy, jelly drinks and dawet can be modified from the raw material of grass jelly leaves which have a lot of protein and vitamin content. The women of the Teger Farmer Group, Mangunsari Village, Gunungpati District, Semarang City mostly work as farmers and factory workers and do not quite know what food modification is, especially those made from grass jelly leaves. There are many grass jelly plants in the environment around the Teger Farmer Group that have not been utilized until now, so we aim to provide information to the Teger Farmer Group's mothers about preparations made from grass jelly leaves, which can be made into candy, dawet and jelly drinks that have a lot of content. nutrition. The service method was carried out with lectures, discussions and simulations of making processed products. The results of the service revealed that the Teger Farmers' Group, Mangunsari Village, Gunungpati District, Semarang City, mostly had eaten dawet and grass jelly drink, but had never eaten grass jelly candy. In addition, they also do not know how to make sweets, jelly drinks and dawet from grass jelly, and do not know what the ingredients are. Furthermore, at the end of this service activity, partners better understand how to make and nutritional content of all processed products from grass jelly.

Context Breech strike is a serious disease for wool sheep. Skin wrinkle and dags are known predisposing factors for breech strike; however, a large part of the variation among sheep is unknown. Aims We studied the natural diversity and difference in microbial populations in the skin around the breech area in Merino sheep genetically resistant and susceptible to breech strike, by using 16S rRNA gene sequence analysis. Methods The sheep were from the breech strike flocks at the Mount Barker research station in Western Australia and from the CSIRO research station near Armidale in New South Wales. Skin samples were collected from the breech of all 2013-born progeny in both flocks before they were struck. Yearling ewes and rams were then naturally exposed to challenge by Lucilia cuprina blowflies. Breeding values for breech strike were estimated and used with phenotypic data to identify breech strike-resistant and -susceptible sheep. Skin samples of 78 unstruck and 73 struck sheep were selected, their microbiomes were analysed using 16S rRNA meta-barcoding, and operational taxonomic unit counts were analysed. Results The diversity analyses showed that the two flocks in the different environments had different microbiome profiles, but no difference was found between sexes or between breech strike-resistant and -susceptible sheep in either flock. Conclusions The results indicated that microbial differences on the skin of sheep are not associated with differences in susceptibility to breech strike. Implications Microbial differences do not offer opportunities to manage breech strike in Merino sheep.

Bats are a group of mammals that harbor the most significant number of coronaviruses. The aim of present review article was to analyze the broad spectrum of the coronavirus coexisting in Chiropterans hosts. Bats have certain types of cell receptors that allow them to be the potential hosts of a large number of viruses without the presence of any clinical manifestations, and to be a source of contagion infections for other animals and human species. Emphasis can be placed on five coronaviruses, such as Porcine Epidemic Diarrhea Disease, Severe Acute Diarrhea Syndrome, Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome, and Severe Acute Respiratory Syndrome 2, which have had significant impacts causing epidemic outbreaks in different parts of the world, and generating implications for both human and animal health. In conclusion, recent research indicated the importance of bats as potential hosts of multiple coroaviruses leading to some zoonotic diseases.

The Bagrada bug, Bagrada hilaris Burmeister (Hemiptera: Pentatomidae), an invasive pest of Palearctic origin, has become a problem in the Western Hemisphere, attacking brassica and other crops. The Bagrada bug was first reported in Chile in 2016, and despite the availability of some efficacious synthetic insecticides, B. hilaris is a growing problem. Currently, few international studies have been performed regarding the biological control of B. hilaris. However, entomopathogenic nematodes (EPNs) are potential candidates, as they cause mortality to other pentatomids. Of the six native Chilean EPN isolates, Steinernema feltiae CH4 caused the highest mortality in B. hilaris adults (97.5%). In a second assay, the mortality of B. hilaris adults increased with higher doses and extension of the post-application time of this isolate, with 96.9 and 100% at 96 and 120 h after application, respectively. A probit analysis indicated that the lethal dose 50% (LD50) dropped from 60.7 to 4.4 IJ/insect at 48 and 168 h, respectively. In a semifield study, a single application of this EPN with an adjuvant achieved approximately 60% mortality of the bugs after 480 h on rocket plants, and the damage to leaves was significantly lower (29%) than the damage to leaves of control plants (54.3%). These novel results represent progress in the use of EPNs for the control of foliage pests and are also the first approach of successful control of B. hilaris with EPNs in any crop. Further field studies will allow the development of integrated pest management programmes using EPNs as biological control agents for B. hilaris populations.

Major protein components of the mammalian skin barrier are encoded by genes clustered in the Epidermal Differentiation Complex (EDC). The skin of cetaceans, i.e. whales, porpoises and dolphins, differs histologically from that of terrestrial mammals. However, the genetic regulation of their epidermal barrier is only incompletely known. Here, we investigated the EDC of cetaceans by comparative genomics. We found that important epidermal cornification proteins, such as loricrin and involucrin are conserved and subtypes of small proline-rich proteins (SPRRs) are even expanded in numbers in cetaceans. By contrast, keratinocyte proline rich protein (KPRP), skin-specific protein 32 (XP32) and late-cornified envelope (LCE) genes with the notable exception of LCE7A have been lost in cetaceans. Genes encoding proline rich 9 (PRR9) and late cornified envelope like proline rich 1 (LELP1) have degenerated in subgroups of cetaceans. These data suggest that the evolution of an aquatic lifestyle was accompanied by amplification of SPRR genes and loss of specific other epidermal differentiation genes in the phylogenetic lineage leading to cetaceans.