Identification of extracellular vesicles from their Raman spectra via self-supervised learning.

Extracellular vesicles (EVs) released from cells attract interest for their possible role in health and diseases. The detection and characterization of EVs is challenging due to the lack of specialized methodologies. Raman spectroscopy, however, has been suggested as a novel approach for biochemical analysis of EVs. To extract information from the spectra, a novel deep learning architecture is explored as a versatile variant of autoencoders. The proposed architecture considers the frequency range separately from the intensity of the spectra. This enables the model to adapt to the frequency range, rather than requiring that all spectra be pre-processed to the same frequency range as it was trained on. It is demonstrated that the proposed architecture accepts Raman spectra of EVs and lipoproteins from 13 biological sources and from two laboratories. High reconstruction accuracy is maintained despite large variances in frequency range and noise level. It is also shown that the architecture is able to cluster the biological nanoparticles by their Raman spectra and differentiate them by their origin without pre-processing of the spectra or supervision during learning. The model performs label-free differentiation, including separating EVs from activated vs. non-activated blood platelets and EVs/lipoproteins from prostate cancer patients versus non-cancer controls. The differentiation is evaluated by creating a neural network classifier that observes the features extracted by the model to classify the spectra according to their sample origin. The classification reveals a test sensitivity of 92.2 % and selectivity of 92.3 % over 769 measurements from two labs that have different measurement configurations.

Rapid and low-cost screening for single and combined effects of drought and heat stress on the morpho-physiological traits of African eggplant (Solanum aethiopicum) germplasm.

Drought and heat are two stresses that often occur together and may pose significant risks to crops in future climates. However, the combined effects of these two stressors have received less attention than single-stressor investigations. This study used a rapid and straightforward phenotyping method to quantify the variation in 128 African eggplant genotype responses to drought, heat, and the combined effects of heat and drought at the seedling stage. The study found that the morphophysiological traits varied significantly among the 128 eggplants, highlighting variation in response to abiotic stresses. Broad-sense heritability was high (> 0.60) for chlorophyll content, plant biomass and performance index, electrolyte leakage, and total leaf area. Positive and significant relationships existed between biomass and photosynthetic parameters, but a negative association existed between electrolyte leakage and morpho-physiological traits. The plants underwent more significant stress when drought and heat stress were imposed concurrently than under single stresses, with the impact of drought on the plants being more detrimental than heat. There were antagonistic effects on the morphophysiology of the eggplants when heat and drought stress were applied together. Resilient genotypes such as RV100503, RV100501, JAMBA, LOC3, RV100164, RV100169, LOC 3, RV100483, GH5155, RV100430, GH1087, GH1087*, RV100388, RV100387, RV100391 maintained high relative water content, low electrolyte leakage, high Fv/Fm ratio and performance index, and increased biomass production under abiotic stress conditions. The antagonistic interactions between heat and drought observed here may be retained or enhanced during several stress combinations typical of plants' environments and must be factored into efforts to develop climate change-resilient crops. This paper demonstrates improvised climate chambers for high throughput, reliable, rapid, and cost-effective screening for heat and drought and combined stress tolerance in plants.

Homocysteine and female fertility, pregnancy loss and offspring birthweight: a two-sample Mendelian randomization study.

BACKGROUND/OBJECTIVES: Observational studies link elevated homocysteine concentrations (Hcy) with female fertility, pregnancy loss, and low offspring birthweight. Maternal rs1801133, a functional variant in MTHFR strongly associated with lifelong elevated Hcy, is associated with recurrent pregnancy loss and offspring birthweight in Asian women. We investigated if genetically elevated Hcy is associated with fertility, pregnancy loss, and offspring birthweight in European women. SUBJECTS/METHODS: We performed a two-sample Mendelian randomization (MR) study using publicly available data. We obtained 18 genetic variants (five involved in Hcy metabolism) explaining up to 5.9% of the variance in Hcy from a genome-wide association meta-analysis of 44,147 European individuals (82% women). We investigated fertility (including age at menopause), pregnancy loss, and offspring birthweight in the UK Biobank (N = 194,174), EGG (N = 190,406), and ReproGen (N = 69,360-252,514) consortia using summary statistics. We calculated inverse-variance weighted, and several sensitivity MR regression statistics. RESULTS: rs1801133 was associated with a 7.45 months (95% CI: 4.09, 10.80) increase in age at menopause and 29.69 (12.87, 46.51) g decrease in offspring birthweight per SD increase in Hcy in the UK biobank, and confirmed in EGG and ReproGen. MR for Hcy metabolism alone (five variants in MTHFR, MTR, CBS) showed similar results for offspring birthweight across consortia. However, using all 18 variants resulted in no association for any of the outcomes across consortia. CONCLUSION: Hcy and suggestively vitamin B variants are most likely the drug targets for folate supplementation in pregnant women on the offspring birthweight, while Hcy variants related to renal function or diabetes are not involved.

Domestic wastewater infiltration process in desert sandy soil and its irrigation prospect analysis.

Although domestic wastewater and its reclaimed water are alternative water resources in arid region, investigation of their negative effect must be done to prevent environmental pollution. In this paper, a short-term column experiment was conducted to simulate the infiltration process of wastewater in desert soil. Alfalfa was planted and irrigated with fresh water for control (CK), tertiary treated domestic wastewater (TTW), secondary treated domestic wastewater (STW) and raw domestic wastewater untreated (RW). The effect of wastewater application on desert soil, drainage and plant properties was evaluated. Experimental results demonstrated that the tested desert soil has no soil structure, organic matter, nor microbial community while possess high infiltration rate. The use of wastewater significantly improved plant growth, and the biomass of TTW, RW, STW were 5.5, 4.3, 2.9 times of CK. The infiltration rate of water in bare soil was high (high to low: TTW, CK, RW, STW), while plant growth reduced infiltration rate (ca. 40% with TTW and RW). Wastewater irrigation and plant growth decreased soil zeta potential, while increased formation of aggregates and bacterial abundance and diversity in soil. Top soil (0-30 cm) accumulation of nitrogen (N), phosphorus (P), organic matter and E. coli was evidenced and all could go down to deep soil and drainage with constant wastewater use. It was concluded that domestic wastewater had big potential in desert soil vegetation recovering and function restoration. Nevertheless, the N, salt, P and organic matter and E. coli in wastewater could give rise to desert soil and groundwater contamination if improper treatment was used.

Genotoxicity and Oxidative Stress Evaluations in Juvenile African Catfish Clarias gariepinus Exposed to NPK Fertilizer.

Juvenile African Catfish (also known as Sharptooth Catfish) Clarias gariepinus were exposed to 2.26, 4.52, and 11.30 mg/L NPK (15-15-15) fertilizer for 21 d followed by 7 d of recovery to assess the genotoxic effects of the fertilizer in erythrocytes. Biomarkers of oxidative stress were evaluated in the liver and gill tissues. The fertilizer induced micronuclei formation with maximum effects on day 7 in erythrocytes of individuals that were exposed to 4.52 and 11.30 mg/L NPK, and on day 14 in individuals exposed to 2.26 mg/L of the same fertilizer. The lipid peroxidation, glutathione reductase, and reduced glutathione values in the exposed fish increased, while the values of catalase, superoxide dismutase, and glutathione peroxidase decreased. There were mixed trends in the recovery patterns after the 7-d withdrawal from the fertilizer. Careful use of the fertilizer in the field is recommended to avoid toxicological effects on nontarget organisms.

Meta-analysis of goal-directed fluid therapy using transoesophageal Doppler monitoring in patients undergoing elective colorectal surgery.

Background: Intraoperative goal-directed fluid therapy (GDFT) is recommended in most perioperative guidelines for intraoperative fluid management in patients undergoing elective colorectal surgery. However, the evidence in elective colorectal surgery alone is not well established. The aim of this meta-analysis was to compare the effects of GDFT with those of conventional fluid therapy on outcomes after elective colorectal surgery. Methods: A meta-analysis of RCTs examining the role of transoesophageal Doppler-guided GDFT with conventional fluid therapy in adult patients undergoing elective colorectal surgery was performed in accordance with PRISMA methodology. The primary outcome measure was overall morbidity, and secondary outcome measures were length of hospital stay, time to return of gastrointestinal function, 30-day mortality, acute kidney injury, and surgical-site infection and anastomotic leak rates. Results: A total of 11 studies were included with a total of 1113 patients (556 GDFT, 557 conventional fluid therapy). There was no significant difference in any clinical outcome measure studied between GDFT and conventional fluid therapy, including overall morbidity (risk ratio (RR) 0·90, 95 per cent c.i. 0·75 to 1·08, P = 0·27; I 2 = 47 per cent; 991 patients), 30-day mortality (RR 0·67, 0·23 to 1·92, P = 0·45; I 2 = 0 per cent; 1039 patients) and length of hospital stay (mean difference 0·01 (95 per cent c.i. -0·92 to 0·94) days, P = 0·98; I 2 = 34 per cent; 1049 patients). Conclusion: This meta-analysis does not support the perceived benefits of GDFT guided by transoesophageal Doppler monitoring in the setting of elective colorectal surgery.

Rice yield estimation based on forecasting the future condition of groundwater salinity in the Caspian coastal strip of Guilan Province, Iran.

Irrigation water salinity is one of the factors that reduces agricultural production. Guilan Province is one of the most important rice-producing areas in Iran where groundwater is used for irrigation. The temporal and spatial variations of groundwater salinity were studied in the coastal strip covering 4285 km2 of the province using data from 73 wells, as well as its estimated effect on the rice yield. Data on mean electrical conductivity (EC) for each 6-month period of 12 consecutive years, from the second half of 2002 until the end of 2014, were analyzed and resulted in 25 mean ECs. EC maps and maps of the probability of higher salinity areas were obtained by using ordinary kriging (OK) and indicator kriging (IK) in ArcGIS 9.3 software, respectively. Thereby, areas belonging to different salinity classes were outlined and places with higher salinity reducing the rice yield were identified. In addition, the Mann-Kendall test and Sen's slope were used to project future changes. The results indicated that due to the salinity of groundwater in the coastal strip area, the minimum and the maximum rice yields were 80% and 100%, respectively. Using the IK method, higher probability of groundwater salinity reducing the yield was found from the central parts toward the east. The Mann-Kendal test result showed significant temporal trends of the size of areas below the 100% yield (EC < 1 dS/m) and 90-100% yield (1 < EC < 1.34 dS/m) thresholds. The equations given by Sen's slope estimator indicated that the groundwater salinity will not be a limiting factor for achieving 100% rice yields from the year of 2021 onward in all of the Guilan coastal area. The trend of increasing precipitation in the area may be an important cause.

In vivo models and decision trees for formulation development in early drug development: A review of current practices and recommendations for biopharmaceutical development.

The ability to predict new chemical entity performance using in vivo animal models has been under investigation for more than two decades. Pharmaceutical companies use their own strategies to make decisions on the most appropriate formulation starting early in development. In this paper the biopharmaceutical decision trees available in four EFPIA partners (Bayer, Boehringer Ingelheim, Bristol Meyers Squibb and Janssen) were discussed by 7 companies of which 4 had no decision tree currently defined. The strengths, weaknesses and opportunities for improvement are discussed for each decision tree. Both pharmacokineticists and preformulation scientists at the drug discovery & development interface responsible for lead optimization and candidate selection contributed to an overall picture of how formulation decisions are progressed. A small data set containing compound information from the database designed for the IMI funded OrBiTo project is examined for interrelationships between measured physicochemical, dissolution and relative bioavailability parameters. In vivo behavior of the drug substance and its formulation in First in human (FIH) studies cannot always be well predicted from in vitro and/or in silico tools alone at the time of selection of a new chemical entity (NCE). Early identification of the risks, challenges and strategies to prepare for formulations that provide sufficient preclinical exposure in animal toxicology studies and in FIH clinical trials is needed and represents an essential part of the IMI funded OrBiTo project. This article offers a perspective on the use of in vivo models and biopharmaceutical decision trees in the development of new oral drug products.

Assessment of rosacea symptom severity by genome-wide association study and expression analysis highlights immuno-inflammatory and skin pigmentation genes.

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention.

Phenome-wide association study using research participants' self-reported data provides insight into the Th17 and IL-17 pathway.

A phenome-wide association study of variants in genes in the Th17 and IL-17 pathway was performed using self-reported phenotypes and genetic data from 521,000 research participants of 23andMe. Results replicated known associations with similar effect sizes for autoimmune traits illustrating self-reported traits can be a surrogate for clinically assessed conditions. Novel associations controlling for a false discovery rate of 5% included the association of the variant encoding p.Ile684Ser in TYK2 with increased risk of tonsillectomy, strep throat occurrences and teen acne, the variant encoding p.Arg381Gln in IL23R with a decrease in dandruff frequency, the variant encoding p.Asp10Asn in TRAF3IP2 with risk of male-pattern balding, and the RORC regulatory variant (rs4845604) with protection from allergies. This approach enabled rapid assessment of association with a wide variety of traits and investigation of traits with limited reported associations to overlay meaningful phenotypic context on the range of conditions being considered for drugs targeting this pathway.

A Rare Finding of Falciform Ligament Thrombosis as a Sequel of Acute Pancreatitis.

Falciform ligament (remnant of umbilical vein) is an anatomical structure that connects the liver to the anterior abdominal wall. This case reports a rare clinical presentation of falciform ligament thrombosis as a consequence of acute gallstone pancreatitis, in a patient with noncirrhotic liver. A 55-year-old female with a history of cholelithiasis was admitted with abdominal pain. Biochemistry profile showed hyperamylasemia and deranged liver function tests. Computerized Tomography (CT) revealed a 3 cm attenuated structure that can be traced up to the left portal vein, which represents an acute thrombosis of the falciform ligament. The patient was treated with Tinzaparin and subsequently anticoagulated. She subsequently had a laparoscopic cholecystectomy and made an uneventful recovery. We suspect that pancreatitis caused thrombophlebitis subsequently leading to recanalization and thrombosis of the umbilical vein. Falciform ligament thrombosis is a rare and poorly described complication following pancreatitis which clinicians and radiologists should be aware of.

Integrated modelling of crop production and nitrate leaching with the Daisy model.

An integrated modelling strategy was designed and applied to the Soil-Vegetation-Atmosphere Transfer model Daisy for simulation of crop production and nitrate leaching under pedo-climatic and agronomic environment different than that of model original parameterisation. The points of significance and caution in the strategy are: •Model preparation should include field data in detail due to the high complexity of the soil and the crop processes simulated with process-based model, and should reflect the study objectives. Inclusion of interactions between parameters in a sensitivity analysis results in better account for impacts on outputs of measured variables.•Model evaluation on several independent data sets increases robustness, at least on coarser time scales such as month or year. It produces a valuable platform for adaptation of the model to new crops or for the improvement of the existing parameters set. On daily time scale, validation for highly dynamic variables such as soil water transport remains challenging. •Model application is demonstrated with relevance for scientists and regional managers. The integrated modelling strategy is applicable for other process-based models similar to Daisy. It is envisaged that the strategy establishes model capability as a useful research/decision-making, and it increases knowledge transferability, reproducibility and traceability.

Early outcome of combined endoscopic third ventriculostomy and choroid plexus cauterization in childhood hydrocephalus.

OBJECT: Although shunts have been the mainstay in treating hydrocephalus over the past 5 decades, the use of endoscopic techniques in addressing this disorder in children offers both the neurosurgeon and the patient a unique opportunity to avoid shunting and its attendant complications. The combination of endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) remains uncommon in most centers despite its potential promise. The authors sought to investigate the efficacy of combining ETV and CPC (ETV+CPC) in treating childhood hydrocephalus in Nigeria. Infection and spina bifida contribute a high percentage of the cases of hydrocephalus in Nigeria. METHODS: Over a 2-year period, all children 0-18 years of age who had endoscopic treatment for hydrocephalus were prospectively evaluated to determine the need for subsequent treatment. Children who had the combination of ETV+CPC were identified as a subcategory and form the basis of this retrospective study. RESULTS: Twenty-two of 38 endoscopically treated children had undergone the combination of ETV+CPC for hydrocephalus of varied etiology. There was a male preponderance (2.5:1), and 90% of the patients were infants. The overall success rate was 75%, with the best outcome in children with spina bifida. One child required a repeat ETV. CONCLUSIONS: The combination of ETV+CPC is useful in treating children with hydrocephalus of varied etiology. The complication profile is acceptable, and the overall success rate is comparable to that associated with shunt insertion.

Retrieval of cement embolus from inferior vena cava after percutaneous vertebroplasty.

Percutaneous vertebroplasty is an accepted treatment for painful vertebral compression fractures caused by osteoporosis and malignant disease. Venous leakage of cement and pulmonary cement embolism have been reported complications. We describe a paravertebral venous cement leak resulting in the deposition of a cement cast in the inferior vena cava and successful retrieval of the cement embolus.

Physiological responses of potato (Solanum tuberosum L.) to partial root-zone drying: ABA signalling, leaf gas exchange, and water use efficiency.

The physiological responses of potato (Solanum tuberosum L. cv. Folva) to partial root-zone drying (PRD) were investigated in potted plants in a greenhouse (GH) and in plants grown in the field under an automatic rain-out-shelter. In the GH, irrigation was applied daily to the whole root system (FI), or to one-half of the root system while the other half was dried, for 9 d. In the field, the plants were drip irrigated either to the whole root system near field capacity (FI) or using 70% water of FI to one side of the roots, and shifted to the other side every 5-10 d (PRD). PRD plants had a similar midday leaf water potential to that of FI, whereas in the GH their root water potential (Psi(r)) was significantly lowered after 5 d. Stomatal conductance (g(s)) was more sensitive to PRD than photosynthesis (A) particularly in the field, leading to greater intrinsic water use efficiency (WUE) (i.e. A/g(s)) in PRD than in FI plants on several days. In PRD, the xylem sap abscisic acid concentration ([ABA](xylem)) increased exponentially with decreasing Psi(r); and the relative [ABA](xylem) (PRD/FI) increased exponentially as the fraction of transpirable soil water (FTSW) in the drying side decreased. In the field, the leaf area index was slightly less in PRD than in FI treatment, while tuber biomass was similar for the two treatments. Compared with FI, PRD treatment saved 30% water and increased crop water use efficiency (WUE) by 59%. Restrictions on leaf area expansion and g(s) by PRD-induced ABA signals might have contributed to reduced water use and increased WUE.

A genome-wide search for linkage to asthma phenotypes in the genetics of asthma international network families: evidence for a major susceptibility locus on chromosome 2p.

Asthma is a complex disease and the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Families with at least two siblings with asthma were collected from Europe, Australia and the US. A genome scan using a set of 364 families with a panel of 396 microsatellite markers was conducted. Nonparametric linkage analyses were conducted for asthma and three asthma-related phenotypes: bronchial hyper-reactivity (BHR), strict definition of asthma and atopic asthma. Nine chromosomal regions with LOD scores greater than 1.5 were identified (chromosomes 1q, 2p, 3q, 4p, 4q, 6q, 12q, 20p and 21). Linkage refinement analysis was performed for three BHR loci by genotyping single nucleotide polymorphisms at an average marker density of 1 cM. The LOD scores increased to 3.07 at chromosome 4p and 4.58 at chromosome 2p, while the chromosome 6p locus did not refine. The LOD score at the chromosome 2p locus is highly significant on a genome-wide basis. The refined locus covers a region with a physical size of 12.2 Mb. Taken together, these results provide evidence for a major asthma susceptibility locus on chromosome 2p.

Consequences for Protaphorura armata (Collembola: Onychiuridae) following exposure to genetically modified Bacillus thuringiensis (Bt) maize and non-Bt maize.

Studies on the effect of genetically modified Bacillus thuringiensis (Bt) crops on true soil dwelling non-target arthropods are scarce. The objective of this study was to assess the influence of a 4-week exposure to two Bt maize varieties (Cry1Ab) Cascade and MEB307 on the collembolan Protaphorura armata. For comparison three non-Bt maize varieties, Rivaldo (isogenic to Cascade), Monumental (isogenic to MEB307) and DK242, and two control diets based on baker's yeast (uncontaminated and contaminated with Bt toxin Cry1Ab) were also tested. Due to a lower C:N ratio, individuals reared on yeast performed significantly better in all of the measured endpoints than those reared on maize. P. armata performed equally well when reared on two Bt and three non-Bt maize varieties. Although there were no negative effects of Bt maize in this experiment, we recommend future studies on Bt crops to focus on species interactions in long-term, multi-species experiments.