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Chlorpyrifos (CPF) is an organophosphate insecticide commonly used to treat fruit and vegetable crops. CPF can cause severe adverse effects on body organs including the liver and central nervous system. This study investigated the CPF-induced inflammation in mice and explored the role of intestinal flora changes in liver inflammation. Adult C57BL/6 male mice were exposed to a CPF of 0.01-, 0.1-, 1- and 10-mg/kg bodyweight for 12 weeks. The mice in experimental group given CPF solution dissolved in corn oil vehicle by gavage, was administered by intraoral gavage for 5 days per week for 12 weeks. Histopathological examination and inflammatory factor detection were performed on mice liver tissue. Faeces were used for 16S ribosomal RNA high-throughput sequencing to explore the impact of CPF on intestinal flora structure and diversity. The results showed that 1- and 10-mg/kg CPF caused different degrees of liver focal inflammation. The structure of intestinal flora changed significantly in mice including the decreased beneficial bacteria (Akkermansia, Prevotella and Butyricimonas) and increased pathogenic bacteria (Helicobacter and Desulfovibrio). Meanwhile, the results of Q-RT-PCR showed that there was more total bacterial DNA in the liver tissue of the mice treated with 10-mg/kg groups. In conclusion, the imbalance of intestinal flora, the decreased abundance of beneficial bacteria and the increased abundance of pathogenic bacteria, as well as the increase of total bacterial DNA in the liver tissues, maybe associated with the liver focal inflammation induced by CPF.

The respiratory tract and the oral mucosa are the first areas contaminated by pesticides. The herbicide dichlorophenoxyacetic acid (2,4-D) is a widely used pesticide across the world for both crops and gardens. The aim of this study was to evaluate oral mucosal damage after an experimental simulation of chronic oral and inhalational environmental exposure to 2,4-D formulation. Eighty male Wistar rats were exposed to three distinct concentrations of 2,4-D formulation (low—187.17 mg/m3; medium—313.31 mg/m3; and high—467.93 mg/m3). Oral exposure (through contaminated feed) or inhalation exposure lasted 6 months. Rat tongues were collected for cyto- and histopathology. There was a difference between exposure groups in the intensity of tissue congestion. Most rats exposed to 2,4-D presented mucosal inflammation at both cytology and histology (P

Paper-based works of art and documents of cultural importance kept in museums and libraries can show notorious signs of deterioration, including foxing stains, caused by fungal colonization. Some of the main chromophore agents of fungal origin that deteriorate paper and therefore affect paper cultural heritage both aesthetically and structurally are the group of pigments called melanins. Thus, knowledge of the diversity and features of fungal melanins and of the melanization pathways of fungi growing on paper is key to removing these pigments from paper-based works of cultural importance. This review provides an approach about the current knowledge of melanins synthesized by paper-colonizing fungi, their localization in the fungal structures, and their role in the deterioration of paper. This knowledge might contribute to developing new, effective, and sustainable strategies of restoration and conservation of historical documents and works of art based on paper.

Objective To report PCR results and vaccination status of rabbits with rabbit haemorrhagic disease following an investigation into sudden or unexpected death. Materials and methods PCR testing for RHDV2 and RHDV1 was performed on rabbit liver samples at two laboratories. Laboratory A reported results as positive or negative; Laboratory B reported results quantitatively as RNA copies per mg liver, categorised as negative, inconclusive or positive. The vaccination status of rabbits with both histopathological features of rabbit haemorrhagic disease and positive PCR test results were collated. Results PCR results matched histopathological findings in 188 of 195 (96%) cases. Seven individuals showed equivocal results, all of which had histopathological features of RHD but three tested PCR-negative and four results conflicted between laboratories. RHDV2 was the serotype detected in all PCR-positive cases. Histological features of rabbit haemorrhagic disease and PCR test results were positive in 125 rabbits; 51 unvaccinated, 56 in-date with Nobivac Myxo-RHD and 13 vaccinated against RHDV2 - although nine of these were vaccinated within 10 days of death. Clinical significance PCR testing complements histopathology in cases of sudden death in rabbits by confirming the diagnosis and identifying virus serotype, but there can be false negatives. Although RHDV2 is currently prevalent in UK pet rabbits, vaccination against both RHDV1 and RHDV2 is recommended. Failures of RHDV2 vaccine are infrequent.

Chlordecone (CD) is one of the common persistent organic pollutants in nature and has a profound impact on the environment and on public health. Accumulating evidence has demonstrated that neonatal exposure of CD influences adult physiology and behavior due to its estrogenic properties. Using socially monogamous mandarin voles as an experimental animal model, the present study aimed to evaluate the impact of neonatal exposure to CD on female social behaviors and central estrogen receptor alpha (ERα) expression in adulthood. After receiving a single subcutaneous injection with sesame seed oil (female control group), 17 beta-estradiol (E2 group), or CD group on postnatal Day 1, the social behaviors of adult animals and ERα expression in specific brain regions were assessed. The data indicated that CD or E2-treated female animals displayed increased affiliative behaviors and decreased aggressive behaviors with regard to the unfamiliar females in the social interaction test. In addition, CD or E2-treated female voles exhibited significant preferences to females over males in the sexual preference test. Moreover, CD-treated female animals exhibited higher levels of ERα expression in the bed nucleus of the stria terminalis, the central amygdala, the medial amygdala and the medial preoptic area compared with those of the control voles. The results suggested that neonatal exposure to CD may masculinize female social behaviors, possibly via CD-induced changes in the ERα expression of relevant brain regions.

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and of inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease (PAD) offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha (TNF-a), and high sensitivity C-reactive protein (hsCRP) were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels < 100 ng/mL. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20—100 ng/mL with % transferrin levels from 20–50%, to ensure adequate iron status and that ferritin levels above 194 ng/mL associate with all-cause mortality in population cohorts., Graphical Abstract Graphical Abstract

International audience; Mosquito control is implemented when arboviruses are detected in patients or in field-collected mosquitoes. However, mass screening of mosquitoes is usually laborious and expensive, requiring specialized expertise and equipment. Detection of virus in mosquito saliva using honey-impregnated filter papers seems to be a promising method as it is non-destructive and allows monitoring the viral excretion dynamics over time from the same mosquito. Here we test the use of filter papers to detect chikungunya virus in mosquito saliva in laboratory conditions, before proposing this method in large-scale mosquito surveillance programs. We found that 0.9 cm 2 cards impregnated with a 50% honey solution could replace the forced salivation technique as they offered a viral RNA detection until 7 days after oral infection of Aedes aegypti and Aedes albopictus mosquitoes with CHIKV.

Sodium benzoate (NaB) is a versatile food preservative that has also found some applications in the treatment of medical disorders. However, till date, its possible widespread effects on the body are not well studied. We examined the likely effect of diet-added NaB on weight/food intake, haematological parameters, neurobehaviour, antioxidant status, lipid profile and anti-inflammatory/apoptotic markers in mice. Animals were assigned randomly into 4 groups of 10 mice each. Groups included normal control (fed rodent chow) and three groups fed NaB at 125 (0.0125%), 250 (0.025% and 500 (0.05%) mg/kg of feed added to diet, respectively, for eight weeks. Body weight and food intake were assessed. At the end of the experimental period animals were euthanized, blood was then taken for the assessment of haematological, biochemical and inflammatory/apoptotic markers. At the lowest concentration, NaB diet increased body weight and food intake. Decrease in haematological cell counts and total antioxidant capacity were observed, whereas serum malondialdehyde levels and superoxide dismutase activity were increased across the three concentrations. Serum tumour necrosis factor-alpha and interleukin-10 decreased, whereas caspase-3 levels showed no significant difference. Lipid profile and biochemical indices of kidney and liver function were also affected by NaB diet. In conclusion, our findings suggest that NaB may be harmful if regulations regarding its limit of consumption are mistakenly or deliberately ignored. Therefore, it is advisable that regulations on quantities to be added to food be enforced.

Significance: Contamination of diffuse correlation spectroscopy (DCS) measurements of cerebral blood flow (CBF) due to systemic physiology remains a significant challenge in the clinical translation of DCS for neuromonitoring. Tunable, multi-layer Monte Carlo-based (MC) light transport models have the potential to remove extracerebral flow cross-talk in cerebral blood flow index (CBFi) estimates. Aim: We explore the effectiveness of MC DCS models in recovering accurate CBFi changes in the presence of strong systemic physiology variations during a hypercapnia maneuver. Approach: Multi-layer slab and head-like realistic (curved) geometries were used to run MC simulations of photon propagation through the head. The simulation data were post-processed into models with variable extracerebral thicknesses and used to fit DCS multi-distance intensity autocorrelation measurements to estimate CBFi timecourses. The results of the MC CBFi values from a set of human subject hypercapnia sessions were compared with CBFi values estimated using a semi-infinite analytical model, as commonly used in the field. Results: Group averages indicate a gradual systemic increase in blood flow following a different temporal profile versus the expected rapid CBF response. Optimized MC models, guided by several intrinsic criteria and a pressure modulation maneuver, were able to more effectively separate CBFi changes from scalp blood flow influence than the analytical fitting, which assumed a homogeneous medium. Three-layer models performed better than two-layer ones; slab and curved models achieved largely similar results, though curved geometries were closer to physiological layer thicknesses. Conclusion: Three-layer, adjustable MC models can be useful in separating distinct changes in scalp and brain blood flow. Pressure modulation, along with reasonable estimates of physiological parameters, can help direct the choice of appropriate layer thicknesses in MC models.

The mycotoxin zearalenone (ZEN) is a common contaminant of swine feed which has been related to a wide range of reproductive anomalies in swine, such as pelvic organ prolapse, anestrous, and pseudopregnancy. New information is needed to understand how ZEN and related metabolites accumulate in swine reproductive tissues. We conducted a feeding study to track ZEN and the metabolite α-zearalenol (α-ZEL) in swine liver and reproductive tissues. Thirty pubertal gilts were randomly assigned one of three treatments, with ten pigs in each treatment group: (1) base feed with solvent for 21 days, (2) ZEN-spiked feed for seven days followed by base feed with solvent for 14 days, and (3) ZEN-spiked feed for 21 days. At the end of the trial, liver, anterior vagina, posterior vagina, cervix, uterus, ovaries, and broad ligament were collected from pigs. ZEN was found in the anterior vagina, posterior vagina, cervix, and ovaries, with significantly higher concentrations in the cervix relative to other reproductive tissues. ZEN and α-ZEL were found in liver tissue from pigs in each treatment group. Our results show that ZEN accumulates more in the cervix than other reproductive tissues. The presence of ZEN in reproductive tissues may be indicative of ZEN-related reproductive symptoms. Future work could examine how ZEN concentrations vary in reproductive tissues as a factor of the pigs age, weight, sex, or parity, to establish parameters that make pig more sensitive to ZEN., Highlights • A feeding trial was conducted where gilts consumed varying amounts of zearalenone. • Zearalenone was found in the anterior vagina, posterior vagina, cervix, and ovaries. • Zearalenone concentrations were highest in the cervix. • Zearalenone and alpha-zearalenol were found in the liver.

Significance: Prenatal exposure to ethanol causes several morphological and neurobehavioral deficits. While there are some studies on the effects of ethanol exposure on blood flow, research focusing on acute changes in the microvasculature is limited. Aim: The first aim of this study was to assess the dose-dependent changes in murine fetal brain microvasculature of developing fetuses in response to maternal alcohol consumption. The second aim was to quantify changes in vasculature occurring concurrently in the mother’s hindlimb and the fetus’s brain after maternal exposure to alcohol. Approach: Correlation mapping optical coherence angiography was used to evaluate the effects of prenatal exposure to different doses of ethanol (3, 1.5, and 0.75 g / kg) on murine fetal brain vasculature in utero. Additionally, simultaneous imaging of maternal peripheral vessels and the fetal brain vasculature was performed to assess changes of the vasculature occurring concurrently in response to ethanol consumption. Results: The fetal brain vessel diameters (VDs) decreased by ∼47 % , 30%, and 14% in response to ethanol doses of 3, 1.5, and 0.75 g / kg, respectively. However, the mother’s hindlimb VD increased by 63% in response to ethanol at a dose of 3 g / kg. Conclusions: Results showed a dose-dependent reduction in vascular blood flow in fetal brain vessels when the mother was exposed to ethanol, whereas vessels in the maternal hindlimb exhibited concurrent vasodilation.

A large outbreak of liver toxicity in dairy cows that were consuming swede (rutabaga, Brassica napus ssp. napobrassica) crops in Southland and Otago, New Zealand in 2014 prompted the search for the toxin(s) responsible for brassica-associated liver disease (BALD). Analysis of swede plant material showed that the ultra-dominant glucosinolate was progoitrin. The two nitrile derivatives of progoitrin, 1-cyano-2-hydroxy-3-butene (CHB, also known as crambene) and 1-cyano-2-hydroxy-3,4-epithiobutane (CHEB), were custom-synthesised. In this pilot trial, individual progoitrin nitriles were administered by gavage to rats in order to establish a “subtoxic” dose, i.e. the dose where apparently clinically normal rats show liver injury based on altered serum biochemical indicators and histological lesions. We found that consecutive daily doses of 1 mmol/kg CHB produced severe pancreatic and mild liver histological lesions in the absence of notable biochemical changes in clinically normal rats. No evidence of a cumulative effect was seen. Single doses of 1 mmol/kg of CHEB caused elevated concentrations of serum creatinine and distinctive renal and stomach histological lesions in apparently clinically normal rats. Consecutive daily 1 mmol/kg doses of CHEB had a considerable cumulative effect and proved severely hepato- and nephrotoxic with creatinine concentrations peaking after three daily doses. Three other commercially available nitriles (3-butenenitrile, 4-pentenenitrile and 5-hexenenitrile) derived from minor glucosinolates in the swedes were also investigated in this pilot trial. Single combined 1 mmol/kg doses of both progoitrin nitriles as well as these two nitriles plus small doses of the other three failed to demonstrate any synergism, however, the characteristic and apparently dominant effects of CHEB were consistently demonstrated. The results of this pilot study confirmed the previously reported pancreatotoxicity of CHB and nephrotoxicity of CHEB. CHEB also caused intraepithelial pustules, submucosal oedema, erosions and ulcers in the squamous portion of the stomach. These stomach lesions, as well as the renal lesions, appear identical to those caused by another epithionitrile, 1-cyano-3,4-epithiobutane, derived from gluconapin, which was a minor glucosinolate in the swedes. Because of the fact that cyanide can be released with the metabolism of some nitriles, we analysed cyanide in the livers of treated rats. The liver of a rat dosed with 1 mmol/kg of 3-butenenitrile contained 0.5 μg/g of cyanide. The hypothesis that BALD is due to nitrile toxicity requires further testing., Highlights • Cause of Brassica-associated liver disease (BALD) in cattle unknown. • Progoitrin is the glucosinolate in highest concentration in implicated Brassica spp. • Pilot trial to find subtoxic dose of two progoitrin nitrile derivatives in rats. • Single 1 mmol/kg 1-cyano-2-hydroxy-3-butene pancreatotoxic, consecutive doses not cumulative, higher doses also hepatotoxic. • Single 1 mmol/kg 1-cyano-2-hydroxy-3,4-epithiobutane nephrotoxic, consecutive doses cumulative, higher doses also hepatotoxic.

Isocoma pluriflora and Isocoma acradenia are toxic plants that contain the putative toxin tremetone. It is common for I. pluriflora to poison livestock in the southwestern United States. I. acradenia has been suspected of poisoning livestock but its toxicity has not been confirmed by association with clinical poisonings or experimental studies. Jersey calves dosed with I. pluriflora and I. acradenia for nine days developed “trembles” characterized by skeletal muscle degeneration and necrosis and large increases in serum creatine kinase activity. This is the first report of I. acradenia toxicity in an animal model. This study also demonstrates that I. pluriflora remains toxic even though tremetone concentrations in the plant were low due to storage of the plant for over five years. Thus, supporting recent research which indicates that another toxin in the plant may be responsible for, or at least contributes to causing “trembles” in livestock., Highlights • The first report of Isocoma acradenia toxicity in an animal model. • Isocoma pluriflora remains toxic even though tremetone concentrations are very low. • A histologic description of the lesions caused by Isocoma acradenia poisoning.

Non-invasive diagnosis on biological liquid samples, such as urine, sweat, saliva, and tears, may allow patients to evaluate their health by themselves. To obtain accurate diagnostic results, target liquid must be precisely sampled. Conventionally, urine sampling using filter paper can be given as an example sampling, but differences in the paper structure can cause variations in sampling volume. This paper describes precise liquid sampling using synthetic microfluidic papers, which are composed of obliquely combined micropillars. Sampling volume accuracy was investigated using different designs and collection methods to determine the optimal design and sample collecting method. The optimized protocol was followed to accurately measure potassium concentration using synthetic microfluidic paper and a commercially available densitometer, which verified the usefulness of the synthetic microfluidic papers for precision sampling.

While many studies have shown that pulp mill effluents can affect ovarian physiology in fish, far fewer studies have considered the effects in males. We conducted a lab study to examine the effects of effluent from a Brazilian pulp and paper mill on hepatic and testicular morphology and various aspects of testicular physiology in the zebrafish Danio rerio. Males were exposed to lab water (control) or 4% effluent for 14 days. Effluent exposure did not affect testis size as measured by the gonadosomatic index, but contributed to morphological changes in the seminiferous tubules. The number of cysts with histopathological changes was elevated in effluent-exposed fish and the number of cysts containing spermatids was significantly reduced. The testis of effluent exposed fish had reduced levels of lactate, elevated lactate dehydrogenase activity, increased levels of reactive oxygen species and reduced levels of phosphorylated P38 mitogen-activated protein kinase (pP38 MAPK). Separate studies showed that the addition of lactate to testicular tissue incubated in vitro increased the activation of P38 MAPK. Effluent exposure also increased vacuolization, necrosis, apoptosis, hyperemia, and fat infiltration of the hepatocytes. Collectively, we provide evidence of short term effects of pulp mill effluent on testicular and hepatic physiology and biochemistry in the zebrafish.

Pulp and paper mill effluent can cause changes in the morphology and energy metabolism in the zebrafish (Danio rerio) testis. Betulin, a naturally occurring triterpene is commonly present in this type of effluent and is suspected of being involved in these effects. The aim of this study was to compare the effects pulp and paper mill effluent and betulin on various aspects of testicular physiology in the zebrafish. This included the in vitro effects of effluent and betulin on testicular lactate content and lactate dehydrogenase (LDH) activity. In addition, the effects of betulin on glucose uptake, glycogen, alanine aminotransferase (ALT), reactive oxygen and nitrogen species formation and oxidative damage in the testes were determined. Furthermore, we compared the effects and mechanism of action of betulin and effluent on calcium homeostasis in testes. In vitro exposure to both effluent and betulin decreased lactate and calcium influx, possibly due to the activation of the sodium‑calcium exchanger (NCX) pump. Additionally, betulin-treated testes had higher reactive oxygen species (ROS) and reduced glutathione (GSH) content, as well as increased glutathione transferase (GST) activity and a tendency towards decreased catalase (CAT) activity. Thus, this study shows that alterations in testis physiology caused by the pulp and paper mill effluent in the testis may be due in part to the actions of betulin.

Bisphenol A (BPA) is an endocrine disruptor frequently detected in human biofluids. Dermal absorption of BPA from thermal paper receipts occurs but BPA pharmacokinetics following dermal exposure is not understood. To compare the pharmacokinetics of dermal and dietary BPA exposure, six male participants handled simulated receipts containing relevant levels of BPA (isotope-labeled BPA-d16) for 5 min, followed by hand-washing 2 h later. Urine (0–48 h) and serum (0–7.5 h) were monitored for free and total BPA-d16. One week later, participants returned for a dietary administration with monitoring as above. One participant repeated the dermal administration with extended monitoring of urine (9 days) and serum (2 days). After dietary exposure, urine total BPA-d16 peaked within 5 h and quickly cleared within 24 h. After dermal exposure, cumulative excretion increased linearly for 2 days, and half the participants still had detectable urinary total BPA-d16 after 1 week. The participant repeating the dermal exposur...

α-Amylase is a starch-hydrolyzing enzyme (EC 3.2.1.1) indispensable for germination of cereal seeds, but it is also expressed during the ripening stage. Previous studies demonstrated that the enzyme is activated in developing rice seeds under extremely hot weather and triggers a loss of grain quality by hindering the accumulation of storage starch in the endosperm. Since inactive or, preferably, heat-labile α-amylases are preferable for breeding premium rice, we developed a method for rapid screening of inactive and temperature-sensitive mutants of the enzyme by combining the random mutagenesis by error-prone PCR and an on-filter activity test of the recombinant enzyme expressed by Escherichia coli. This technique was applied to a major α-amylase in the developing seed, Amy3D, and the activity of the isolated mutant enzymes was verified with both the bacteria-expressed recombinant proteins and the extract from the endosperm overexpressing each of them. Then, we identified several substitutions leading to loss of the activity of amino acid residues (Leu28, Asp112, Cys149, Trp201, Asp204, Gly295, Leu300 and Cys342), as well as a variety of heat-sensitive substitutions of Asp83, Asp187 and Glu252. Furthermore, variations of the heat-labile enzymes were created by combining these heat-sensitive mutations. The effects of the respective mutations and their relationship to the structure of the enzyme molecule are discussed.

Non-contact vital sign monitoring enables the estimation of vital signs, such as heart rate, respiratory rate and oxygen saturation (SpO2), by measuring subtle color changes on the skin surface using a video camera. For patients in a hospital ward, the main challenges in the development of continuous and robust non-contact monitoring techniques are the identification of time periods and the segmentation of skin regions of interest (ROIs) from which vital signs can be estimated. We propose a deep learning framework to tackle these challenges. Approach: This paper presents two convolutional neural network (CNN) models. The first network was designed for detecting the presence of a patient and segmenting the patient’s skin area. The second network combined the output from the first network with optical flow for identifying time periods of clinical intervention so that these periods can be excluded from the estimation of vital signs. Both networks were trained using video recordings from a clinical study involving 15 pre-term infants conducted in the high dependency area of the neonatal intensive care unit (NICU) of the John Radcliffe Hospital in Oxford, UK. Main results: Our proposed methods achieved an accuracy of 98.8% for patient detection, a mean intersection-over-union (IOU) score of 88.6% for skin segmentation and an accuracy of 94.5% for clinical intervention detection using two-fold cross validation. Our deep learning models produced accurate results and were robust to different skin tones, changes in light conditions, pose variations and different clinical interventions by medical staff and family visitors. Significance: Our approach allows cardio-respiratory signals to be continuously derived from the patient’s skin during which the patient is present and no clinical intervention is undertaken.

Background Reduced susceptibility of mosquito vectors to currently used insecticides hampers control interventions. Recently pyriproxyfen, an insect growth regulator has been demonstrated to effectively reduce the reproductive potential in vector mosquitoes. Methods Pyriproxyfen (PPF), in different concentrations (0.75%, 0.075%, 0.0075%, and 0.00075%) was applied on papers and Indian wild type Aedes aegypti female mosquitoes (N ≥ 20 for each treatment) were exposed onto it as per WHO guidelines, to study the reproductive disruption. PPF concentration on treated papers was quantitatively cross-determined using HPLC method. Reduction in fecundity, fertility and adult emergence in exposed female Ae. aegypti was determined. Abnormal development in ovary and eggs of exposed females was studied microscopically after different time intervals. Results Eggs laid, eggs hatched, pupae formed and adults emerged per female exposed in both before blood meal and after blood meal groups declined significantly from lowest to highest concentration of PPF (F ≥ 5.2; p < 0.02). Adult emergence inhibition in females exposed to PPF before and after blood meal groups ranged from 58.8% [OR = 0.18 (95% CI = 0.09–0.36)] to 79.2% [OR = 0.04 (95% CI = 0.02–0.10)] and 64.4% [OR = 0.12 (95% CI = 0.05–0.28)] to 77.1% [OR = 0.05 (95% CI = 0.02–0.14)] respectively in different concentrations. The probit model used suggested that FI50 (50% fertility inhibition) and EI50 (50% emergence inhibition) were 0.002% (p = 0.82) and 0.0001% (p = 0.99) for females exposed before blood meal, while 0.01% (p = 0.63) and, Author summary Development of resistance against insecticides has challenged mosquito control programmes globally and prompted the research of alternative options that can complement insecticides. An insect growth regulator, pyriproxyfen (PPF) usage against mosquitoes can effectively reduce the vector population. PPF mainly inhibits the metamorphosis of mosquito larvae into pupae and prevent the adult emergence, therefore it is generally applied in mosquito breeding habitats. PPF has been shown to exhibit delayed residual effect that may impair the reproductive capacity by affecting the survival, fecundity and fertility of adult mosquito exposed through tarsal contact. Presently, the effectiveness of different concentrations of PPF intended to be delivered through contact have been evaluated against dengue vector Ae. aegypti. Results suggested that very low PPF concentration treated surfaces drastically reduce the fecundity, fertility and adult emergence in mosquitoes. Study suggests that control interventions based on PPF-treated surfaces could provide an additional route to target mosquito vector control by overall population density reduction.

Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (StO2), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in StO2 and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology.

Previous studies have demonstrated that skin vibration is an important factor affecting the roughness perception of fine textures. For coarse textures, the determining physical factor is much less clear and there are indications that this might be participant-dependent. In this paper, we focused on roughness perception of both coarse and fine textures of different materials (glass particle surfaces and sandpapers). We investigated the relationship between subjective roughness ratings and three physical parameters (skin vibration, friction coefficient, and particle size) within a group of 30 participants. Results of the glass particle surfaces showed both spatial information (particle size) and temporal information (skin vibration) had a high correlation with subjective roughness ratings. The former correlation was slightly but significantly higher than the latter. The results also indicated different weights of temporal information and spatial information for roughness ratings among participants. Roughness ratings of a different material (sandpaper versus glass particles) could be either larger, similar or smaller, indicating differences among individuals. The best way to describe our results is that in their perceptual evaluation of roughness, different individuals weight temporal information, spatial information, and other mechanical properties differently.

Some thermal paper receipts, commonly referred to as cash register receipts, contain high levels of bisphenol A (BPA). The goal of this study is to investigate whether increased contact with thermal paper receipts is associated with an increase in urinary BPA excretion. Individuals from the NHANES 2003-2004 survey were stratified based on occupation to compare urinary BPA excretion levels. The first major finding demonstrates that individuals with potential occupational exposure to thermal paper receipts are more likely to have detectable levels of urinary BPA compared to individuals with unlikely occupational exposure (p-value0.001). The second major finding is that females with potential occupational exposure to thermal paper receipts have significantly higher levels of urinary BPA excretion (geometric mean (GM): 5.45 μg/L, 95% CI: (4.02, 7.39)) compared to females with unlikely occupational exposure (GM: 2.16 μg/L, 95% CI: (1.73, 2.70)). This association continues to remain statistically significant when controlling for creatinine, race, body mass index (BMI), and age. Notably, there was no statistically significant association between occupation and urinary BPA excretion among males. These results suggest that exposure to BPA from thermal paper should be considered when determining aggregate BPA exposure.

Bisphenol A (BPA) is an endocrine disrupting environmental chemical. Urinary concentrations of BPA were measured in samples collected nationwide from Chinese young adults. The geometric mean urinary concentration of BPA in Chinese young adults was 2.23 ng/mL. The estimated daily exposure dose for BPA was 64.8 ng/kg bw/day. Contributions of various BPA sources to exposure in Chinese young adults were estimated. Dietary intake was the primary exposure pathway. The contribution of dietary intake, indoor dust, paper products and personal care products to BPA intake was 72.5 %, 0.74 %, 0.98 %, 0.22 % of the total exposure dose, respectively. This is the first study on the occurrence of BPA in young adults from most provinces and autonomous regions of China. The results can be used to establish a database for BPA exposure assessment for Chinese general population.

Most infectious diseases are unequally distributed between male and female subjects. This sex dimorphism is confirmed by epidemiologic studies which suggest an increased number of male septic patients, while, due to the class age of septic patients, an overrepresentation of female patients would be expected. Lifestyle, recreational activities, professional exposition and access to care are plausible reasons for this dimorphism. However, biological differences should be carefully considered, particularly the weight of X-linked variability and the role of sex hormones. Animal models clearly show that clinical response to infection is more exuberant in males than in females. This is partly explained by an attenuation of the inflammatory response by female sex hormones. However, the translation from experimental studies to the bedside remains challenging as a result of confounding factors like age, hormone changes and response to treatment. Keywords: Bacteria, estradiol, gender, infection, sex

Introduction \ud Data collection using paper-based questionnaires can be time consuming and return errors affect data accuracy, completeness, and information quality in health surveys. We compared smartphone and paper-based data collection systems in the Burden of Obstructive Lung Disease (BOLD) study in rural Sudan. \ud Methods \ud This exploratory pilot study was designed to run in parallel with the cross-sectional household survey. The Open Data Kit was used to programme questionnaires in Arabic into smartphones. We included 100 study participants (83% women; median age = 41.5 ± 16.4 years) from the BOLD study from 3 rural villages in East-Gezira and Kamleen localities of Gezira state, Sudan. Questionnaire data were collected using smartphone and paper-based technologies simultaneously. We used Kappa statistics and inter-rater class coefficient to test agreement between the two methods. Results Symptoms reported included cough (24%), phlegm (15%), wheezing (17%), and shortness of breath (18%). One in five were or had been cigarette smokers. The two data collection methods varied between perfect to slight agreement across the 204 variables evaluated (Kappa varied between 1.00 and 0.02 and inter-rater coefficient between 1.00 and -0.12). Errors were most commonly seen with paper questionnaires (83% of errors seen) vs smartphones (17% of errors seen) administered questionnaires with questions with complex skip-patterns being a major source of errors in paper questionnaires. Automated checks and validations in smartphone-administered questionnaires avoided skip-pattern related errors. Incomplete and inconsistent records were more likely seen on paper questionnaires. \ud Conclusion \ud Compared to paper-based data collection, smartphone technology worked well for data collection in the study, which was conducted in a challenging rural environment in Sudan. This approach provided timely, quality data with fewer errors and inconsistencies compared to paper-based data collection. We recommend this method for future BOLD studies and other population-based studies in similar settings.

Electrical impedance tomography (EIT) could provide images of fast neural activity in the adult human brain with a resolution of 1 ms and 1 mm by imaging impedance changes which occur as ion channels open during neuronal depolarization. The largest changes occur at dc and decrease rapidly over 100 Hz. Evoked potentials occur in this bandwidth and may cause artefactual apparent impedance changes if altered by the impedance measuring current. These were characterized during the compound action potential in the walking leg nerves of Cancer pagurus, placed on Ag/AgCl hook electrodes, to identify how to avoid artefactual changes during brain EIT. Artefact-free impedance changes (δZ) decreased with frequency from −0.045 ± 0.01% at 225 Hz to −0.02 ± 0.01% at 1025 Hz (mean ± 1 SD, n = 24 in 12 nerves) which matched changes predicted by a finite element model. Artefactual δZ reached c.300% and 50% of the genuine membrane impedance change at 225 Hz and 600 Hz respectively but decreased with frequency of the applied current and was negligible above 1 kHz. The proportional amplitude (δZ (%)) of the artefact did not vary significantly with the amplitude of injected current of 5–20 µA pp. but decreased significantly from −0.09 ± 0.024 to −0.03 ± 0.023% with phase of 0 to 45°. For fast neural EIT of evoked activity in the brain, artefacts may arise with applied current of >10 µA. Independence of δZ with respect to phase but not the amplitude of applied current controls for them; they can be minimized by randomizing the phase of the applied measuring current and excluded by recording at >1 kHz.

A gram positive, rod shaped, bacterium was isolated from pulp and paper mill sludge and characterized as Brevibacillus parabrevis (MTCC 12105) by biochemical tests and 16S rRNA gene sequencing. CD and EOP stage wastewater, collected from a leading pulp and paper mill situated in North India, was used for degradation study. Wastewater degradation efficiency of the bacterial isolate was evaluated by Flask study in batch mode and Reactor study in semi continuous mode. The isolated bacterium showed a considerable reduction of the colour (59%), chemical oxygen demand (62%) and lignin (53.8%) content of Kraft paper mill effluent at 37 °C after 5 days. During reactor study it reduced 42.6% Lignin, 51.6% Colour and 60.3% COD (chemical oxygen demand) of the wastewater at 48 h RT (retention time). The isolate was deposited at MTCC Chandigarh, India with an accession no. MTCC 12105.

International audience; Background: Identification of the source of mosquito blood meals is an important component for disease control and surveillance. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has emerged as an effective tool for mosquito blood meal identification, using the abdomens of freshly engorged mosquitoes. In the field, mosquito abdomens are crushed on Whatman filter papers to determine the host feeding patterns by identifying the origin of their blood meals. The aim of this study was to test whether crushing engorged mosquito abdomens on Whatman filter papers was compatible with MALDI-TOF MS for mosquito blood meal identification. Both laboratory reared and field collected mosquitoes were tested.Material and methods: Sixty Anopheles gambiae Giles were experimentally engorged on the blood of six distinct vertebrate hosts (human, sheep, rabbit, dog, chicken and rat). The engorged mosquito abdomens were crushed on Whatman filter papers for MALDI-TOF MS analysis. 150 Whatman filter papers, with mosquitoes engorged on cow and goat blood, were preserved. A total of 77 engorged mosquito abdomens collected in the Comoros Islands and crushed on Whatman filter papers were tested with MALDI-TOF MS. Results The MS profiles generated from mosquito engorged abdomens crushed on Whatman filter papers exhibited high reproducibility according to the original host blood. The blood meal host was correctly identified from mosquito abdomens crushed on Whatman filter papers by MALDI-TOF MS. The MS spectra obtained after storage were stable regardless of the room temperature and whether or not they were frozen. The MS profiles were reproducible for up to three months. For the Comoros samples, 70/77 quality MS spectra were obtained and matched with human blood spectra. This was confirmed by molecular tools.Conclusion: The results demonstrated that MALDI-TOF MS could identify mosquito blood meals from Whatman filter papers collected in the field during entomological surveys. The application of MALDI-TOF MS has proved to be rapid and successful, making it a new and efficient tool for mosquito-borne disease surveillance.

Bisphenol A (BPA) is an endocrine disrupting chemical used in a wide range of consumer products including photoactive dyes used in thermal paper. Recent studies have shown that dermal absorption of BPA can occur when handling these papers. Yet, regulatory agencies have largely dismissed thermal paper as a major source of BPA exposure. Exposure estimates provided by agencies such as the European Food Safety Authority (EFSA) are based on assumptions about how humans interact with this material, stating that ‘typical’ exposures for adults involve only one handling per day for short periods of time (30% of individuals hold thermal paper with more than three fingertips, and >60% allow the paper to touch their palm. Only 11% of the participants we observed were consistent with the EFSA model for time of contact and dermal surface area. Mathematical modeling based on handling times we measured and previously published transfer coefficients, concentrations of BPA in paper, and absorption factors indicate the most conservative estimated intake from handling thermal paper in this population is 51.1 ng/kg/day, similar to EFSA’s estimates of 59 ng/kg/day from dermal exposures. Less conservative estimates, using published data on concentrations in thermal paper and transfer rates to skin, indicate that exposures are likely significantly higher. Based on our observational data, we propose that the current models for estimating dermal BPA exposures are not consistent with normal human behavior and should be reevaluated.

Many complex physical systems exhibit a rich variety of discrete behavioural modes. Often, the system complexity limits the applicability of standard modelling tools. Hence, understanding the underlying physics of different behaviours and distinguishing between them is challenging. Although traditional machine learning techniques could predict and classify behaviour well, typically they do not provide any meaningful insight into the underlying physics of the system. In this paper we present a novel method for extracting physically meaningful clusters of discrete behaviour from limited experimental observations. This method obtains a set of physically plausible functions that both facilitate behavioural clustering and aid in system understanding. We demonstrate the approach on the V-shaped falling paper system, a new falling paper type system that exhibits four distinct behavioural modes depending on a few morphological parameters. Using just 49 experimental observations, the method discovered a set of candidate functions that distinguish behaviours with an error of 2.04%, while also aiding insight into the physical phenomena driving each behaviour. © 2019 Howison et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Mangrove fungi are vastly unexplored for enzymes with industrial application. This study aimed to assess the biocatalytic activity of mangrove fungal xylanases on recycled paper pulp. Forty-four mangrove fungal (MF) isolates were initially screened for xylanolytic activity in minimal medium with corn cob xylan as the sole carbon source. Eight MF were further cultivated under submerged fermentation for the production of crude xylanases. These crude enzymes were then characterized and tested for the pretreatment of recycled paper pulps. Results showed that 93 % of the tested MF isolates exhibited xylanolytic activity in solid medium. In submerged fermentation, salinity improved the growth of the fungal isolates but did not influence xylanase production. The crude xylanases were mostly optimally active at 50 °C and pH 7. Changes in pH had a greater effect on xylanase stability than temperature. More than half of the activity was lost at pH 9 for majority of the crude enzymes. However, two thermophilic xylanases from Fusarium sp. KAWIT-A and Aureobasidium sp. 2LIPA-M and one alkaliphilic xylanase from Phomopsis sp. MACA-J were also produced. All crude enzymes exhibited cellulase activities ranging from 4 to 21 U/ml. Enzymatic pretreatment of recycled paper pulps with 5 % consistency produced 70-650 mg of reducing sugars per gram of pulp at 50 °C after 60 min. The release of high amounts of reducing sugars showed the potential of mangrove fungal crude xylanases in the local paper and pulp industry. The diverse properties shown by the tested crude enzymes also indicate its potential applications to other enzyme-requiring industries.

In the veterinary professional curriculum, methods of examination in many courses are transitioning from the traditional paper-based exams to electronic-based exams. Therefore, a controlled trial to evaluate the impact of testing methodology on examination performance in a veterinary physiology course was designed and implemented. Formalized surveys and focus group discussions were also used to determine student attitudes toward the examination formats. In total, 134 first-year veterinary students and 11 PhD/MS students were administered a total of 4 exams throughout 1 semester (2 on paper and 2 electronically) using a split-halves design. The paper (P) and electronic (E) exams contained 25 identical multiple-choice questions. Students were randomly assigned to two groups and were given exams in one of two sequences (E-P-E-P or P-E-P-E). Participants consented to and completed two anonymous surveys vis à vis their experience. Out of a maximum raw score of 25, the mean score for electronic examinations (20.8; 95% confidence interval, 20.3–21.2) was significantly ( P = 0.01) greater than that for paper examinations (20.3; 95% confidence interval, 20.0–20.7). However, students expressed numerous concerns with the electronic examination format, and, at the completion of the study, 87% preferred to take their examination on paper rather than the electronic format. These data show that student attitudes concerning the examination format are not primarily determined by examination results, and that the additional anxiety related to the electronic examination format plays a large role in student attitudes.

It is well established that the contamination sources of cholera causing bacteria, Vibrio cholerae, are water and food, but little is known about the transmission role of the fomites (surfaces that can carry pathogens) commonly used in households. In the absence of appropriate nutrients or growth conditions on fomites, bacteria have been known to assume a viable but non-culturable (VBNC) state after a given period of time. To investigate whether and when V. cholerae O1 assumes such a state, this study investigated the survival and viable quantification on a range of fomites such as paper, wood, glass, plastic, cloth and several types of metals under laboratory conditions. The fomites were inoculated with an outbreak strain of V. cholerae and its culturability was examined by drop plate count method at 30 min intervals for up to 6 h. For molecular detection, the viable/dead stain ethidium monoazide (EMA) which inhibits amplification of DNA from dead cells was used in combination with real-time polymerase chain reaction (EMA-qPCR) for direct quantitative analyses of viable V. cholerae at 2, 4, 6, 24 h and 7 day time intervals. Results showed that V. cholerae on glass and aluminum surfaces lost culturability within one hour after inoculation but remained culturable on cloth and wood for up to four hours. VBNC V. cholerae on dry fomite surfaces was detected and quantified by EMA-qPCR even 7 days after inoculation. In conclusion, the prolonged survival of V. cholerae on various household fomites may play vital role in cholera transmission and needs to be further investigated.

Blood being a vehicle for the transport of industrial pollutants in living system, fish hematology is considered as potent biomarker. In the present study, we investigated respective sublethal effects of pulp and paper mill effluents on hematology of two commonly cultured carps, Cyprinus carpio and Ctenopharyngodon idella, using optical, scanning electron microscopy and energy-dispersive X-ray spectroscopy. Irrespective of species, results showed significant decrease in erythrocyte, hematocrit and hemoglobin contents while an increase in white blood cell counts (P

Background The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, ‘Dried Blood Spots’ or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). Methodology and Principal Findings Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200μl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end-dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009–15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25–30°C showed 81.6% (65.7–92.3 95%CI) positive agreement, 96.8% (91.0–99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70–0.92 95%CI). Conclusions/Significance The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids., Author Summary Japanese encephalitis virus infection is widespread in Asia, and primarily affects children in poor, rural areas. The virus spreads to the brain and spinal cord resulting in significant death and disability. Diagnosis requires testing for the immune response ‘antibody’ specific to Japanese encephalitis virus in the cerebrospinal fluid that surrounds the brain and spinal cord. However, in most areas where the infection occurs there are no laboratory facilities. In the absence of laboratory diagnosis, we have poor knowledge of the extent of the problem in these areas. Dried blood spots on filter paper have been used widely for many years as simple, cost-effective tools for transporting samples for testing. However, there have been few attempts at using dried cerebrospinal fluid spots. We developed a technique for using dried spots to store and test cerebrospinal fluid for antibodies to Japanese encephalitis virus. We compared the results of dried spots with routine neat cerebrospinal fluid in 132 patient samples, and demonstrated excellent agreement between the two tests. This novel method for saturating dried cerebrospinal fluid spots has the potential to enhance our knowledge of Japanese encephalitis virus epidemiology, and inform health policies where they are most needed. It could also be transferred for use in diagnosing other infectious diseases, including using other body fluid samples.

Krill are filter feeders that consume algae, plankton and detritus, indicating that krill possess an adequate cellulose digesting system. However, less is known about the enzymatic properties of crustacean cellulases compared to termite cellulases. In the present study, 48 kDa-cellulase was highly purified from krill ( Euphausia pacifica ) in an effort to determine the cleavage specificity of the enzyme. The most notable characteristic of the enzyme was its high activity against both lichenan and carboxymethyl cellulose. The enzyme hydrolyzed internal β-1,4 glycosidic bonds within lichenan as well as carboxymethyl cellulose to release oligosaccharides and glucose. The effects of pH and temperature on the activity and stability of both enzyme activities were almost identical. Cello-oligosaccharides with a degree of polymerization of 4–6 were hydrolyzed by the enzyme, and the same endo-products, cellotriose, cellobiose and glucose, were produced from these oligosaccharides. Neither cellotriose nor cellobiose was hydrolyzed by the enzyme. The enzyme digested filter paper and sea lettuce to produce cellobiose, cellotriose and glucose as major products. Although amino acid sequence homology of the enzyme with termite cellulases and the presence of oligosaccharides in the enzyme suggested that the enzyme is produced by krill itself, further analysis is necessary.

Dehydration-responsive element binding/C-repeat-binding factors (DREB/CBF) control the activity of multiple stress response genes and therefore represent attractive targets for genetic improvement of abiotic stress tolerance. Paper mulberry (Broussonetia papyrifera L. Vent) is well known for its bark fibers and high levels of chalcone and flavonoid derivatives. Transgenic paper mulberry plants expressing a tall fescue (Festuca arundinacea Schreb.) FaDREB1 gene under the control of CaMV 35S were produced to examine the potential utility of FaDREB1 to increase the tolerance of paper mulberry plants to abiotic stress. The overexpressing FaDREB1 plants showed higher salt and drought tolerance than the wild-type plants (WT). After 13 days of withholding water, or 15 days in the presence of 250 mM NaCl, all the WT plants died, while the over-expressing FaDREB1 plants survived. The FaDREB1 plants had higher leaf water and leaf chlorophyll contents, accumulated more proline and soluble sugars, and had less ion leakage (which reflects membrane damage) than the WT plants had under high salt- and water-deficient conditions. The 35S promoter-driven expression of FaDREB1 did not cause growth retardation under normal growth conditions. Therefore, improved tolerance to multiple environmental stresses in paper mulberry might be achieved via genetic engineering through the ectopic expression of an FaDREB1 gene.

In recent years, it has been proposed that conflicts between transcription and active chromosomal replication engender genome instability events. Furthermore, transcription elongation factors have been reported to prevent conflicts between transcription and replication and avoid genome instability. Here, we examined transcriptional de-repression as a genetic diversity-producing agent and showed, through the use of physiological and genetic means, that transcriptional de-represssion of a leuC defective allele leads to accumulation of Leu+ mutations. We also showed, by using riboswitches that activate transcription in conditions of tyrosine or methionine starvation, that the effect of transcriptional de-repression of the leuC construct on the accumulation of Leu+ mutations was independent of selection. We examined the role of Mfd, a transcription elongation factor involved in DNA repair, in this process and showed that proficiency of this factor promotes mutagenic events. These results are in stark contrast to previous reports in Escherichia coli, which showed that Mfd prevents replication fork collapses. Because our assays place cells under non-growing conditions, by starving them for two amino acids, we surmised that the Mfd mutagenic process associated with transcriptional de-repression does not result from conflicts with chromosomal replication. These results raise the interesting concept that transcription elongation factors may serve two functions in cells. In growing conditions, these factors prevent the generation of mutations, while in stress or non-growing conditions they mediate the production of genetic diversity.

Evolution hinges on the ability of organisms to adapt to their environment. A key regulator of adaptability is mutation rate, which must be balanced to maintain genome fidelity while permitting sufficient plasticity to cope with environmental changes. Multiple mechanisms govern an organism’s mutation rate. Constitutive mechanisms include mutator alleles that drive global, permanent increases in mutation rates, but these changes are confined to the subpopulation that carries the mutator allele. Other mechanisms focus mutagenesis in time and space to improve the chances that adaptive mutations can spread through the population. For example, environmental stress can induce mechanisms that transiently relax the fidelity of DNA repair to bring about a temporary increase in mutation rates during times when an organism experiences a reduced fitness for its surroundings, as has been demonstrated for double-strand break repair in Escherichia coli. Still, other mechanisms control the spatial distribution of mutations by directing changes to especially mutable sequences in the genome. In eukaryotic cells, for example, the stress-sensitive chaperone Hsp90 can regulate the length of trinucleotide repeats to fine-tune gene function and can regulate the mobility of transposable elements to enable larger functional changes. Here, we review the regulation of mutation rate, with special emphasis on the roles of tandem repeats and environmental stress in genome evolution.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting almost all organs. It has wider phenotypic variation than often appreciated, with less than half showing the combination of characteristic facial angiofibromas, epilepsy, and mental retardation. Renal angiomyolipomata or cysts are found in 90% and renal failure was historically a common mode of adult death from the disease. Pulmonary lymphangioleiomyomatosis is restricted to females. Angiomyolipomata or cystic disease, or both, may cause renal failure. Angiomyolipomata may also haemorrhage, especially from larger lesions. Manifestations of brain involvement substantially complicate management of many patients with TSC. The causative genes TSC1 and TSC2 encode tuberin and hamartin which are involved in control of the mammalian target of rapamycin pathway. Inhibitors of that pathway, such as sirolimus and everolimus, are therefore logical approaches to therapy and have been shown to be effective in reducing angiomyolipomata volume. It remains to be seen whether they can protect renal function.

An emerging group of human genetic diseases termed ‘ciliopathies’ are caused by dysfunction of two functionally and physically associated organelles, the centrosome and cilium. These organelles are central to perception of the physical environment through detection of a diverse variety of extracellular signals such as growth factors, chemicals, light and fluid flow. Many of the described ciliopathies display multi-organ involvement, with renal and retina being the most commonly affected. Nephronophthisis is a recessive disorder of the kidney that is the leading cause of end-stage renal failure in children. Through positional cloning, many of the causative mutations have been mapped to genes involved in centrosome and cilia function. In this review, we discuss the identified causative mutations that give rise to nephronophthisis and how these are related to the disease etiology in both the kidney and other organs.

Advances in monitoring technology allow blood pressure waveforms to be collected at sampling frequencies of 250-1000Hz for long time periods. However, much of the raw data are under analysed. Heart rate variability (HRV) methods, in which beat-to-beat interval lengths are extracted and analysed, have been extensively studied, However, this approach discards the majority of the raw data.OBJECTIVE:Our aim is to detect changes in the shape of the waveform in long streams of blood pressure data.APPROACH:Our approach involves extracting key features from large complex datasets by generating a reconstructed attractor in a three-dimensional phase space using delay coordinates from a window of the entire raw waveform data. The naturally occurring baseline variation is removed by projecting the attractor onto a plane from which new quantitative measures are obtained. The time window is moved through the data to give a collection of signals which relate to various aspects of the waveform shape.MAIN RESULTS:This approach enables visualisation and quantification of changes in the waveform shape and has been applied to blood pressure data collected from conscious unrestrained mice and to human blood pressure data. The interpretation of the attractor measures is aided by the analysis of simple artificial waveforms.SIGNIFICANCE:We have developed and analysed a new method for analysing blood pressure data that uses all of the waveform data and hence can detect changes in the waveform shape that HRV methods cannot, which is confirmed with an example, and hence our method goes "beyond HRV".