[Low grade fibromixoid sarcoma: a purpose of 3 cases and review of the bibliography].
Low grade fibromyxoid sarcoma or tumor Evans is a variety of soft tissue sarcoma that represents 1% of all malignancies. More common in limbs and trunk (50%), we present 3 new cases of retroperitoneal reviewing their characteristics and performing a literature review. In the retroperitoneal location highlights the poor specificity of clinical symptoms, demonstrating, according to their growth and size, as an abdominal tumor, usually painless, or by compression and/or invasion of nearby structures. In cases that present the most important finding was the presence of a palpable abdominal tumor without other symptoms despite remarkable infiltration of other organs that should be included in surgical resection. We emphasize the difficulty of correct diagnosis preoperatively because preoperative studies are inconclusive and only the histological and immuno-histo-typing chemistry allow precise identification.


From graphemes to abstract letter shapes: levels of representation in written spelling.
The letter substitution errors of 2 dysgraphic subjects who, despite relatively intact oral spelling, made well-formed letter substitution errors in written spelling, were studied. Many of these errors bear a general physical similarity to the intended target. Analyses revealed that this similarity apparently was based on the features of the component strokes of letters rather than on visuospatial characteristics. A comparison of these subjects' letter substitution errors with those of 2 other individuals with brain damage, whose damage was at a different level of processing, revealed that the latter subjects' errors are not explicable in terms of stroke-feature similarity. Strong support was found for the computation of multiple representational types in the course of written spelling. This system includes a relatively abstract, effector-independent representational level that specifies the features of the component strokes of letters.


A smart tumor microenvironment responsive nanoplatform based on upconversion nanoparticles for efficient multimodal imaging guided therapy.
Near-infrared (NIR) light-induced imaging-guided cancer therapy has been studied extensively in recent years. Herein, we report a novel theranostic nanoplatform by modifying polyoxometalate (POM) nanoclusters onto mesoporous silica-coated upconversion nanoparticles (UCNPs), followed by loading doxorubicin (DOX) in the mesopores and coating a folate-chitosan shell onto the surface. In this nanoplatform, the core-shell structured UCNPs (NaYF4:Yb,Er@NaYF4:Yb,Nd) showed special upconverting luminescence (UCL) when irradiated with high-penetration 808 nm NIR light, and the doped Yb and Nd ions endowed the sample with CT imaging properties, thus achieving a dual-mode imaging function. Moreover, the simultaneously generated heat mediated by the 808 nm NIR light may coordinate with the chemotherapy generated from the released DOX to realize an efficient synergistic therapy, verified by diverse in vitro and in vivo assays. The coated folate-chitosan shell can target the platform to tumor tissues when it was transported in the blood vessels and accumulated in tumor sites via the enhanced permeability and retention effect (EPR). Due to the acidic and reductive microenvironment of the tumor, the DOX released quickly with the dissolved folate-chitosan shell, exhibiting obvious tumor microenvironment (TME) responsive properties. The smart imaging-guided therapeutic nanoplatform should be highly promising in TME responsive therapy.


Resistance of New Zealand Provenance Leptospermum scoparium, Kunzea robusta, Kunzea linearis, and Metrosideros excelsa to Austropuccinia psidii.
Resistance to the pandemic strain of Austropuccinia psidii was identified in New Zealand provenance Leptospermum scoparium, Kunzea robusta, and K. linearis plants. Only 1 Metrosideros excelsa-resistant plant was found (of the 570 tested) and no resistant plants of either Lophomyrtus bullata or L. obcordata were found. Three types of resistance were identified in Leptospermum scoparium. The first two, a putative immune response and a hypersensitive response, are leaf resistance mechanisms found in other myrtaceous species while on the lateral and main stems a putative immune stem resistance was also observed. Both leaf and stem infection were found on K. robusta and K. linearis plants as well as branch tip dieback that developed on almost 50% of the plants. L. scoparium, K. robusta, and K. linearis are the first myrtaceous species where consistent infection of stems has been observed in artificial inoculation trials. This new finding and the first observation of significant branch tip dieback of plants of the two Kunzea spp. resulted in the development of two new myrtle rust disease severity assessment scales. Significant seed family and provenance effects were found in L. scoparium, K. robusta, and K. linearis: some families produced significantly more plants with leaf, stem, and (in Kunzea spp.) branch tip dieback resistance, and provenances provided different percentages of resistant families and plants. The distribution of the disease symptoms on plants from the same seed family, and between plants from different seed families, suggested that the leaf, stem, and branch tip dieback resistances were the result of independent disease resistance mechanisms.


Database Resources of the BIG Data Center in 2018.
The BIG Data Center at Beijing Institute of Genomics (BIG) of the Chinese Academy of Sciences provides freely open access to a suite of database resources in support of worldwide research activities in both academia and industry. With the vast amounts of omics data generated at ever-greater scales and rates, the BIG Data Center is continually expanding, updating and enriching its core database resources through big-data integration and value-added curation, including BioCode (a repository archiving bioinformatics tool codes), BioProject (a biological project library), BioSample (a biological sample library), Genome Sequence Archive (GSA, a data repository for archiving raw sequence reads), Genome Warehouse (GWH, a centralized resource housing genome-scale data), Genome Variation Map (GVM, a public repository of genome variations), Gene Expression Nebulas (GEN, a database of gene expression profiles based on RNA-Seq data), Methylation Bank (MethBank, an integrated databank of DNA methylomes), and Science Wikis (a series of biological knowledge wikis for community annotations). In addition, three featured web services are provided, viz., BIG Search (search as a service; a scalable inter-domain text search engine), BIG SSO (single sign-on as a service; a user access control system to gain access to multiple independent systems with a single ID and password) and Gsub (submission as a service; a unified submission service for all relevant resources). All of these resources are publicly accessible through the home page of the BIG Data Center at http://bigd.big.ac.cn.


Effects of food limitation on 9 metal concentrations in liver and polycyclic aromatic hydrocarbon metabolites in bile of juvenile turbot (Scophthalmus maximus) previously exposed to contaminated sediments.
A 2-step experimental design was employed in the present study on juvenile turbot (Scophthalmus maximus): 1) juveniles were exposed for 26 d to 2 contaminated sediments and a reference one, and 2) they were transferred in clean seawater with clean sediment for 35 d, feeding fish once a day, twice a week, or once a week. Fish exposed to contaminated sediments presented a significant increase of hepatic Cd, Cu, and Pb concentrations compared with the reference condition after the 26-d exposure. Higher fluorescence signals of polycyclic aromatic hydrocarbon (PAH) metabolites were found in bile from turbot exposed to contaminated sediments for 26 d compared with reference. These signals returned to values similar to reference fish after depuration whatever the food quantity. The metal bioaccumulation of Cd, Cu, and Pb was no longer observed after 35-d depuration with once-a-day feeding but was still found with restricted feeding conditions. Results on reference fish also showed significantly higher concentrations of most metals analyzed in fish fed twice a week and once a week compared with fish fed once a day. These results could be related to a decrease of fish hepatosomatic index with food limitation and, thus, a dilution effect on metal concentrations. The present study clearly demonstrates that changes in feeding status have significant effects on metal concentrations in fish and no observed effect on PAH metabolites.


Cigarette smoking is not associated with hyperinsulinemia: evidence against a causal relationship between smoking and insulin resistance.
Previous reports of a relationship between cigarette smoking and hyperinsulinemia and insulin resistance provide an important possible mechanism by which smoking could be associated with the metabolic cardiovascular syndrome and hence with ischemic heart disease. However, few previous studies have been able to adjust for all the possible confounding factors related both to smoking and to insulin resistance. Therefore, we examined this association in a population-based cohort study of 1,122 individuals aged 40 to 65 years who underwent a 75-g oral glucose tolerance test with specific measurement of insulin, 32,33-split proinsulin, and intact proinsulin concentrations. Physical activity was quantified using the Paffenbarger questionnaire, and smoking status and alcohol consumption were determined using the Health and Lifestyle Survey questionnaire; 17.4% of the population were current smokers and 32.4% were ex-smokers. Current smoking was associated with reduced overall obesity as indicated by the body mass index (BMI) but an increase in central adiposity as measured by the waist to hip ratio (WHR). There were also significant associations between cigarette smoking and the pattern of alcohol intake and physical inactivity. In unadjusted analyses, current smoking was associated with lower fasting and 120-minute insulin and also 120-minute glucose compared with levels in nonsmokers. Adjustment for confounding by age and BMI reduced these differences, but they were increased by adjustment for central obesity. We conclude from this study that a causal relationship between cigarette smoking and insulin resistance is unlikely.


Comparison and Incorporation of Reasoning and Learning Approaches for Cancer Therapy Research.
Representing knowledge in a comprehensible and maintainable way and transparently providing inferences thereof are important issues, especially in the context of applications related to artificial intelligence in medicine. This becomes even more obvious if the knowledge is dynamically growing and changing and when machine learning techniques are being involved. In this paper, we present an approach for representing knowledge about cancer therapies collected over two decades at St.-Johannes-Hospital in Dortmund, Germany. The presented approach makes use of InteKRator, a toolbox that combines knowledge representation and machine learning techniques, including the possibility of explaining inferences. An extended use of InteKRator's reasoning system will be introduced for being able to provide the required inferences. The presented approach is general enough to be transferred to other data, as well as to other domains. The approach will be evaluated, e. g., regarding comprehensibility, accuracy and reasoning efficiency.


Involvement of serotoninergic receptors in the anteroventral preoptic region on hypoxia-induced hypothermia.
Hypoxia causes a regulated decrease in body temperature (Tb). There is circumstantial evidence that the neurotransmitter serotonin (5-HT) in the anteroventral preoptic region (AVPO) mediates this response. However, which 5-HT receptor(s) is (are) involved in this response has not been assessed. Thus, we investigated the participation of the 5-HT receptors (5-HT1, 5-HT2, and 5-HT7) in the AVPO in hypoxic hypothermia. To this end, Tb of conscious Wistar rats was monitored by biotelemetry before and after intra-AVPO microinjection of methysergide (a 5-HT1 and 5-HT2 receptor antagonist, 0.2 and 2 microg/100 nL), WAY-100635 (a 5-HT(1A) receptor antagonist, 0.3 and 3 microg/100 nL), and SB-269970 (a 5-HT7 receptor antagonist, 0.4 and 4 micro/100 nL), followed by 60 min of hypoxia exposure (7% O2). During the experiments, the mean chamber temperature was 24.6 +/- 0.7 degrees C (mean +/- SE) and the mean room temperature was 23.5 +/- 0.8 degrees C (mean +/- SE). Intra-AVPO microinjection of vehicle or 5-HT antagonists did not change Tb during normoxic conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced hypothermia after vehicle microinjection, which was not affected by both doses of methysergide. However, WAY-100635 and SB-269970 treatment attenuated the drop in Tb in response to hypoxia. The effect was more pronounced with the 5-HT7 antagonist since both doses (0.4 and 4 microg/0.1 microL) were capable of attenuating the hypothermic response. As to the 5-HT(1A) antagonist, the attenuation of hypoxia-induced hypothermia was only observed at the higher dose. Therefore, the present results are consistent with the notion that 5-HT acts on both 5-HT(1A) and 5-HT7 receptors in the AVPO to induce hypothermia, during hypoxia.


Mechanism for multiplicity of steady states with distinct cell concentration in continuous culture of mammalian cells.
Continuous culture for the production of biopharmaceutical proteins offers the possibility of steady state operations and thus more consistent product quality and increased productivity. Under some conditions, multiplicity of steady states has been observed in continuous cultures of mammalian cells, wherein with the same dilution rate and feed nutrient composition, steady states with very different cell and product concentrations may be reached. At those different steady states, cells may exhibit a high glycolysis flux with high lactate production and low cell concentration, or a low glycolysis flux with low lactate and high cell concentration. These different steady states, with different cell concentration, also have different productivity. Developing a mechanistic understanding of the occurrence of steady state multiplicity and devising a strategy to steer the culture toward the desired steady state is critical. We establish a multi-scale kinetic model that integrates a mechanistic intracellular metabolic model and cell growth model in a continuous bioreactor. We show that steady state multiplicity exists in a range of dilution rate in continuous culture as a result of the bistable behavior in glycolysis. The insights from the model were used to devise strategies to guide the culture to the desired steady state in the multiple steady state region. The model provides a guideline principle in the design of continuous culture processes of mammalian cells.


Intestinal Transcytosis of a Protein Cargo and Nanoparticles Mediated by a Non-Toxic Form of Pseudomonas aeruginosa Exotoxin A.
The low permeability of nanoparticles (NPs) across the intestinal epithelium remains a major challenge for their application of delivering macromolecular therapeutic agents via the oral route. Previous studies have demonstrated the epithelial transcytosis capacity of a non-toxic version of Pseudomonas aeruginosa exotoxin A (ntPE). Here, we show that ntPE can be used to deliver the protein cargo green fluorescent protein (GFP) or human growth hormone (hGH), as genetic fusions, across intact rat jejunum in a model where the material is administered by direct intra-luminal injection (ILI) in vivo in a transcytosis process that required less than 15 min. Next, ntPE chemically coupled onto biodegradable alginate/chitosan condensate nanoparticles (AC NPs-ntPE) were shown to transport similarly to ntPE-GFP and ntPE-hGH across rat jejunum. Finally, AC NPs-ntPE loaded with GFP as a model cargo were demonstrated to undergo a similar transcytosis process that resulted in GFP being colocalized with CD11c+ cells in the lamina propria after 30 min. Control NP preparations, not decorated with ntPE, were not observed within polarized epithelial cells or within the cells of the lamina propria. These studies demonstrate the capacity of ntPE to facilitate the transcytosis of a covalently associated protein cargo as well as a biodegradable NP that can undergo transcytosis across the intestinal epithelium to deliver a noncovalently associated protein cargo. In sum, these studies support the potential applications of ntPE to facilitate the oral delivery of macromolecular therapeutics under conditions of covalent or non-covalent association.


Effect of noncancerous pelvic problems on health-related quality of life and sexual functioning.
To assess the effect of abnormal uterine bleeding and pelvic pain and pressure on health-related quality of life and sexual functioning and assess treatment satisfaction. This is a cross-sectional study of 1,493 sociodemographically diverse women who were seeking care for noncancerous pelvic problems and who had not undergone hysterectomy. Participants were asked about symptoms, attitudes, health-related quality of life, sexual functioning, and treatment satisfaction. Preference for current health was measured using the time tradeoff metric, which asked respondents to estimate the number of years of life they would be willing to trade off to not have a uterine condition. Multivariable logistic regression was used to identify determinants of treatment satisfaction. Most (82.7%) participants reported a complete lack of or only partial symptom resolution, and 42.3% reported that their pelvic problems interfered with their ability to have and enjoy sex. Mean Short Form-12 Physical (43-49) and Mental (41-44) Component Summary scores were substantially lower than population norms for women aged 40-49 years. Mean current health time tradeoff scores ranged from 0.78 to 0.88. Satisfaction with Western medicines ranged from 31.3% (progestin intrauterine device) to 58.2% (opiates) and with uterine-preserving surgery from 20.0% (dilation and curettage) to 51.0% (myomectomy); 27.7 % of the women who used acupuncture were satisfied. Participants with lower educational attainment, greater symptom resolution, and less interference of pelvic problems with sex were more likely to be satisfied. Noncancerous pelvic problems are associated with serious decrements in health-related quality of life and sexual functioning and low rates of treatment satisfaction. II.


Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene.
Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown. Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation. Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11 years old, respectively) were completely asymptomatic. This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.


Solid-State Reaction in Cu/a-Si Nanolayers: A Comparative Study of STA and Electron Diffraction Data.
The kinetics of the solid-state reaction between nanolayers of polycrystalline copper and amorphous silicon (a-Si) has been studied in a Cu/a-Si thin-film system by the methods of electron diffraction and simultaneous thermal analysis (STA), including the methods of differential scanning calorimetry (DSC) and thermogravimetry (TG). It has been established that, in the solid-state reaction, two phases are formed in a sequence: Cu + Si → η″-Cu3Si → γ-Cu5Si. It has been shown that the estimated values of the kinetic parameters of the formation processes for the phases η″-Cu3Si and γ-Cu5Si, obtained using electron diffraction, are in good agreement with those obtained by DSC. The formation enthalpy of the phases η″-Cu3Si and γ-Cu5Si has been estimated to be: ΔHη″-Cu3Si = -12.4 ± 0.2 kJ/mol; ΔHγ-Cu5Si = -8.4 ± 0.4 kJ/mol. As a result of the model description of the thermo-analytical data, it has been found that the process of solid-state transformations in the Cu/a-Si thin-film system under study is best described by a four-stage kinetic model R3 → R3 → (Cn-X) → (Cn-X). The kinetic parameters of formation of the η″-Cu3Si phase are the following: Ea = 199.9 kJ/mol, log(A, s-1) = 20.5, n = 1.7; and for the γ-Cu5Si phase: Ea = 149.7 kJ/mol, log(A, s-1) = 10.4, n = 1.3, with the kinetic parameters of formation of the γ-Cu5Si phase being determined for the first time.


Patients' prediction of their wound healing time.
Understanding and managing patients' expectations can help improve their adherence to treatment for chronic wounds; however, little is known concerning about their expectations regarding healing time. Recruited subjects were asked to predict how long their wounds would take to heal and their charts were reviewed to retrieve real time of healing. We recruited 100 subjects from which 77% have healed. Fifty-three subjects (68.8%) had a longer healing time than they predicted (underestimated), and 17 (22.1%) had a shorter healing time than they predicted (overestimated). Subjects with shorter wound duration history tended to predict shorter healing time than subjects with longer wound duration (p < 0.01). However, wound duration did not affect prediction accuracy (p = 0.65). Subjects with chronic wounds seem more often to underestimate their time of healing. Wound duration significantly influenced patients' prediction time, although it did not make their prediction more accurate. Patient education about expectations may be important as patients often expect their wounds to heal faster than they actually do.


18F-5-FPN: A Specific Probe for Monitoring Photothermal Therapy Response in Malignant Melanoma.
Previously, we successfully synthesized a 18F-labeled positron-emission tomography (PET) tracer, termed 18F-5-fluoro-N-(2-[diethylamino]ethyl)picolinamide (18F-5-FPN), with high specificity for melanin. In this study, we sought to investigate the value of 18F-5-FPN in assessing the response to photothermal therapy (PTT) in melanoma via comparison with 18F-fluorodeoxyglucose (18F-FDG) to reveal an early response, recognize early recurrence, and distinguish the inflammatory response during the treatment. B16F10, inflammatory, and MDA-MB-231 models were subjected to 18F-FDG PET and 18F-5-FPN PET static acquisitions. We compared quantitative data to assess the specificity of different agents for different diseases. B16F10 and MDA-MB-231subcutaneous tumor models were irradiated with an 808 nm laser for PTT. Their survival was documented to observe the efficacy of and response to PTT, using 18F-5-FPN and 18F-FDG PET. 18F-5-FPN accumulated in B16F10 cell xenografts only, whereas 18F-FDG accumulated in all three models. Melanin in B16F10 cell xenografts successfully transformed the optical energy into heat. Hematoxylin and eosin (H&E) staining at 24 h revealed destruction and extensive necrosis of tumor tissue. PTT rapidly inhibited the growth of B16F10 cell xenografts and prolonged the median survival. The mean tumor uptakes of 18F-5-FPN on day 2 (7.52 ± 3.65 %ID/g) and day 6 (10.22 ± 6.00 %ID/g) were much lower than that before treatment (18.33 ± 4.98 %ID/g, p < 0.01). However, a significant difference in 18F-FDG uptakes was not found between day 1 after PTT and before treatment. Compared with 18F-FDG, 18F-5-FPN PET could estimate PTT efficacy in melanoma, monitor minimal recurrence, and distinguish melanoma from inflammation and other carcinoma types, thanks to its high affinity to melanin. 18F-5-FPN may provide a new approach for precise and accurate evaluation of response, timely management of therapeutic regimens, and sensitive follow-up.


Varenicline precipitating psychosis in a patient with no previous psychiatric history: a case report of a Spanish patient who was later diagnosed with paranoid personality disorder.
Varenicline is gaining popularity for the treatment of nicotine dependence. General treatment guidelines recommend monitoring for behavioral changes in patients with a mental illness. There are very few cases reported on patients developing psychiatric symptoms with no previous history. We are reporting the case of a Spanish patient who had developed a first-psychotic episode after he was started on varenicline. He was ultimately diagnosed with a paranoid personality disorder. Therefore, prior to starting a patient on varenicline, the clinician must identify possible paranoid and other cluster A personality traits. It is essential to monitor for new onset of psychotic symptoms during the treatment with this drug.


Hippocampal N-methyl-D-aspartate receptor subunit expression profiles in a mouse model of prenatal alcohol exposure.
Although several reports have been published showing prenatal ethanol exposure is associated with alterations in N-methyl-D-aspartate (NMDA) receptor subunit levels and, in a few cases, subcellular distribution, results of these studies are conflicting. We used semi-quantitative immunoblotting techniques to analyze NMDA receptor NR1, NR2A, and NR2B subunit levels in the adult mouse hippocampal formation isolated from offspring of dams who consumed moderate amounts of ethanol throughout pregnancy. We employed subcellular fractionation and immunoprecipitation techniques to isolate synaptosomal membrane- and postsynaptic density protein-95 (PSD-95)-associated pools of receptor subunits. We found that, compared to control animals, fetal alcohol-exposed (FAE) adult mice had: (i) increased synaptosomal membrane NR1 levels with no change in association of this subunit with PSD-95 and no difference in total NR1 expression in tissue homogenates; (ii) decreased NR2A subunit levels in hippocampal homogenates, but no alterations in synaptosomal membrane NR2A levels and no change in NR2A-PSD-95 association; and (iii) no change in tissue homogenate or synaptosomal membrane NR2B levels but a reduction in PSD-95-associated NR2B subunits. No alterations were found in mRNA levels of NMDA receptor subunits suggesting that prenatal alcohol-associated differences in subunit protein levels are the result of differences in post-transcriptional regulation of subunit localization. Our results demonstrate that prenatal alcohol exposure induces selective changes in NMDA receptor subunit levels in specific subcellular locations in the adult mouse hippocampal formation. Of particular interest is the finding of decreased PSD-95-associated NR2B levels, suggesting that synaptic NR2B-containing NMDA receptor concentrations are reduced in FAE animals. This result is consistent with various biochemical, physiological, and behavioral findings that have been linked with prenatal alcohol exposure.


Ovarian hyperstimulation syndrome complicated by peritonitis due to perforated appendicitis.
We describe a case of ovarian hyperstimulation syndrome (OHSS) complicated by peritonitis due to perforated appendicitis. A 29-year-old woman presented with abdominal distension after ovarian stimulation with HMG followed by ovulation induction with HCG. Massive ascites with swollen ovaries was observed on ultrasound, and she was admitted on the diagnosis of OHSS. Daily infusion of serum albumin and low dose dopamine failed to increase her urine output and her abdominal symptoms became increasingly deteriorated after her urine pregnancy test turned out to be positive. Paracentesis performed for alleviation of her abdominal distension revealed infected, foul-smelling fluid. An emergency laparotomy was performed, and the definite diagnosis was made as panperitonitis due to perforated appendicitis with right tubal pregnancy. Appendectomy, right tubectomy and vigorous irrigation with drainage were performed. The case implies that OHSS might not only mask typical manifestations of appendicitis, but could also compromise concurrent intraperitoneal infection.


Cyclophosphamide treatment expands the circulating hematopoietic stem cell pool in dogs.
Increased numbers of circulating granulocyte-monocyte precursor cells (CFUc) have been observed in the peripheral blood of man after antineoplastic chemotherapy. We have developed a canine model to study the biologic significance of this phenomenon for hematopoietic reconstitution following hematopoietically lethal exposure to total body irradiation (TBI). After cyclophosphamide administration, a 16-fold expansion of circulating CFUc numbers was observed during the period of rapid leukocyte recovery that occurred after the chemotherapy-induced leukocyte nadir. We had previously noted this association between leukocyte recovery and CFUc expansion in our human studies. After 900 rad TBI hematopoietic reconstitution was attempted with autologous, cryopreserved collections of peripheral blood mononuclear cells obtained either at times of post-cyclophosphamide CFUc expansion (group A, 14 dogs) or without CFUc expansion (group B, 12 dogs). Asd compared to group B collections, group A collections contained 11-fold more CFUc and were 12.5-fold more potent in fostering hematopoietic recovery after TBI. These results suggest that the expansion of CFUc numbers we observed was accompanied by a similar expansion of more primitive hematopoietic stem cell numbers. We conclude that chemotherapy-induced expansion of circulating CFUc numbers appears to be of substantial import in effecting hematopoietic reconstitution--an observation that may be of significance for further studies of autologous hematopoietic reconstitution in man.


The effect of a parenting intervention on relationship quality of recently deployed military service members and their partners.
Couples form the foundation of military families. However, on average, couples become significantly less satisfied with their relationships and marriages across the deployment cycle. Reduced satisfaction places partners at risk for psychological distress and family problems. The present study examines the effects of a family based reintegration program aimed at enhancing reflective functioning in recently deployed service members and their home-front partners on relationship satisfaction. Results reveal that most dyads report being satisfied in their relationship at baseline. However, greater couple distress was related to more psychological distress in both partners. For spouses, intervention had a positive, significant effect on relationship satisfaction. Variations in relative risk for couple distress among service members and their spouses highlight the need to assess both partners to clarify risk factors and modifiable targets of intervention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Management of infected wounds and trophic ulcers by low frequency ultrasound].
The article is devoted to the investigation of the use of low frequency ultrasound surgical instrument in treatment of trophic ulcers and infected wounds in surgical patients. The method of treatment of these wounds and ulcers by cavitation influence through an intermediate medium was established, an ultrasound surgical apparatus "SUSA-2lf.02", being used, which has been developed and manufactured by AOZT "Medilen"--(St Petersburg). On the base of the experience in treatment of 76 patients intensification of diffusion of the medical preparations into the tissues was shown, among them--into the deep layers of the wound channel. The application of ultrasound provides favourable metabolic changes (normalization of pH of the medium), ensures deep diffusion of medicamentous preparations into the tissues surrounding the ulcers, and enhances therapeutic activity of the preparation.


Machine Learning and Simulation-Optimization Coupling for Water Distribution Network Contamination Source Detection.
This paper presents and explores a novel methodology for solving the problem of a water distribution network contamination event, which includes determining the exact source of contamination, the contamination start and end times and the injected contaminant concentration. The methodology is based on coupling a machine learning algorithm for predicting the most probable contamination sources in a water distribution network with an optimization algorithm for determining the values of contamination start time, end time and injected contaminant concentration for each predicted node separately. Two slightly different algorithmic frameworks were constructed which are based on the mentioned methodology. Both algorithmic frameworks utilize the Random Forest algorithm for classification of top source contamination node candidates, with one of the frameworks directly using the stochastic fireworks optimization algorithm to determine the contamination start time, end time and injected contaminant concentration for each predicted node separately. The second framework uses the Random Forest algorithm for an additional regression prediction of each top node's start time, end time and contaminant concentration and is then coupled with the deterministic global search optimization algorithm MADS. Both a small sized (92 potential sources) network with perfect sensor measurements and a medium sized (865 potential sources) benchmark network with fuzzy sensor measurements were used to explore the proposed frameworks. Both algorithmic frameworks perform well and show robustness in determining the true source node, start and end times and contaminant concentration, with the second framework being extremely efficient on the fuzzy sensor measurement benchmark network.


Potential role of new-generation antibiotics in acute bacterial skin and skin structure infections.
To summarize the available results of primary analyses from high-quality randomized studies of either recently approved or possible future agents for the treatment of acute bacterial skin and skin structure infections (ABSSSI). In the last 2 decades, several novel agents have been approved for the treatment of ABSSSI, that are also active against methicillin-resistant Staphylococcus aureus (MRSA). In addition to already available agents, further molecules are in clinical development that could become available for treating ABSSSI in the forthcoming future. The current and future availability of several new-generation antibiotics will allow to modulate therapeutic choices not only on efficacy but also on other relevant factors such as the combination of the drug safety profile and the comorbidities of any given patient, the expected adherence to outpatient therapy, and the possibilities of early discharge or avoiding hospitalization by means of oral formulations, early switch from intravenous to oral therapy, or single-dose administration of long-acting intravenous agents. With the advent of new-generation antibiotics, all these factors are becoming increasingly essential for tailoring treatment to individual patients in line with the principles of personalized medicine, and for optimizing the use of healthcare resources.


Combining Spinal Cord Transcutaneous Stimulation with Activity-based Training to Improve Upper Extremity Function Following Cervical Spinal Cord Injury.
Recovery of upper extremity (UE) function is the top priority following cervical spinal cord injury (SCI); even partial function restoration would greatly improve the quality of their life and thus remains an important goal in SCI rehabilitation. Current clinical therapies focus on promoting neuroplasticity by performing task-specific activities with high intensity and high repetition. Repetitive training, paired with functional electrical, somatosensory, or transcranial magnetic stimulation, has been evaluated to augment functional recovery in chronic SCI, but improvements were modest. Evidence has demonstrated that the non-invasive spinal cord transcutaneous stimulation (scTS) can increase the excitability of spinal circuits and facilitate the weak or silent descending drive for restoration of sensorimotor function. Currently, we are conducting a multicenter randomized clinical trial to investigate the efficacy and potential mechanisms of scTS combined with activity-based training (ABT) to facilitate UE function recovery in individuals with tetraplegia. The preliminary outcomes from our four individuals with complete and incomplete injury demonstrated that the combination of scTS and ABT led to immediate and sustained (for up to 1-month follow-up) UE function recovery. Notably, one individual with motor complete injury showed a 5-fold improvement in UE function quantified by the Graded Redefined Assessment of Strength, Sensibility, and Prehension following scTS+ABT, as compared to receiving ABT alone. These functional gains were also reflected in the increased spinal excitability by measuring the scTS-evoked muscle response of UE motor pools, suggesting physiological evidence of reorganization of the non-functional, but surviving spinal networks after spinal transcutaneous stimulation.Clinical Relevance-This study offered the preliminary efficacy of combining scTS and ABT to facilitate UE function recovery following cervical SCI.


The diversity, plasticity, and adaptability of cap-dependent translation initiation and the associated machinery.
Translation initiation is a critical facet of gene expression with important impacts that underlie cellular responses to stresses and environmental cues. Its dysregulation in many diseases position this process as an important area for the development of new therapeutics. The gateway translation factor eIF4E is typically considered responsible for 'global' or 'canonical' m7G cap-dependent translation. However, eIF4E impacts translation of specific transcripts rather than the entire translatome. There are many alternative cap-dependent translation mechanisms that also contribute to the translation capacity of the cell. We review the diversity of these, juxtaposing more recently identified mechanisms with eIF4E-dependent modalities. We also explore the multiplicity of functions played by translation factors, both within and outside protein synthesis, and discuss how these differentially contribute to their ultimate physiological impacts. For comparison, we discuss some modalities for cap-independent translation. In all, this review highlights the diverse mechanisms that engage and control translation in eukaryotes.


Intensive care unit-acquired weakness and the COVID-19 pandemic: A clinical review.
Patients with severe cases of coronavirus disease 2019 (COVID-19) often become critically ill requiring intensive care unit (ICU) management. These individuals are at risk for developing ICU-acquired weakness (ICUAW), a multifactorial condition in which polyneuropathy, myopathy, and/or disuse muscle atrophy result in motor weakness. This weakness is thought to contribute to the long-term functional disability frequently observed in survivors of critical illness. This review discusses the current evidence regarding the epidemiology, pathophysiology, evaluation, risk factors, and rehabilitation-specific management of ICUAW in patients with COVID-19. Because of the novelty of COVID-19, the exact prevalence of ICUAW is not well delineated among COVID-19 patients. However, ICUAW has been reported in this population with retrospective studies showing weakness occurring in up to 45.5% of patients with severe COVID-19. There are multiple risk factors for developing ICUAW among COVID-19 patients, including premorbid health status, sepsis, multiple organ failure, mechanical ventilation, immobilization, neuromuscular blockade, corticosteroid use, and glycemic control. ICUAW is more likely to occur after prolonged mechanical ventilation and long hospital stays and can be diagnosed with manual muscle and electrodiagnostic testing. Although the long-term sequela of COVID-19 after ICU stays is not fully studied, increasing evidence indicates significant risk for this population developing long-term functional impairments. Establishing postacute rehabilitation programs for COVID-19 survivors will be important for recovery of endurance, mobility, and function.


Stoichiometric pore mutations of the GABAAR reveal a pattern of hydrogen bonding with picrotoxin.
Picrotoxin (PTX) is a noncompetitive antagonist of many ligand-gated ion channels, with a site of action believed to be within the ion-conducting pore. In the A-type gamma-aminobutyric acid receptor, a threonine residue in the second transmembrane domain is of particular importance for the binding of, and ultimate inhibition by, PTX. To better understand the relationship between this residue and the PTX molecule, we mutated this threonine residue to serine, valine, and tyrosine to change the structural and biochemical characteristics at this location. The known subunit stoichiometry of the A-type gamma-aminobutyric acid receptor allowed us to create receptors with anywhere from zero to five mutations. With an increasing number of mutated subunits, each amino acid substitution revealed a unique pattern of changes in PTX sensitivity, ultimately encompassing sensitivity shifts over several orders of magnitude. The electrophysiological data on PTX-mediated block, and supporting modeling and docking studies, provide evidence that an interaction between the PTX molecule and three adjacent uncharged polar amino acids at this position of the pore are crucial for PTX-mediated inhibition.


[The inverted ipsilateral reflex: is it an artefact?].
We have studied the characteristics of the inverted reflex obtained by ipsilateral stimulation in nineteen patients. Six of them were affected by perceptual hypoacusis, eleven of those patients had an otosclerosis and two a facial paralysis. The conclusion about our investigation is that in all the cases, it was produced by an artefact and it was not a response from the muscles of the middle ear.


Glutaredoxin in Rice Growth, Development, and Stress Resistance: Mechanisms and Research Advances.
Rice (Oryza sativa L.) is a staple food for more than half of the global population. Various abiotic and biotic stresses lead to accumulation of reactive oxygen species in rice, which damage macromolecules and signaling pathways. Rice has evolved a variety of antioxidant systems, including glutaredoxin (GRX), that protect against various stressors. A total of 48 GRX gene loci have been identified on 11 of the 12 chromosomes of the rice genome; none were found on chromosome 9. GRX proteins were classified into four categories according to their active sites: CPYC, CGFS, CC, and GRL. In this paper, we summarized the recent research advances regarding the roles of GRX in rice development regulation and response to stresses, and discussed future research perspectives related to rice production. This review could provide information for rice researchers on the current status of the GRX and serve as guidance for breeding superior varieties.


[CRISPR gene therapy enters the clinic: the future starts now].
In 2020, the Nobel Prize in Chemistry was awarded to American molecular biologist Jennifer Doudna and her French colleague Emmanuelle Charpentier for their fundamental research on CRISPR, an ingenious bacterial immune system. Studies into the working mechanism of CRISPR led to many Eureka moments. Through smart biotechnological engineering, CRISPR became suitable for applications in 'DNA surgery': the targeted editing of the genetic code. Here, we discuss emerging medical CRISPR applications for the treatment of human genetic disorders, including in vivo therapy. This Nobel Prize-winning discovery is powerful, adaptable and accurate, and clinical trials are being launched at an amazing pace. However, extensive research is needed on safe clinical use and possible side effects of CRISPR. In addition, the regulations on market authorization and reimbursement are not yet tailored to this very personal and potentially expensive therapy. Whereas challenges remain, CRISPR gene therapy will continue to rapidly mature as a clinical reality.


Efficacy trial of pipobroman in essential thrombocythemia: a study of 24 patients.
Pipobroman (PB) was tested in a prospective efficacy trial in 24 previously untreated patients with essential thrombocythemia and followed up for a median of 47 months (range, 12-120). Plateletpheresis was not done. Hematologic complete response (platelet count less than 450 X 10(9)/L for 3 consecutive months) was achieved in 92% of the cases, in a median time of 12 weeks (range, 2-22). However, continuous low-dose maintenance therapy with PB was necessary to avoid recurrences of the disease. Major thrombocythemia-related complications were observed in 20% of the cases; the 5-year overall and complication-free survival rates were 92% and 75%, respectively. No acute or chronic toxicity was observed; no drug-induced amenorrhea and subsequent acute leukemia occurred. PB does appear to be efficacious in essential thrombocythemia; however, the evaluation of its leukemogenic risk will await further experience.


Surgery for aortic dilatation in patients with bicuspid aortic valves: A statement of clarification from the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Two guidelines from the American College of Cardiology (ACC), the American Heart Association (AHA), and collaborating societies address the risk of aortic dissection in patients with bicuspid aortic valves and severe aortic enlargement: The "2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease" (J Am Coll Cardiol. 2010;55:e27-130) and the "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease" (J Am Coll Cardiol. 2014;63:e57-185). However, the 2 guidelines differ with regard to the recommended threshold of aortic root or ascending aortic dilatation that would justify surgical intervention in patients with bicuspid aortic valves. The ACC and AHA therefore convened a subcommittee representing members of the 2 guideline writing committees to review the evidence, reach consensus, and draft a statement of clarification for both guidelines. This statement of clarification uses the ACC/AHA revised structure for delineating the Class of Recommendation and Level of Evidence to provide recommendations that replace those contained in Section 188.8.131.52 of the thoracic aortic disease guideline and Section 5.1.3 of the valvular heart disease guideline.


Influence of renal artery variants, number, location, and degree of renal artery stenoses on the atherosclerotic burden of the aorta.
To determine the assumed influence of the number of renal arteries, the distribution and extent of renal artery stenosis (RAS), and the kidney length on calcified aortic atherosclerotic plaque burden. The computed tomographic angiographies of 1381 patients were analyzed retrospectively using a volumetric aortic calcium scoring method. The Spearman method was used to calculate the correlation between kidney length, number and diameter of renal arteries, as well as number, degree, and location of RASs on main or additional renal arteries with the extent of aortic atherosclerosis. Logistic regression analyses were conducted with the target variable "calcification present or absent." Patients with multiple renal arteries (38.3%) had lower plaque volumes than patients without such variants (0.55 ± 0.97 vs 0.64 ± 1.06 mL; P < 0.05). Renal artery stenoses affected all renal vessels with equal frequency. The aortic calcium score correlated with the number of RASs (P < 0.0001) and the maximum degree of RAS up to a threshold of 60%. Location of an RAS in the various renal arteries was irrelevant. In regression analyses, the presence of RAS (Wald = 5.523), the degree of RAS (Wald = 6.251), and age (Wald = 223.1) were positive predictors of the aortic calcium score, whereas kidney length (Wald = 9.564) proved to be a negative predictor. The aortic calcium score correlates with both the number of RASs and the maximum degree of RAS up to a threshold of 60% but correlates inversely with the number of renal arteries. Renal artery stenosis affects all renal vessels with equal frequency, and this finding should be considered in screening procedures.


Human Amnion Epithelial Cells Produce Soluble Factors that Enhance Liver Repair by Reducing Fibrosis While Maintaining Regeneration in a Model of Chronic Liver Injury.
Human amnion epithelial cells (hAECs) exert potent antifibrotic and anti-inflammatory effects when transplanted into preclinical models of tissue fibrosis. These effects are mediated in part via the secretion of soluble factors by hAECs which modulate signaling pathways and affect cell types involved in inflammation and fibrosis. Based on these reports, we hypothesized that these soluble factors may also support liver regeneration during chronic liver injury. To test this, we characterized the effect of both hAECs and hAEC-conditioned medium (CM) on liver repair in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis. Liver repair was assessed by liver fibrosis, hepatocyte proliferation, and the liver progenitor cell (LPC) response. We found that the administration of hAECs or hAEC-CM reduced liver injury and fibrosis, sustained hepatocyte proliferation, and reduced LPC numbers during chronic liver injury. Additionally, we undertook in vitro studies to document both the cell-cell and paracrine-mediated effects of hAECs on LPCs by investigating the effects of co-culturing the LPCs and hAECs and hAEC-CM on LPCs. We found little change in LPCs co-cultured with hAECs. In contrast, hAEC-CM enhances LPC proliferation and differentiation. These findings suggest that paracrine factors secreted by hAECs enhance liver repair by reducing fibrosis while promoting regeneration during chronic liver injury.


Insulin signalling in mushroom body neurons regulates feeding behaviour in Drosophila larvae.
Whereas the pivotal role of insulin signalling in cell division, growth and differentiation is well documented, its role in the regulation of neuronal function and behaviour has recently become the focus of intense investigation. The simple organization of the Drosophila larval brain and the availability of genetic tools to impair the function of insulin receptor signalling in a spatially specific manner makes Drosophila an attractive model to investigate the role of the insulin pathway in specific behaviours. Here, we show that impairment of insulin signalling in the mushroom body neurons, a structure involved in associative learning, impairs feeding behaviour in the Drosophila larva.


A mathematical model of particle retention in the air-spaces of human lungs.
Knowledge of the total and regional lung retention of particles inhaled continuously by man over long periods can be useful in understanding the potential role of inhaled particles in the pathogenesis of lung diseases. Owing to practical and ethical considerations, however, little or no experimental information exists. A mathematical model of particle retention simulating environmental and occupational exposures has therefore been developed that takes into account particle deposition, tracheobronchial clearance, and two phases of alveolar clearance in the Weibel A anatomical lung model. The derived equations of retention kinetics predict retention of particles as a function of exposure time. For a continuous exposure (simulating environmental conditions) to 4 microns particles, the model predicts that retained particles approach an equilibrium between deposited and cleared particles with the 95% level being reached in 293 days. For an intermittent exposure (simulating occupational conditions) equilibrium is approached in five years. The whole lung burden of particles is predicted to be 9% of the total mass that entered the lung after a one-year environmental exposure and 1.5% after a 25-year occupational exposure. The equilibrium surface concentration and integrated dose of particles per airway generation predict enhanced risk to the pathogenic effects of inhaled particles in the large airways and respiratory bronchioles.


Potential role of senescence in radiation-induced damage of the aged skeleton.
Human aging-related changes are exacerbated in cases of disease and cancer, and conversely aging is a catalyst for the occurrence of disease and multimorbidity. For example, old age is the most significant risk factor for cancer and among people who suffer from cancer, >60% are above the age of 65. Oxidative stress and DNA damage, leading to genomic instability and telomere dysfunction, are prevalent in aging and radiation-induced damage and are major cellular events that lead to senescence. Human exposures from nuclear fallout, cosmic radiation and clinical radiotherapy (RT) are some common sources of irradiation that affect bone tissue. RT has been used to treat malignant tumors for over a century, but the effects of radiation damage on tumor-adjacent normal tissue has largely been overlooked. There is an increase in the percent survivorship among patients post-RT, and it is in older survivors where the deleterious synergy between aging and radiation exposure conspires to promote tissue deterioration and dysfunction which then negatively impacts their quality of life. Thus, an aging skeleton is already pre-disposed to architectural deterioration, which is further worsened by radiation-induced bone damage. Effects of senescence and the senescence associated secretory phenotype (SASP) have been implicated in age-associated bone loss, but their roles in radiation-associated bone damage are still elusive. RT is used in treatment for a variety of cancers and in different anatomical locations, the sequelae of which include long-term morbidity and lifelong discomfort. Therefore, consideration of the growing evidence that implicates the role of senescence in radiation-induced bone damage argues in favor of exploiting current senotherapeutic approaches as a possible prevention or treatment.


The zinc fingers of HIV nucleocapsid protein NCp7 direct interactions with the viral regulatory protein Vpr.
The 96-amino acid protein Vpr functions as a regulator of cellular processes involved in human immunodeficiency virus, type 1 (HIV-1) life cycle, in particular by interrupting cells division in the G2 phase. Incorporation of Vpr in the virion was reported to be mediated by the C-terminal domain of the Pr55(Gag) polyprotein precursor, which includes NCp7, a protein involved in the genomic RNA encapsidation and p6, a protein required for particle budding. To precisely define the Gag and Vpr sequences involved in this protein-protein interaction, NCp7, p6, and Vpr as well as a series of derived peptides were synthesized using Fmoc (N-(9-fluorenyl)methoxycarbonyl) chemistry. Binding assays were carried out by Far Western experiments and by competition studies using (52-96)Vpr immobilized onto agarose beads. The results show that interaction between NCp7 and Vpr occurs in vitro by a recognition mechanism requiring the zinc fingers of NCp7 and the last 16 amino acids of Vpr. Moreover, NCp10, the equivalent of NCp7 in Moloney murine leukemia virus but not polysine inhibits Vpr-NCp7 complexation. Interestingly enough, Vpr was found to interact with Gag, NCp15, and NCp7 but not with mature p6 in vitro. In vivo mutations in NCp7 zinc fingers in an HIV-1 molecular clone led to viruses with important defects in Vpr encapsidation. Together, these results suggest that NCp7 cooperates with p6 to induce Vpr encapsidation in HIV-1 mature particles. The NCp7-Vpr complex could also be important for interaction of Vpr with cellular proteins involved in cell division.


Psychosocial characteristics of cancer patients who choose to attend an educational session on cancer-related fatigue.
Little is known about cancer patients who seek specific educational interventions on cancer-related fatigue (CRF). The objectives of this study were (1) to describe the level of CRF, and emotional distress; social support; coping styles; and quality of life of patients who chose to attend a 1-hour educational session on CRF and (2) to examine the relationship between the selected demographic, psychosocial, and treatment-related variables and CRF. A questionnaire-based survey of 41 cancer patients who volunteered after a 1-hour education session on CRF at the Tom Baker Cancer Centre was conducted. The sample consisted mostly of married white women who lived in an urban environment. The average age was 56 years, and participants had an average of 14 years of education; 78% of the sample reported moderate to severe fatigue, 27% had significant levels of emotional distress, and 63% had a problematic coping style. Higher fatigue was associated with emotional distress, poorer quality of life, hopelessness, and reduced social support. To conclude, patients who self-refer to an educational session on CRF present a wide range of emotional difficulties and problematic coping styles. Therefore, educational sessions with patients with CRF should emphasize coping with emotional distress and building a support system.


Atomic force microscopy of human hair.
The atomic force microscope (AFM) was used to investigate the surface architecture of the entire lengths of cleaned human head hairs. Many features previously seen with the scanning electron microscope (SEM) were identified. However, the AFM has provided much greater detail and, in particular, the hair's cuticular surfaces appear not to be as smooth as had been previously supposed. A consistent feature was of step discontinuities or "ghosts" on the scale surfaces. These delineated the original location of each overlying scale before its edge had been chipped away. There was a change in the longitudinal angular presentation of the surfaces about each ghost. This means the distal ends of each cuticle cell have been synthesised in the follicle to be thicker than where that same cuticle cell is bounded on both sides by other cuticle cells. The undamaged outer cuticular surfaces at the root end of each hair were covered everywhere by longitudinal ridges (striations). Where the hair surface was worn, the striations terminated at a scale edge ghost. The ridges were approximately 9 nm high and were in parallel array with a lateral repeat spacing of about 350 nm. The striations are evidently formed on the outer surface of each cuticle cell following earlier contact in the hair follicle with the inner root sheath. The study of stained transverse sections of hairs in the transmission electron microscope (TEM) is suggested as a means for throwing some light on the underlying structure and chemistry of the striations. Finally, our AFM studies have revealed that the surface of the freshly emergent hair gradually changes over a distance of about 20 mm and that the surface of the hair for most of its length is quite different from that near the root. This is likely to be of import to those engaged in the hair toiletries industry.


Effects of bite block speech on intrinsic segment duration.
The fact that low vowels tend to have longer intrinsic duration than high vowels is sometimes attributed to mechanical characteristics associated with the greater distance the jaw travels in producing low vowels. To investigate this tendency, 6 adult speakers of English each produced 72 [h]-vowel-consonant stimuli containing high and low vowels under 'normal' conditions and with their jaw fixed. If duration differences commonly observed between high and low vowels are a result of only mechanical effects of mandibular movement, it was hypothesized that stabilizing the jaw would eliminate these intrinsic vowel duration differences. Based on acoustic measurements that were made, it was found that the fixed-jaw conditions affected the intrinsic durational differences between high and low vowels to some extent, but the contrast was not entirely removed. In addition to the vowel duration changes, a number of systematic effects upon consonant closure duration were also observed as a result of the normal versus fixed-jaw conditions.


An experimental test for body size-dependent effects of male harassment and an elevated copulation rate on female lifetime fecundity and offspring performance.
Many studies investigate the benefits of polyandry, but repeated interactions with males can lower female reproductive success. Interacting with males might even decrease offspring performance if it reduces a female's ability to transfer maternal resources. Male presence can be detrimental for females in two ways: by forcing females to mate at a higher rate and through costs associated with resisting male mating attempts. Teasing apart the relative costs of elevated mating rates from those of greater male harassment is critical to understand the evolution of mating strategies. Furthermore, it is important to test whether a male's phenotype, notably body size, has differential effects on female reproductive success versus the performance of offspring, and whether this is due to male body size affecting the costs of harassment or the actual mating rate. In the eastern mosquitofish Gambusia holbrooki, males vary greatly in body size and continually attempt to inseminate females. We experimentally manipulated male presence (i.e., harassment), male body size and whether males could copulate. Exposure to males had strong detrimental effects on female reproductive output, growth and immune response, independent of male size or whether males could copulate. In contrast, there was a little evidence of a cross-generational effect of male harassment or mating rate on offspring performance. Our results suggest that females housed with males pay direct costs due to reduced condition and offspring production and that these costs are not a consequence of increased mating rates. Furthermore, exposure to males does not affect offspring reproductive traits.


Detecting falls with wearable sensors using machine learning techniques.
Falls are a serious public health problem and possibly life threatening for people in fall risk groups. We develop an automated fall detection system with wearable motion sensor units fitted to the subjects' body at six different positions. Each unit comprises three tri-axial devices (accelerometer, gyroscope, and magnetometer/compass). Fourteen volunteers perform a standardized set of movements including 20 voluntary falls and 16 activities of daily living (ADLs), resulting in a large dataset with 2520 trials. To reduce the computational complexity of training and testing the classifiers, we focus on the raw data for each sensor in a 4 s time window around the point of peak total acceleration of the waist sensor, and then perform feature extraction and reduction. Most earlier studies on fall detection employ rule-based approaches that rely on simple thresholding of the sensor outputs. We successfully distinguish falls from ADLs using six machine learning techniques (classifiers): the k-nearest neighbor (k-NN) classifier, least squares method (LSM), support vector machines (SVM), Bayesian decision making (BDM), dynamic time warping (DTW), and artificial neural networks (ANNs). We compare the performance and the computational complexity of the classifiers and achieve the best results with the k-NN classifier and LSM, with sensitivity, specificity, and accuracy all above 99%. These classifiers also have acceptable computational requirements for training and testing. Our approach would be applicable in real-world scenarios where data records of indeterminate length, containing multiple activities in sequence, are recorded.


Analysis of Artifactual Components Rejection Threshold towards Enhanced Characterization of Neural Activity in Post-Stroke Survivor.
Research advancement has spurred the usage of electroencephalography (EEG)-based neural oscillatory rhythms as a biomarker to complement clinical rehabilitation strategies for the recovery of motor functions in stroke survivors. However, the inevitable contamination of EEG signals with artifacts from various sources limits its utilization and effectiveness. Thus, the integration of Independent Component Analysis (ICA) and Independent Component Label (ICLabel) has been widely employed to separate neural activity from artifacts. A crucial step in the ICLabel preprocessing pipeline is the artifactual ICs rejection threshold (TH) parameter, which determines the overall signal's quality. For instance, selecting a high TH will cause many ICs to be rejected, thereby leading to signal over-cleaning, and choosing a low TH may result in under-cleaning of the signal. Toward determining the optimal TH parameter, this study investigates the effect of six different TH groups (NO-TH and TH1-TH6) on EEG signals recorded from post-stroke patients who performed four distinct motor imagery (MI) tasks including wrist and grasping movements. Utilizing the EEG-beta band signal at the brain's sensorimotor cortex, the performance of the TH groups was evaluated using three notable EEG quantifiers. Overall, the obtained result shows that the considered THs will significantly alter neural oscillatory patterns. Comparing the performance of the TH-groups, TH-3 with a confidence level of 60% showed consistently stronger signal desynchronization and lateralization. The correlation result shows that most of the electrode pairs with high correlation values are replicable across all the MI tasks. It also revealed that brain activity correlates linearly with distance, and a strong correlation between electrode pairs is independent of the different brain cortices. The study outcome may facilitate adequate therapeutic intervention for stroke rehab.Clinical Relevance: This study indicated that optimal selection of the ICLabel artifactual rejection threshold is essential for EEG enhancement for adequate signal characterization. Thus, a TH-values with a confidence level between 50% - 70% would be suggested for artifactual ICs rejection in MI-EEG.


New purine analogues for the treatment of chronic B-cell malignancies.
Adenosine deaminase (ADA), a purine salvage pathway enzyme, appears to play a key role in normal lymphocyte growth, development, and differentiation. Three new purine nucleoside analogues, deoxycoformycin, fludarabine, and 2-chlorodeoxyadenosine, affect the normal function of the purine salvage pathway by inhibiting ADA or by acting as analogs of the ADA substrates. These agents show significant activity in the treatment of chronic B-cell leukemias and low-grade lymphomas. The pharmacology, mechanism of action, and clinical usefulness of these agents are discussed.


Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome.
Patients with a primary neurodegenerative disorder associated with cognitive impairment are at increased risk for epilepsy. The goal of the present study was to characterize seizure type(s), etiological diagnosis of dementia, electroencephalogram (EEG) and imaging findings, and response to antiepileptic drug (AED) therapy in these individuals. A retrospective study was performed identifying patients in the Mayo Alzheimer Disease Patient Registry (ADPR) and Alzheimer Disease Research Center (ADRC) who were classified as having dementia and epilepsy from 1986 to 2006. Multiple clinical parameters were extracted from patient charts and evaluated to characterize the primary neurodegenerative disorder and seizure outcomes. Sixty-three of the 1738 ADPR and ADRC patients (3.6%) had epilepsy. Twenty-four of the 63 patients were excluded because of insufficient information regarding their epilepsy. The remaining 39 patients were analyzed. Twenty-eight of the 63 patients (72%) experienced complex partial seizures. Head MRI was performed in 35 patients (90%). Fourteen patients (36%) had MRI-identified structural lesions that included remote stroke and prior intracerebral hemorrhage. EEGs were obtained in 29 patients (74%). Fifteen patients (38%) had epileptiform discharges. Overall, it was found that 79% had an excellent response to AED therapy. Approximately one-third of the patients had dose-related side effects from an AED. The present study indicated that most individuals with the comorbidity of epilepsy and dementia have complex partial seizures that may be adequately controlled on AED therapy. The long-term effect of seizure activity on the neurodegenerative disorder is unknown.


[Two Turkish manuscripts on gems (jauhar) and the treatment by means of gems].
Literary works of the genre called cevâhir-nâme or cevher-nâme are written in order to give information on how gems (cevher-jauhar) are formed, where they are found, their estimated values, how to distinguish them from the imitations, what their particular colours are and on their uses and harmful effects. These literary works are sometimes titled in accordance with the genre they belong to and sometimes they are given different titles. The literary works dealing with the subject of cevher are mostly written in prose and only a few of them are in verse. The Turkish versions of cevâhir-nâme texts started to be written in the 15th century. These texts, covering the earlier knowledge of medicine, give information on gems and perfumes; how they effect human health; and the way they should be used in medical treatment. Therefore, these texts should be discussed in relation with their place in the history of Turkish science. Two cevâhir-nâmes, which were translated into Turkish by Mustafâ bin Seydî and Za'îfî in the 15th and 16th centuries are still available. The translations by Mustafâ bin Seydî and Za'îfî, did not only convey the classical and medieval knowledge on cevhers to the contemporary readers, but they also confirm the fact that this information was a part of the Ottoman social life.


[Rat man. A review].
We will focus on one of the key cases analyzed by Freud, the one he himself named the "Rat Man" (fictional name for patient Ernst Lanzer) and analyzed as an "obsessive neurosis". As in the Dora case, in this clinical case Freud intends to describe the prototype of obsessive neurosis in which no element is missing. Everything is there: sexual and forbidden thoughts that obsess the subject, aggressive thoughts towards the people he loves (especially the one called the "lady" and his own father), the sense of duty and debt that are imposed in the form of an expensive constraint, etc. However, a careful examination of the patient's symptoms and behavior both in his daily life and with his therapist allows us to ask ourselves whether this is really a "neurotic" disorder and not a different pathology, particularly in relation to psychotic disorders. Although Freud's diagnosis of obsessive neurosis may evoke the current obsessive-compulsive disorder, other pathologies and comorbidities that would relativize the main diagnosis must be considered.


[Major, minor and trace-elemental contents analysis in northeast soybeans by ICP-AES].
Major, minor and trace elemental contents in northeast China soybeans were determined by using inductively coupled plasma atomic emission spectrometry (ICP-AES). Three different sample digestion methods including two wet digestions, HNO3-HClO4 and HNO3-H2SO4 and a dry ash method were compared. Owing to the high oil content in soybeans, long time is needed and access acid should be added with mixed acid digestion methods, which may result in higher sample blank. Therefore, the dry ask method would be more proper for the pre-treatment of soybean samples. Potassium and phosphorus are major elements in soybeans, so the effect of potassium and phosphorus on the other elements was investigated. Results showed that the potassium and phosphorus did not affect the determination of other trace elements. There are not significant differences in trace elemental contents for the eleven northeast China soybeans.


A Bayesian seamless phase I-II trial design with two stages for cancer clinical trials with drug combinations.
The use of drug combinations in clinical trials is increasingly common during the last years since a more favorable therapeutic response may be obtained by combining drugs. In phase I clinical trials, most of the existing methodology recommends a one unique dose combination as "optimal," which may result in a subsequent failed phase II clinical trial since other dose combinations may present higher treatment efficacy for the same level of toxicity. We are particularly interested in the setting where it is necessary to wait a few cycles of therapy to observe an efficacy outcome and the phase I and II population of patients are different with respect to treatment efficacy. Under these circumstances, it is common practice to implement two-stage designs where a set of maximum tolerated dose combinations is selected in a first stage, and then studied in a second stage for treatment efficacy. In this article we present a new two-stage design for early phase clinical trials with drug combinations. In the first stage, binary toxicity data is used to guide the dose escalation and set the maximum tolerated dose combinations. In the second stage, we take the set of maximum tolerated dose combinations recommended from the first stage, which remains fixed along the entire second stage, and through adaptive randomization, we allocate subsequent cohorts of patients in dose combinations that are likely to have high posterior median time to progression. The methodology is assessed with extensive simulations and exemplified with a real trial.


[Blood lipids, lipid peroxidation and the effect on them of antianginal preparations in ischemic heart disease patients].
The origin and development of ischemic heart disease (IHD) is attended with activation of lipid free-radical oxidation facilitating further advancement of the disease and with decrease of the organism's antioxidant protection. The antianginal drugs which are used in IHD treatment differ in their effect on the blood lipid composition and their peroxidation. beta-Adrenoblocking agents may cause proatherogenic disorders of the blood lipid graph, this increases the risk of IHD advancement. Long-acting nitro preparations are lipid-neutral. Calcium antagonists, mainly those of the nifedipin group, suppress LPO superactivity, possess a high antioxidant effect, and, probably, retard the advancement of coronary atherosclerosis and IHD.


Incomplete coronary vasodilation during myocardial ischemia in swine.
To determine if endogenous (ENDG) vasodilation was maximum during myocardial ischemia, left anterior descending (LAD) mean pressure (P) was reduced for 20 min in 13 swine. At LAD P of 45 mmHg (LAD P45) flow fell during ENDG = 25 but rose to 44 ml/min during adenosine (AD) infusion (P less than 0.01). Flow increased to subendocardium (ENDG 0.65 vs. AD 1.04 ml X min-1 X g-1) and to subepicardium (ENDG 0.99 vs. AD 1.83 ml X min-1 X g-1; P less than 0.05). No significant change occurred in myocardial O2 consumption (MVO2; ENDG 2.91 vs. AD 3.18 ml X min-1 X g-1), lactate extraction (ENDG = -5 vs. AD-1%), and wall thickening (WTh; ENDG + 16 vs. AD + 17%). At LAD P35, flow during ENDG was 12 but rose to 19 ml/min during AD (P less than 0.01). Flow increased to subendocardium (ENDG 0.24 vs. AD 0.46 ml X min-1 X g-1; P less than 0.02) and subepicardium (ENDG 0.51 vs. AD 0.87 ml X min-1 X g-1; P less than 0.01). No significant change occurred in MVo2 (ENDG 1.38 vs. AD 1.59 ml/min), lactate extraction (ENDG -38 vs. AD -22%), WTh (ENDG -1 vs. AD + 1%). Thus endogenous vasodilation reserve was not used fully during ischemia. AD increased flow but did not improve abnormalities in myocardial function or metabolism.


Breaking the win-win narrative: The dark side of older people's political participation.
Studies on older adults' civic engagement have been dominated by a win-win narrative, which assumes that the activity is beneficial both for the individuals involved and for communities. However, civic engagement may also be a source of negative experiences. The aim of this study was to understand these experiences in greater depth through an analysis of older Spanish activists' narratives of negative episodes of political participation. We also aimed to contribute to the methodological literature on narrative research by highlighting the strengths of analysing not just the content but also the structure of older people's stories. Life story interviews were carried out with 40 members of Spanish political organisations aged between 65 and 86 years old. As part of the interview, they were invited to narrate a negative event related to their stories of political participation. Answers were analysed both for their content (using thematic analysis) and for their structure (using Christopher Booker's plot typology). Participants recounted many negative experiences of political participation, which challenged the win-win master cultural narrative around civic engagement. These stories, which often reflected Booker's plots of 'tragedy', 'overcoming the monster', 'the quest', and 'redemption', recorded political defeats, conflicts with other members in the organisation, feelings of loneliness associated with engagement, and undesired consequences for relatives and friends. The results highlight the importance of providing a more nuanced understanding of what it means to be politically engaged in later life. This understanding would integrate the positive aspects assumed by the master win-win narrative with others that clearly challenge its assumptions.


Flavonoid-derived anisotropic silver nanoparticles inhibit growth and change the expression of virulence genes in Escherichia coli SM10.
We hereby present a novel greener and ecofriendly synthesis of anisotropic silver nanoparticles (AgNPs) using water soluble quercetin diphosphate (QDP). QDP was employed as a reducing, capping and stabilizing agent at room temperature without any extraneous reagents. The purpose of this study was to determine the effects of modified quercetin pentaphosphate silver nanoparticles (QPP-AgNPs) and quercetin diphosphate derived silver nanoparticles (QDP-AgNPs) on microbial growth and expressions of virulence-related genes in Escherichia coli SM10. The gene expression analysis was carried out for 12 genes which are related to virulence and stress in E. coli SM10, namely: RpoD, RpoS, ibpB, clpB, uspA, fliC, fimH, fimF, kdpE, artJ, hyaA, and gyrA. Results showed that QDP-AgNPs reduced the swarming motility by 98% which correlated with the reduction in the expression of FliC flagellar gene. A simultaneous increase in the expression of the fimbrial genes FimH and FimF that are related to motility was recorded. In contrast, treatment of the microbes with QPP-AgNPs resulted in 90% of the swarming motility at different patterns compared to QDP-AgNPs treatment for the gene expressions of motility elements. The study revealed that QDP-AgNPs up-regulated the stress related RpoD and ibpB expressions, while QPP-AgNPs up-regulated the stress related RpoS and uspA gene expressions. However, both QDP-AgNPs and QPP-AgNPs up-regulated kpdE, artJ and gry at different levels. QDP-AgNPs were also tested for their antibacterial and antifungal activities, which showed µmolar cidal activity. The growth kinetics of both Gram (-) and Gram (+) bacteria were strongly altered by QDP-AgNPs activity. Energy dispersive absorption spectroscopy (EDS) studies revealed that silver ions and/or the nanoparticles themselves transferred into bacterial cells. To the best of our knowledge, this is the first report ofstudying the genetic and kinetic response of bacteria to modified quercetin phosphate mediated silver nanoparticles and we hereby report that the molecules used to synthesize AgNPs bring about a strong effect on AgNPs manipulatory activity on the tested 12-genes.


Estimating and modeling the dynamics of the intensity of infection with schistosoma japonicum in villagers of leyte, Philippines. Part II: Intensity-specific transmission of S. japonicum. The schistosomiasis transmission and ecology project.
A dynamic model of Schistosoma japonicum transmission is presented that incorporates effects of infection intensity, age, and sex. We use four infection intensity classes to investigate the impact of ecologic changes and public health interventions on the burden of infection within communities. Age- and sex-specific infection data from three disease-endemic villages in the Philippines are used to estimate the parameters of the model. The model gives good qualitative agreement with observed fecal egg counts adjusted for the accuracy of the Kato-Katz examination. Our results suggest that differences in infection burden between villages are caused by differences in both the infection process and the recovery process in humans. We describe the potential impact of mass treatment of all humans on the numbers with high infection. Furthermore, we show that a sudden reduction in snail population size would affect high prevalence and low prevalence communities in different ways.


Idiopathic spontaneous liver hemorrhage A report of two cases and a review of the literature.
Spontaneous liver hemorrhage (SLH) is a serious, extremely rare, and life-threatening occurrence requiring a multidisciplinary approach. Since diagnosis might be difficult, a high mortality rate is reported. Survival depends on a prompt diagnosis followed by an appropriate management. If left untreated, SLH progresses, in fact, to a hemorrhagic shock and death. SLH is rarely idiopathic, whereas more commonly is secondary to severe preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome, hepatocellular carcinoma (HCC), adenoma, focal nodular hyperplasia or hemangioma, and connective tissue diseases. We report two patients presenting with an idiopathic SLH successfully treated with angioembolization, and the results of an extensive literature review. KEY WORDS: Intrahepatic hematoma, Spontaneous liver hemorrhage, Spontaneous liver rupture.


[Concept analysis of the nursing outcome Mobility in patients with stroke].
This study aimed a concept analysis of the nursing outcome Mobility in patients with stroke. A literature review was conducted, through the online access to databases: Scopus, Pubmed, CINAHL, Cochrane, and Lilacs, using the descriptors: mobility, stroke, nursing and their synonyms in Portuguese and Spanish. 1.521 articles were identified, resulting in 49, after careful selection. Noteworthy are the articles published in Canada (26.7%), on 2001 (95.9%), by physiotherapists (34.6%), and in rehabilitation units (61.5%). The attributes identified for Mobility were: walking, standing, sitting, put the leg side to side, turn around, start and stop walking, stair climbing, motor function, and motor skill transfer. A model case and a contrary case were built, and identified, as antecedents: postural control and balance; and, as consequents: performs tasks inside and outside the house and wanders without difficulty. It was concluded that the concepts of Mobility found in this study need to be validated with experts in the field and in clinical practice.


Performance evaluation of fuzzy classifier systems for multidimensional pattern classification problems.
We examine the performance of a fuzzy genetics-based machine learning method for multidimensional pattern classification problems with continuous attributes. In our method, each fuzzy if-then rule is handled as an individual, and a fitness value is assigned to each rule. Thus, our method can be viewed as a classifier system. In this paper, we first describe fuzzy if-then rules and fuzzy reasoning for pattern classification problems. Then we explain a genetics-based machine learning method that automatically generates fuzzy if-then rules for pattern classification problems from numerical data. Because our method uses linguistic values with fixed membership functions as antecedent fuzzy sets, a linguistic interpretation of each fuzzy if-then rule is easily obtained. The fixed membership functions also lead to a simple implementation of our method as a computer program. The simplicity of implementation and the linguistic interpretation of the generated fuzzy if-then rules are the main characteristic features of our method. The performance of our method is evaluated by computer simulations on some well-known test problems. While our method involves no tuning mechanism of membership functions, it works very well in comparison with other classification methods such as nonfuzzy machine learning techniques and neural networks.


Evaluation of esmolol and fentanyl in controlling increases in heart rate and blood pressure during endotracheal intubation.
Laryngoscopy and intubation cause an adrenergic response manifested by tachycardia and hypertension. Various pharmacological agents, including fentanyl, have been administered prior to induction in an attempt to attenuate the adrenergic response but they all have limitations. Esmolol, an ultrashort-acting cardioselective beta blocker, has been administered by infusion to successfully protect surgical patients from the stresses of intubation. The objective of our study was to determine if esmolol would be equally effective when administered in a bolus with and without fentanyl. Forty-four ASA I and II females undergoing elective surgery were randomly divided into four groups and received the following agents prior to intubation: Group 1-esmolol 1 mg/kg and fentanyl 2 micrograms/kg, Group 2-placebo (normal saline), Group 3-esmolol 1 mg/kg and Group 4-fentanyl 3.5 micrograms/kg. Groups 1 and 4, which received fentanyl, demonstrated significantly less elevation in blood pressure. Esmolol appeared to attenuate increases in heart rate. Esmolol has a tissue distribution time of 2 minutes and an elimination half-life of 9 minutes. The window of its availability to the tissues is narrow, and timing of bolus administration is more critical than in administration by infusion. Doses in excess of 1 mg/kg appear to be necessary for effective control of heart rate. However, when used with fentanyl, esmolol provides effective protection against the adrenergic response to laryngoscopy and intubation.


The odyssey of guaiac.
The history of guaiac is outlined herein. Guaiac owes its existence as a chemical to a rumor that it had antisyphilitic healing powers in the early 16th century. Guaiac was either the drug of choice or second drug of choice for therapy of syphilis for 200 years. Van Deen discovered its property of detecting occult blood in 1864.


EC-QCL mid-IR transmission spectroscopy for monitoring dynamic changes of protein secondary structure in aqueous solution on the example of β-aggregation in alcohol-denaturated α-chymotrypsin.
In this work, a novel EC-QCL-based setup for mid-IR transmission measurements in the amide I region is introduced for monitoring dynamic changes in secondary structure of proteins. For this purpose, α-chymotrypsin (aCT) acts as a model protein, which gradually forms intermolecular β-sheet aggregates after adopting a non-native α-helical structure induced by exposure to 50 % TFE. In order to showcase the versatility of the presented setup, the effects of varying pH values and protein concentration on the rate of β-aggregation were studied. The influence of the pH value on the initial reaction rate was studied in the range of pH 5.8-8.2. Results indicate an increased aggregation rate at elevated pH values. Furthermore, the widely accessible concentration range of the laser-based IR transmission setup was utilized to investigate β-aggregation across a concentration range of 5-60 mg mL(-1). For concentrations lower than 20 mg mL(-1), the aggregation rate appears to be independent of concentration. At higher values, the reaction rate increases linearly with protein concentration. Extended MCR-ALS was employed to obtain pure spectral and concentration profiles of the temporal transition between α-helices and intermolecular β-sheets. Comparison of the global solutions obtained by the modelled data with results acquired by the laser-based IR transmission setup at different conditions shows excellent agreement. This demonstrates the potential and versatility of the EC-QCL-based IR transmission setup to monitor dynamic changes of protein secondary structure in aqueous solution at varying conditions and across a wide concentration range. Graphical abstract EC-QCL IR spectroscopy for monitoring protein conformation change.


[Effect of endogenous oligopeptides and brain-specific proteins on aggressive behavior in the rat].
In experiments on non-bred males of white rats, the effect was studied on their aggressive behaviour of intraventricular injections of brain-specific proteins of S-100 group, gamma-globuline fraction from the serum of rabbits immunized by proteines S-100 (gamma S-100) and non-immunized rabbits (gamma-SNK) as well as of angiotensin, bradikinin and saline. S-100 lowered intermales aggressivity and that connected with pain, and had phasic inhibitory effects on rats emotional reactivity. gamma S-100 increased the aggressivity connected with pain, did not affect the intermales aggressivity and phasically raised (as well as gamma-SNK) the emotional reactivity. gamma-SNK, angiotensin and bradikinin did not change these kinds of aggressivity. None of the administered agents influenced the level of rats predetary aggressivity.


Markhor-derived Introgression of a Genomic Region Encompassing PAPSS2 Confers High-altitude Adaptability in Tibetan Goats.
Understanding the genetic mechanism of how animals adapt to extreme conditions is fundamental to determine the relationship between molecular evolution and changing environments. Goat is one of the first domesticated species and has evolved rapidly to adapt to diverse environments, including harsh high-altitude conditions with low temperature and poor oxygen supply but strong ultraviolet radiation. Here, we analyzed 331 genomes of domestic goats and wild caprid species living at varying altitudes (high > 3000 m above sea level and low < 1200 m), along with a reference-guided chromosome-scale assembly (contig-N50: 90.4 Mb) of a female Tibetan goat genome based on PacBio HiFi long reads, to dissect the genetic determinants underlying their adaptation to harsh conditions on the Qinghai-Tibetan Plateau (QTP). Population genomic analyses combined with genome-wide association studies (GWAS) revealed a genomic region harboring the 3'-phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2) gene showing strong association with high-altitude adaptability (PGWAS = 3.62 × 10-25) in Tibetan goats. Transcriptomic data from 13 tissues revealed that PAPSS2 was implicated in hypoxia-related pathways in Tibetan goats. We further verified potential functional role of PAPSS2 in response to hypoxia in PAPSS2-deficient cells. Introgression analyses suggested that the PAPSS2 haplotype conferring the high-altitude adaptability in Tibetan goats originated from a recent hybridization between goats and a wild caprid species, the markhor (Capra falconeri). In conclusion, our results uncover a hitherto unknown contribution of PAPSS2 to high-altitude adaptability in Tibetan goats on QTP, following interspecific introgression and natural selection.


Comprehensive evaluation of fatty acids in foods. V. Unhydrogenated fats and oils.
This paper summarizes representative values for the fatty acid composition of unprocessed vegetable fats, vegetable oils, and animal fats. The data for these unprocessed fats and oils are identical with those of the processed, but unhydrogenated fats and oils. Calculations to convert the fatty acid methyl ester data to grams fatty acid per 100 gm. food are discussed, and the converted data are presented in tabular form. Climatic and cultivar effects on the fatty acid composition of some of these oils are reviewed.


Porcine milk exosomes modulate the immune functions of CD14+ monocytes in vitro.
Exosomes mediate near and long-distance intercellular communication by transferring their molecular cargo to recipient cells, altering their biological response. Milk exosomes (MEx) are internalized by immune cells and exert immunomodulatory functions in vitro. Porcine MEx can accumulate in the small intestine, rich in macrophages. No information is available on the immunomodulatory ability of porcine MEx on porcine monocytes, which are known precursors of gut macrophages. Therefore, this study aims at (1) assessing the in vitro uptake of porcine MEx by porcine monocytes (CD14+), and (2) evaluating the in vitro impact of porcine MEx on porcine monocytes immune functions. MEx were purified by ultracentrifugation and size exclusion chromatography. The monocytes' internalization of PKH26-labeled MEx was examined using fluorescence microscopy. Monocytes were incubated with increasing exosome concentrations and their apoptosis and viability were measured. Lastly, the ability of MEx to modulate the cells' immune activities was evaluated by measuring monocytes' phagocytosis, the capacity of killing bacteria, chemotaxis, and reactive oxygen species (ROS) production. MEx were internalized by porcine monocytes in vitro. They also decreased their chemotaxis and phagocytosis, and increased ROS production. Altogether, this study provides insights into the role that MEx might play in pigs' immunity by demonstrating that MEx are internalized by porcine monocytes in vitro and exert immunomodulatory effects on inflammatory functions.


Short communication: Effect of a citrus extract in lactating dairy cows.
Dry matter intake is a main driver of energy balance in lactating dairy cows, and some plant extracts have been commercially fed to dairy cows to stimulate feed intake. Citrus extracts contain several bioactive components and have been shown to modify metabolism in other animal models. Our hypothesis was that a citrus extract would increase dry matter intake. Two experiments were conducted to determine the effect of a citrus extract on intake and milk production in lactating dairy cows. In experiment one, 11 early-lactation dairy cows (experiment 1; 77 ± 15 d in milk, mean ± standard deviation) were used in a switchback design, and in experiment two, 15 mid-lactation Holstein cows (experiment 2; 157 ± 44 d in milk, mean ± standard deviation) were used in a crossover design. In both experiments, treatments were control (no supplement) or a citrus extract (4 g/d in experiment 1 and 4.5 g/d in experiment 2). Treatment periods were 21 and 14 d in experiment 1 and experiment 2, respectively, with the final 7 d used for sample and data collection. No effect was observed for treatment on dry matter intake, feeding behavior, milk yield, milk fat yield, milk protein yield, or milk composition in either experiment. Treatment also had no effect on milk trans fatty acid profile, but the extract increased total 16 carbon fatty acids 0.9 and 0.6 percentage points in experiment 1 and experiment 2, respectively. Plasma nonesterified fatty acids were decreased 6 h after feeding in both experiments (11.1 and 16.0 μEq/L in experiment 1 and experiment 2, respectively). Plasma insulin was increased 1 h before feeding compared with the control in experiment 1 (3.36 vs. 2.13 µIU/mL) and tended to increase 1.79 units 1 h before feeding in experiment 2. The citrus extract had no effect on feed intake or milk production at the dose investigated, but changed plasma insulin and nonesterified fatty acids, indicating some metabolic effects requiring further investigation.


The influence of family groups on inferences made with the program Structure.
Unsupervised clustering algorithms, like the program Structure, are increasingly used to infer the presence of population structure from a sample of genotyped individuals. We evaluate the extent to which the presence of related individuals can lead such algorithms to the false inference that there is population structure. First, we demonstrate this problem using a real data set from a rainbow trout (Oncorhynchus mykiss) population. Then we perform an extensive series of simulations involving the program Structure. Our simulations encompass both a simple scenario with fixed numbers of full- and half-siblings in the sample, and a more complicated scenario in which we investigate 360 combinations of population divergence, fraction of population sampled, variance in family size, mating system and number of loci. We find that the inclusion of family members in a sample may produce very strong evidence of population structure, even when population structure is absent. This problem becomes more pronounced when more loci are genotyped, and it is particularly likely in studies of monogamous species, especially if variance in family size is high and a large fraction of a small population has been sampled. Researchers working in such situations should test observed clusters for the presence of family members to distinguish family-induced structure from real population structure. Additionally, this work shows that Structure's ability to estimate the number of subpopulations may be influenced by a number of factors, and therefore should be interpreted guardedly.