Synthesis, Physicochemical and Biological Study of Gallium-68- and Lutetium-177-Labeled VEGF-A165/NRP-1 Complex Inhibitors Based on Peptide A7R and Branched Peptidomimetic.
Neuropilin-1 (NRP-1) is a surface receptor found on many types of cancer cells. The overexpression of NRP-1 and its interaction with vascular endothelial growth factor-165 (VEGF165) are associated with tumor growth and metastasis. Therefore, compounds that block the VEGF165/NRP-1 interaction represent a promising strategy to image and treat NRP-1-related pathologies. The aim of the presented work was to design and synthesize radioconjugates of two known peptide-type inhibitors of the VEGF165/NRP-1 complex: A7R peptide and its shorter analog, the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg. Both peptide-type inhibitors were coupled to a radionuclide chelator (DOTA) via a linker (Ahx) and so radiolabeled with Ga-68 and Lu-177 radionuclides, for diagnostic and therapeutic uses, respectively. The synthesized radioconjugates were tested for their possible use as theranostic-like radiopharmaceuticals for the imaging and therapy of cancers that overexpress NRP-1. The obtained results indicate good efficiency of the radiolabeling reaction and satisfactory stability, at least 3t1/2 for the 68Ga- and 1t1/2 for the 177Lu-radiocompounds, in solutions mimicking human body fluids. However, enzymatic degradation of both the studied inhibitors caused insufficient stability of the radiocompounds in human serum, indicating that further modifications are needed to sufficiently stabilize the peptidomimetics with inhibitory properties against VEGF165/NRP-1 complex formation.


Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation "MSC-FFM"-Outcome Report of 92 Patients.
(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82% and 81% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64%, while the cumulative incidence of death from underlying disease was 3%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.


Close online relationships in a national sample of adolescents.
This paper uses data from a national survey of adolescent Internet users (N = 1,501) to describe online relationships. Fourteen percent of the youths interviewed reported close online friendships during the past year, 7% reported face-to-face meetings with online friends, and 2% reported online romances. Two hundred forty-six youths provided details about one close online relationship. Most of these relationships were with same-age peers (70%) and crossed gender lines (71%). Many intersected with face-to-face social networks because they were initiated by introductions from friends or family (32%), involved people who lived in the vicinity (26%), were known to parents (74%), included offline contact by mail or telephone (70%), or involved face-to-face meetings (41%). Few youths reported bad experiences with online friends.


Bacteriophage lambda: The path from biology to theranostic agent.
Viral particles provide an attractive platform for the engineering of semisynthetic therapeutic nanoparticles. They can be modified both genetically and chemically in a defined manner to alter their surface characteristics, for targeting specific cell types, to improve their pharmacokinetic features and to attenuate (or enhance) their antigenicity. These advantages derive from a detailed understanding of virus biology, gleaned from decades of fundamental genetic, biochemical, and structural studies that have provided mechanistic insight into virus assembly pathways. In particular, bacteriophages offer significant advantages as nanoparticle platforms and several have been adapted toward the design and engineering of "designer" nanoparticles for therapeutic and diagnostic (theranostic) applications. The present review focuses on one such virus, bacteriophage lambda; I discuss the biology of lambda, the tools developed to faithfully recapitulate the lambda assembly reactions in vitro and the observations that have led to cooptation of the lambda system for nanoparticle design. This discussion illustrates how a fundamental understanding of virus assembly has allowed the rational design and construction of semisynthetic nanoparticles as potential theranostic agents and illustrates the concept of benchtop to bedside translational research. This article is categorized under: Biology-Inspired Nanomaterials> Protein and Virus-Based Structures Biology-Inspired Nanomaterials> Nucleic Acid-Based Structures.


Monocular vertical oscillations of amblyopia. The Heimann-Bielschowsky phenomenon.
The Heimann-Bielschowsky phenomenon is an unusual ocular motility pattern which may develop years following uniocular visual loss and may be mistaken as a neuro-ophthalmologic sign pointing to a posterior fossa or brain stem lesion. It consists of strictly monocular coarse, pendular vertical oscillations occurring only in the amblyopic eye. It is noted primarily with distance fixation and is inhibited by convergence or fixation. The oscillations vary between 1-5 cycles/second, and amplitude, often only 2-5 degrees, may be quite large, up to 20-30 degrees (40-60 prism diopters). A faden operation improved the disorder in one patient. The importance of recognizing this characteristic motility pattern is emphasized to ophthalmologists and neurologists.


Postnatal developmental changes in blood flow to choroid plexuses and cerebral cortex of the rat.
Postnatal developmental changes in blood flow to choroid plexuses of the lateral (LVCP) and fourth (4VCP) ventricles and cerebral cortex were studied in pentobarbital-anesthetized rats at 2, 3, 5, and 7-8 wk. Blood flow was measured by indicator fractionation with N-isopropyl-p-[125I]iodoamphetamine as the marker. Blood flow to the LVCP and 4VCP was 2.5 +/- 0.1 and 2.7 +/- 0.1 ml.g-1.min-1, respectively, and did not change between the 2nd and 3rd wk. However, it increased by 34% between the 3rd and 5th wk. From the age of 5 wk on, 4VCP was characterized by higher blood flow rates than LVCP. Cerebral cortical blood flow gradually increased between the 2nd and 5th wk. There was no difference in cortical blood flow between 5-wk-old and adult animals. The changes in choroidal blood flow likely represent a continuing adjustment of the choroidal vascular system to steadily increasing secretory capabilities of the maturing choroidal epithelium.


Risk of cardiovascular events in patients with polycystic ovary syndrome.
Women with polycystic ovary syndrome (PCOS) have increased prevalence of cardiovascular (CV) risk factors. However, data on the incidence of CV events are lacking in this population. Using Rochester Epidemiology Project resources, we conducted a retrospective cohort study comparing CV events in women with PCOS with those of women without PCOS in Olmsted County, Minnesota. Between 1966 and 1988, 309 women with PCOS and 343 without PCOS were identified. Mean (SD) age at PCOS diagnosis was 25.0 (5.3) years; mean age at last follow-up was 46.7 years. Mean (SD) follow-up was 23.7 (13.7) years. Women with PCOS had a higher body mass index (29.4 kg÷m2 vs 28.3 kg÷m2; p=.01). Prevalence of type 2 diabetes mellitus and hypertension and levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were similar in the two groups. We observed no increase in CV events, including myocardial infarction (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.32 to 1.72; p=.48); coronary artery bypass graft surgery (adjusted HR 1.52; 95% CI 0.42 to 5.48; p=.52); death (adjusted HR 1.03; 95% CI, 0.29 to 3.71; p=.96); death due to CV disease (adjusted HR 5.67; 95% CI 0.51 to 63.7; p=.16); or stroke (adjusted HR 1.05; 95% CI 0.28 to 3.92; p=.94). Although women with PCOS weighed more than controls, there was no increased prevalence of other CV risk factors. Furthermore, we found no increase in CV events. While prospective studies are needed to confirm these findings, women with PCOS do not appear to have adverse CV outcomes in midlife.


A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline in Patients with Alcohol Use Disorder.
Alcohol use disorder is a major societal and individual burden that exacerbates health outcomes, decreases quality of life, and negatively affects U.S. healthcare spending. Although pharmacological treatments are available for alcohol use disorder, many of them are limited by small effect sizes and used infrequently. Citicoline is a widely available over-the-counter supplement with a favorable side effect profile. It acts through cholinergic pathways and phospholipid metabolism. The current report examines the effect of oral citicoline on alcohol use, craving, depressive symptoms, and cognitive outcomes in individuals with alcohol use disorder. A 12-week, randomized, double-blind, parallel-group, placebo-controlled, pilot study of citicoline (titrated to 2,000 mg/d) in 62 adults (age 18 to 75) with alcohol use disorder was conducted. Alcohol use, such as number of drinking days, amount used, and number of heavy drinking days, was assessed using the Timeline Followback method and liver enzymes, while alcohol craving was measured using the Penn Alcohol Craving Scale. A neurocognitive battery (e.g., Rey Auditory Verbal Learning Test) and depressive symptoms scale (e.g., Inventory of Depressive Symptomatology Self-Report) scores were also collected. Data were analyzed using a random regression analysis. The primary outcome analysis was conducted in the intent-to-treat sample and consisted of 55 participants (78.2% men and 21.8% women, mean age of 46.47 ± 9.15 years). In the assessment period, the drinking days, on average, represented 77% of the assessed days. Significant between-group differences were not observed on alcohol use, craving, and cognitive or depressive symptom measures. Citicoline was well tolerated. This proof-of-concept study observed that citicoline was well tolerated, but was not associated with a reduction in alcohol use or other outcomes, as compared to placebo. The favorable effects reported with citicoline for cocaine use, cognitive disorders, and other conditions do not appear to extend to alcohol use disorder.


Light Transmittance and Polymerization of Bulk-Fill Composite Materials Doped with Bioactive Micro-Fillers.
This study investigated the effect of bioactive micro-fillers on the light transmittance and polymerization of three commercially available bulk-fill resin composites. These were mixed with 20 wt% bioactive glass 45S5, Portland cement, inert dental barium glass, or nothing (controls). Composites were photo-activated and light transmittance through 4 mm thick specimens was measured in real time. Moreover, degree of conversion (DC) and Knoop hardness (KHN) were assessed. Light transmittance of all bulk-fill composites significantly decreased (p < 0.05) with addition of 20 wt% bioactive glass 45S5 but not when inert barium glass was added. For bulk-fill composites modified with Portland cement, light irradiance dropped below the detection limit at 4 mm depth. The DC at the top surface of the specimens was not affected by addition of bioactive or inert micro-fillers. The bottom-to-top ratio of both DC and KHN surpassed 80% for bulk-fill composites modified with 20 wt% bioactive or inert glass fillers but fell below 20% when the composites were modified with Portland cement. In contrast to Portland cement, the addition of 20 wt% bioactive glass maintains adequate polymerization of bulk-fill composites placed at 4 mm thickness, despite a decrease in light transmittance compared to the unmodified materials.


Artificial intelligence as a noninvasive tool for pancreatic cancer prediction and diagnosis.
Pancreatic cancer (PC) has a low incidence rate but a high mortality, with patients often in the advanced stage of the disease at the time of the first diagnosis. If detected, early neoplastic lesions are ideal for surgery, offering the best prognosis. Preneoplastic lesions of the pancreas include pancreatic intraepithelial neoplasia and mucinous cystic neoplasms, with intraductal papillary mucinous neoplasms being the most commonly diagnosed. Our study focused on predicting PC by identifying early signs using noninvasive techniques and artificial intelligence (AI). A systematic English literature search was conducted on the PubMed electronic database and other sources. We obtained a total of 97 studies on the subject of pancreatic neoplasms. The final number of articles included in our study was 44, 34 of which focused on the use of AI algorithms in the early diagnosis and prediction of pancreatic lesions. AI algorithms can facilitate diagnosis by analyzing massive amounts of data in a short period of time. Correlations can be made through AI algorithms by expanding image and electronic medical records databases, which can later be used as part of a screening program for the general population. AI-based screening models should involve a combination of biomarkers and medical and imaging data from different sources. This requires large numbers of resources, collaboration between medical practitioners, and investment in medical infrastructures.


Electroacupuncture treatments for gut motility disorders.
Functional gastrointestinal (GI) diseases are common and there are patients who are refractory to medical therapies as not all treatments work in all patients. Consequently, a large number of patients with functional GI diseases use complementary and alternative medicine, such as acupuncture or electroacupuncture (EA). In this issue, Zheng et al. reported interesting results of a multi-center placebo-controlled clinical study on the use of EA for treating refractory functional dyspepsia; another study reported a multi-center clinical trial on EA for chronic functional constipation; Liang et al. studied mechanisms of EA involving enteric nervous system and neurotransmitters in treating constipation in rats. While controversial reports are available in the literature, EA with appropriate methodologies as shown in these recent studies is believed to be effective in treating certain functional GI diseases. In this mini-review, a number of clinical studies, including those included in this issue on the use of EA for treating gastro-esophageal reflux, functional dyspepsia, irritable bowel syndrome, and constipation are reviewed. Some critically important issues, such as the choice of stimulation parameters for EA, the administration frequency of the therapy, and the appropriate choice of placebo for clinical research are also discussed. Mechanisms of action involved in the therapeutic effects of EA for gut dysmotility and future research directions are also presented.


Does fully closed-loop automated insulin delivery improve glycaemic control in patients with type 2 diabetes? A meta-analysis of randomized controlled trials.
This meta-analysis investigated the efficacy and safety of fully closed-loop automated insulin delivery (AID) in patients with type 2 diabetes. We systemically searched PubMed, Scopus, Web of Science, and Cochrane Central from inception until April 26, 2023. We included randomized controlled trials (RCTs) comparing fully closed-loop AID versus conventional insulin therapy. The outcomes were pooled as the mean difference (MD) and risk ratio with 95% confidence interval (CI) in the random effect model. Our primary outcome was the proportion of time in the target glucose range (5.6-10 mmol/L, 3.9-10 mmol/L, or 3.9-8 mmol/L, depending on the study). Key secondary outcomes included the proportion of time spent in hyperglycaemia or hypoglycaemia. We included seven RCTs (three crossover and four parallel design), compromising 390 patients. Our analysis showed that compared to the control group, fully closed-loop AID increased the proportion of time spent within the target glucose range by additional 337 min per 24 h (MD = 23.39%, 95% CI [16.64%, 30.14%], p < 0.01), additional 108 min overnight (MD = 22.40%, 95% CI [12.88%, 31.91%], p < 0.01), and additional 258 min during the daytime period (MD = 26.85%, 95% CI [21.06%, 32.63%], p < 0.01). Compared to the control group, the overall time in hyperglycaemia was shortened by 326 min per 24 h (MD = -22.67%, 95% CI [-30.87%, -14.46%], p < 0.01). There was no significant difference between the two groups in terms of overall, overnight, and daytime periods spent in hypoglycaemia. Our meta-analysis suggests that fully closed-loop AID may improve glycaemic control in patients with type 2 diabetes, particularly for those with more challenging diabetes management. Further research is required to establish the feasibility of implementing these systems in clinical practice. [Correction added on 26 August 2023 after first online publication: Under Results, the first sentence "We included seven RCTs (three crossover and one parallel designs)" has been changed to "We included seven RCTs (three crossover and four parallel designs)".].


Effectiveness of curcumin against Enterococcus faecalis biofilm.
To evaluate the antimicrobial efficacy of curcumin against Enterococcus faecalis biofilm formed on tooth substrate in vitro. Sodium hypochlorite (NaOCl) and chlorhexidine (CHX) served as standards for comparison. Biofilms of E.faecalis were formed on instrumented, extracted human teeth (n = 96). At the end of the 2nd day, 2nd and 8th weeks, specimens were treated for 30 min with one of the test solutions or saline (control) and the surviving colony-forming units (CFU/mL) was recorded. Results were analyzed by Kruskal-Wallis test and Dunnet test for pair-wise comparison with Bonferroni correction (p = 0.05). Only NaOCl showed complete eradication of bacteria at all time periods. In the 2-day and 2nd week biofilms, curcumin and NaOCl showed complete inhibition, which was significantly lower than the CFU recovered in the CHX and saline groups (p < 0.05). In 8 week biofilms, samples treated with curcumin showed 553 ± 137.6 CFU/mL, which was significantly higher than NaOCl (0 CFU/mL), but significantly lower than CHX (2551 ± 129.8) and saline control (1.42 × 1011 ± 2.12 × 1010; p < 0.05). Sodium hypochlorite (3%) showed maximum antibacterial activity against E.faecalis biofilm formed on the tooth substrate, followed by curcumin and CHX. Considering the potential for undesirable properties of NaOCl, the use of herbal alternatives in endodontics might prove to be advantageous.


The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification.
Haematopoietic cells arise from endothelial cells within the dorsal aorta of the embryo via a process called the endothelial-haematopoietic transition (EHT). This process crucially depends on the transcription factor RUNX1 which rapidly activates the expression of genes essential for haematopoietic development. Using an inducible version of RUNX1 in a mouse embryonic stem cell differentiation model we showed that prior to the EHT, haematopoietic genes are primed by the binding of the transcription factor FLI1. Once expressed, RUNX1 relocates FLI1 towards its binding sites. However, the nature of the transcription factor assemblies recruited by RUNX1 to reshape the chromatin landscape and initiate mRNA synthesis are unclear. Here, we performed genome-wide analyses of RUNX1-dependent binding of factors associated with transcription elongation to address this question. We demonstrate that RUNX1 induction moves FLI1 from distal ETS/GATA sites to RUNX1/ETS sites and recruits the basal transcription factors CDK9, BRD4, the Mediator complex and the looping factor LDB1. Our study explains how the expression of a single transcription factor can drive rapid and replication independent transitions in cellular shape which are widely observed in development and disease.


Alkali metal salts of formazanate ligands: diverse coordination modes as a result of the nitrogen-rich [NNCNN] ligand backbone.
Alkali metal salts of redox-active formazanate ligands were prepared, and their structures in the solid-state and in solution are determined. The nitrogen-rich [NNCNN] backbone of formazanates results in a varied coordination chemistry, with both the internal and terminal nitrogen atoms available for bonding with the alkali metal. The potassium salt K[PhNNC(p-tol)NNPh]·2THF (1-K) is dimeric in the solid state and even in THF solution, as a result of the K atom bridging via interaction with a terminal N atom and the aromatic ring of a second unit. Conversely, for the compounds Na[MesNNC(CN)NNMes]·2THF (2-Na) and Na[PhNNC((t)Bu)NNPh] (3-Na) polymeric and hexameric structures are found in the solid state respectively. The preference for binding the alkali metal through internal N atoms (1-K and 2-Na) to give a 4-membered chelate, or via internal/external N atoms (5-membered chelate in 3-Na), contrasts with the 6-membered chelate mode observed in our recently reported formazanate zinc complexes.


Trade-off between local replication and long-distance dissemination during experimental evolution of a satellite RNA.
Satellite RNAs (satRNAs) are molecular parasites that depend on their non-homologous helper viruses (HVs) for essential biological functions. While there are multiple molecular and phylogenetic studies on satRNAs, there is no experimental evolution study on how satRNAs may evolve in common infection conditions. In this study, we serially passaged the Bamboo mosaic virus (BaMV) associated-satRNA (satBaMV) under conditions in which satBaMV either coinfects an uninfected host plant, Nicotiana benthamiana, with BaMV or superinfects a transgenic N. benthamiana expressing the full-length BaMV genome. Single-nucleotide polymorphisms (SNPs) of satBaMV populations were analyzed by deep sequencing. Forty-eight SNPs were identified across four different experimental treatments. Most SNPs are treatment-specific, and some are also ephemeral. However, mutations at positions 30, 34, 63, and 82, all located at the 5' untranslated region (UTR), are universal in all treatments. These universal SNPs are configured into several haplotypes and follow different population dynamics. We constructed isogenic satBaMV strains only differing at positions 30 and 82 and conducted competition experiments in protoplasts and host plants. We found that the haplotype that reached high frequency in protoplasts and inoculation leaves also exhibited poor dissemination to systemic leaves and vice versa, thus suggesting an apparent trade-off between local replication and long-distance dissemination. We posit that the trade-off is likely caused by antagonistic pleiotropy at the 5' UTR. Our findings revealed a hitherto under-explored connection between satRNA genome replication and movement within a host plant. The significance of such a connection during satRNA evolution warrants a more thorough investigation.


B7/CD28-dependent and -independent induction of CD40 ligand expression.
The induction of a T cell-dependent Ab response is mediated by the interaction of the T cell activation Ag, CD40 ligand (CD40L), with CD40. Since this interaction is independent of Ag, coreceptors such as CD4, and MHC molecules, the expression of the CD40L must be strictly regulated or B cell-mediated autoimmunity may be produced. In this study, we examined the requirements for costimulatory signals for induction of CD40L expression in vitro and in vivo on CD4+ T cells from normal and CD28-deficient mice following stimulation with anti-CD3, Con A, or specific peptide Ag. Expression of B7-1 was both necessary and sufficient for induction of the CD40L on normal CD4+ T cells when L cell transfectants were used as APCs. When normal accessory cell populations were used, only partial inhibition of induction of the CD40L was observed with reagents that inhibit B7/CD28 interactions. Furthermore, the CD40L could be induced on CD4+ T cells from CD28-deficient mice. Thus, non-B7/CD28 cellular interactions can also mediate the costimulatory signals needed for induction of CD40L expression.


Effect of Prior Health Knowledge on the Usability of Two Home Medical Devices: Usability Study.
Studies on the usability of health care devices are becoming more common, although usability standards are not necessarily specified and followed. Yet, there is little knowledge about the impact of the context of use on the usability outcome. It is specified in the usability standard (ISO 9241-11, 2018) of a device that it may be affected by its context of use and especially by the characteristics of its users. Among these, prior health knowledge (ie, knowledge about human body functioning) is crucial. However, no study has shown that prior health knowledge influences the usability of medical devices. Our study aimed to fill this gap by analyzing the relationship between the usability of two home medical devices (soon to be used in the context of ambulatory surgery) and prior health knowledge through an experimental approach. For assessing the usability of two home medical devices (blood pressure monitor and pulse oximeter), user tests were conducted among 149 students. A mixed-methods approach (subjective vs objective) using a variety of standard instruments was adopted (direct observation, video analysis, and questionnaires). Participants completed a questionnaire to show the extent of their previous health knowledge and then operated both devices randomly. Efficiency (ie, handling time) and effectiveness (ie, number of handling errors) measures were collected by video analysis. Satisfaction measures were collected by a questionnaire (system usability scale [SUS]). The qualitative observational data were coded using inductive analysis by two independent researchers specialized in cognitive psychology and cognitive ergonomics. Correlational analyses and clusters were performed to test how usability relates to sociodemographic characteristics and prior health knowledge. The results indicated a lack of usability for both devices. Regarding the blood pressure monitor (137 participants), users made approximately 0.77 errors (SD 1.49), and the mean SUS score was 72.4 (SD 21.07), which is considered "satisfactory." The pulse oximeter (147 participants) appeared easier to use, but participants made more errors (mean 0.99, SD 0.92), and the mean SUS score was 71.52 (SD 17.29), which is considered "satisfactory." The results showed a low negative and significant correlation only between the effectiveness of the two devices and previous knowledge (blood pressure monitor: r=-0.191, P=.03; pulse oximeter: r=-0.263, P=.001). More subtly, we experimentally identified the existence of a threshold level (χ²2,146=10.9, P=.004) for health knowledge to correctly use the pulse oximeter, but this was missing for the blood pressure monitor. This study has the following two contributions: (1) a theoretical interest highlighting the importance of user characteristics including prior health knowledge on usability outcomes and (2) an applied interest to provide recommendations to designers and medical staff.


The impact of tensorial temperature on equilibrium thermodynamics.
Thermodynamic temperature is a scalar. However, the connection with the kinetic energy tensor in statistical mechanics leaves open the possibility to define a tensorial temperature. This concept has sometimes been used to simulate isothermal conditions in out-of-equilibrium systems. Here, we show, by studying a sessile water droplet, that a tensorial temperature leads to the wrong thermodynamics, or, in other words, the equilibrium isothermal ensemble generated using a tensorial temperature is not the canonical one, with interfacial free energies that can differ up to 40% from the correct ones.


[Arterial vascularization of the bony acetabulum].
The arterial supply of the acetabulum is studied in 30 human hip-pelvis specimens utilizing conventional angiography, 3 D-CT and maceration. 3 specimens out of 30 had to be excluded due to extravasation and incomplete filling. The arteries of the pelvis were filled with barium sulfate in 16 cases and in 11 cases with a solution of resin and lead powder. Conventional angiograms were performed in all specimens. In preparations with resin/lead powder additional CT with 3 D reconstructions of the surface of the acetabulum and arteries were done. 3 D-CTs show precise relationship of the arteries to the acetabulum. Filling with resin and lead powder is optimal for anatomical studies. It permits comparative 3 D-CT and conventional X-ray examination and subsequent preparation of the vessels in corrosion technique. The central parts of the acetabulum are vascularized by the obturator artery, the cranio-lateral part by the a. glutea superior and the ischial parts by the a. glutea inferior. The arterial supply of the acetabulum can be saved knowing the way and entry of the arteries into the bone. This is of importance for triple osteotomies of the pelvis but as well for difficult total hip replacements and revisions. The described method can be used for anatomical studies of the vessel to bone correlation in different anatomical sites.


A comparison of serratus anterior muscle activation during a wall slide exercise and other traditional exercises.
Single-group repeated-measures design. To investigate the ability of the wall slide exercise to activate the serratus anterior muscle (SA) at and above 90 degrees of humeral elevation. Strengthening of the SA is a critical component of rehabilitation for patients with shoulder impingement syndromes. Traditional SA exercises have included scapular protraction exercises such as the push-up plus. These exercises promote activation of the SA near 90 degrees of humeral elevation, but not in positions above 90 degrees where patients typically experience pain. Twenty healthy subjects were studied performing 3 exercises: (1) wall slide, (2) plus phase of a wall push-up plus, and (3) scapular plane shoulder elevation. Three-dimensional position of the thorax, scapula, and humerus and muscle activity from the SA, upper and lower trapezius, and latissimus dorsi were recorded. The magnitudes of activation for each muscle at 90 degrees, 120 degrees, and 140 degrees of humeral elevation were quantified from EMG records. Repeated-measures analyses of variance were used to determine the degree to which the different exercises activated the SA at the 3 humeral positions. The intensity of SA activity was not significantly different between the 3 exercises at 90 degrees of humeral elevation (P = .40). For the wall slide and scapular plane shoulder elevation exercises, SA activity increased with increasing humeral elevation angle (P = .001), with no significant differences between the 2 exercises (P = .36). The wall slide is an effective exercise to activate the SA muscle at and above 90 degrees of shoulder elevation. During this exercise, SA activation is not significantly different from SA activation during the push-up plus and scapular plane shoulder elevation, 2 exercises previously validated in the literature.


Tumor Necrosis Factor Alpha Preconditioned Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Enhance the Inhibition of Necroptosis of Acinar cells in Severe Acute Pancreatitis.
Severe acute pancreatitis (SAP) is a common abdominal emergency with a high mortality rate and a lack of effective therapeutic options. Although mesenchymal stem cell (MSC) transplantation is a potential treatment for SAP, the mechanism remains unclear. It has been suggested that MSCs may act mainly through paracrine effects; therefore, we aimed to demonstrate the therapeutic efficacy of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (UCMSCs) for SAP. Na-taurocholate was used to induce a rat SAP model through retrograde injection into the common biliopancreatic duct. After 72 h of EVs transplantation, pancreatic pathological damage was alleviated, along with a decrease in serum amylase activity and pro-inflammatory cytokine levels. Interestingly, when UCMSCs were preconditioned with 10 ng/mL tumor necrosis factor alpha (TNF-α) for 48 h, the obtained EVs (named TNF-α-EVs) performed an enhanced efficacy. Furthermore, both animal and cellular experiments showed that TNF-α-EVs alleviated the necroptosis of acinar cells of SAP through RIPK3/MLKL axis. In conclusion, our study demonstrated that TNF-α-EVs were able to enhance the therapeutic effect on SAP by inhibiting necroptosis compared to normal EVs. This study heralds that TNF-α-EVs may be a promising therapeutic approach for SAP in the future.


Computational detection and quantification of human and mouse neutrophil extracellular traps in flow cytometry and confocal microscopy.
Neutrophil extracellular traps (NETs) are extracellular defense mechanisms used by neutrophils, where chromatin is expelled together with histones and granular/cytoplasmic proteins. They have become an immunology hotspot, implicated in infections, but also in a diverse array of diseases such as systemic lupus erythematosus, diabetes, and cancer. However, the precise assessment of in vivo relevance in different disease settings has been hampered by limited tools to quantify occurrence of extracellular traps in experimental models and human samples. To expedite progress towards improved quantitative tools, we have developed computational pipelines to identify extracellular traps from an in vitro human samples visualized using the ImageStream® platform (Millipore Sigma, Darmstadt, Germany), and confocal images of an in vivo mouse disease model of aspergillus fumigatus pneumonia. Our two in vitro methods, tested on n = 363/n =145 images respectively, achieved holdout sensitivity/specificity 0.98/0.93 and 1/0.92. Our unsupervised method for thin lung tissue sections in murine fungal pneumonia achieved sensitivity/specificity 0.99/0.98 in n = 14 images. Our supervised method for thin lung tissue classified NETs with sensitivity/specificity 0.86/0.90. We expect that our approach will be of value for researchers, and have application in infectious and inflammatory diseases.


Absence of low-frequency variability of sympathetic nerve activity in severe heart failure.
In normal humans, variability of blood pressure, RR interval, and sympathetic activity occurs predominantly at a low frequency (LF; 0.04 to 0.14 Hz) and a high frequency (HF; +/-0.25 Hz). In conditions that increase sympathetic activation in normal humans, the LF component is increased relative to the HF component. Patients with heart failure have high levels of sympathetic activity. We tested the hypothesis that the LF component of sympathetic nerve activity variability is increased in heart failure. We performed spectral analysis of simultaneous recordings of resting muscle sympathetic nerve activity (MSNA) and RR interval in 21 patients with chronic heart failure and 12 age-matched control subjects. MSNA was higher in patients with heart failure (62 +/- 4 bursts per minute) than in the normal subjects (39 +/- 4 bursts per minute; P < .01). LF components of RR interval and MSNA variability were lower in the heart failure patients versus the control subjects (P < .01). HF variability of RR interval and MSNA was preserved, at least in part, in heart failure. There was close coherence between variability patterns of RR interval and MSNA. Furthermore, in 14 heart failure patients who had no LF variability in MSNA compared with 7 heart failure patients who did manifest LF variability in MSNA, RR interval was shorter, the variance of RR interval was lower, MSNA was higher, respiratory rate was faster, and left ventricular ejection fraction was lower (all P < .05). At a median follow-up of 12 months, 4 heart failure patients had died, all of whom had had absent LF oscillations in MSNA and RR interval. The LF variability of sympathetic nerve activity is absent in patients with severe heart failure. This disturbed pattern of variability is closely coherent with the abnormal variability of RR interval. These disturbances of rhythmic oscillations of autonomic outflow, evident in both RR interval and MSNA, suggest a central autonomic regulatory impairment in heart failure and may have important prognostic implications.


[Hand exzema: think about work].
Skin conditions such as acne, urticaria, psoriasis, and particularly eczema (dermatitis) may have many causes. However, a work-related aetiology is often forgotten. Hand eczema is the most common occupational dermatosis. Exposure to skin irritants is the main cause with wet work playing a major role. The cause cannot be inferred from the clinical picture and it is almost impossible to distinguish between irritant and allergic contact dermatitis. Besides observation and history-taking, epicutaneous contact allergological (patch) testing is necessary for this. In occupational dermatoses, patch testing using the European Standard Series alone is often inadequate for diagnosing. Everyone with hand eczema in a risk profession is eligible for patch testing. The prognosis of hand eczema is poor: in 60% of patients the eczema becomes chronic. Genetic predisposition, such as atopic dermatitis, is seriously underestimated. This is the main risk factor for irritant contact dermatitis and, indirectly, for allergic contact dermatitis. This predisposition should give direction to career choices in young people.


Comparison between Conventional IMRT Planning and a Novel Real-Time Adaptive Planning Strategy in Hypofractionated Regimes for Prostate Cancer: A Proof-of-Concept Planning Study.
In prostate cancer external beam radiation therapy (EBRT), intra-fraction prostate drifts may compromise the treatment efficacy by underdosing the target and/or overdosing the organs at risk. In this study, a recently developed real-time adaptive planning strategy for intensity-modulated radiation therapy (IMRT) for prostate cancer was evaluated in hypofractionated regimes against traditional treatment planning based on a treatment volume margin expansion. The proposed workflow makes use of a "library of plans" corresponding to possible intra-fraction prostate positions. During delivery, at each beam end, the plan prepared for the position of the prostate closest to the current one is selected and the corresponding beam delivered. This adaptive planning strategy was compared with the traditional approach on a clinical prostate cancer case where different prostate shift magnitudes were considered. Five, six and fifteen fraction hypofractionated schemes were considered for each of these scenarios. When shifts larger than the treatment margin were present, using the traditional approach the seminal vesicles were underdosed by 3-4% of the prescribed dose. The adaptive approach instead allowed for correct target dose coverage and lowered the dose on the rectum for each dosimetric endpoint on average by 3-4% in all the fractionation schemes. Standard intensity-modulated radiation therapy planning did not always guarantee a correct dose distribution on the seminal vesicles and the rectum. The adaptive planning strategy proposed resulted insensitive to the intra-fraction prostate drifts, produced a dose distribution in agreement with the dosimetric requirements in every case analysed and significantly lowered the dose on the rectum.


Lapatinib and poziotinib overcome ABCB1-mediated paclitaxel resistance in ovarian cancer.
Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer.


[Status of nutrition and cell immunity in sportsmen-weightlifters].
The analysis of average daily nutrient intake, indexes of lipids metabolism parameters of cell immunity on 30 weightlifters and 14 individuals, who does not be engaged in sport, are carried out. Results of the present research show the imbalance in athletes diet with unfavourable ratio of proteins, fats, carbohydrates as 1:1,7:3--in women and 1:1,4:2,9--in men. Lipid storage disease include the rise of low-density lipoproteins level (in women-- 3,2 +/- 0,2; in men--3,4 +/- 0,2 (p < 0,05); in control group--2,2 +/- 0,3 mmol/l) and the fall--of high-density lipoproteins (in women--1,3 +/- 0,1; in men--0,9 +/- 0,1; p < 0,05); in control group--1,7 +/- 0,2 mmol/l). Result of disbalance in sportsmen immune system was statistically authentic decrease in an immunoregulatory index of CD4/CD8 (in women--0,89 +/- 0,08, in men--0,77 +/- 0,11; p < 0,05) at the expense of increase of the relative maintenance of cytotoxic CD3+CD8+ T-killers (in women--39,42 +/- 4,0; in men--41,28 +/- 3,28%; p < 0,05) and reduction of the T-helpers CD3+CD4+ content in peripheral blood (32,48 +/- 1,06 and 31,33 +/- 2,95%; p < 0,05) at 17% of women and 42% of male athletes owing to intense physical activities. This suggests that athletes engaging in longer periods of intensified training can exhibit an inefficiency of cell immunity. The cause of immune response decreasing can be metabolic disorders. The imbalance in athletes' diet leads to dislipoproteinemia, which play a pathogenetic role in cell immunosuppression.


Colectomy risk score predicts pouchitis in patients with ulcerative colitis.
Risk stratification is required to improve the management of pouchitis with ulcerative colitis (UC) patients who undergo ileal pouch-anal anastomosis (IPAA). Recently, the colectomy risk score (CRS) has been used to assess UC severity and predict the need for surgery. We explored whether the CRS predicted pouchitis in patients with UC who underwent IPAA. This retrospective study included 168 UC patients who underwent IPAA. Pouchitis was diagnosed according to the pouchitis disease activity index. The primary endpoint was the cumulative incidence of pouchitis. The risk factors for pouchitis using preoperatively obtained data, including the CRS, were investigated. Based on their CRS, patients were assigned to low- (scores 0-3), intermediate- (scores 4-6), and high-risk (scores 7-9) groups. The incidence of pouchitis was estimated using the Kaplan-Meier curve. CRS validity was assessed using the Cox proportional hazards model. During the median 7.2 (interquartile range [IQR] 2.8-11.1) years' follow-up, 37 (28.5%) patients were diagnosed with pouchitis. Patients with pouchitis had significantly higher CRS than patients without pouchitis (median 7.0; IQR, 4.0-7.0 vs median 5.0; IQR, 3.0-7.0). The cumulative incidences of pouchitis in the low-, intermediate-, and high-risk groups were 10.3%, 18.3%, and 36.1% at 5 years, respectively. Thus, the incidence trended to increase significantly as CRS increased. Multivariate analysis revealed high-risk CRS status was an independent predictor of pouchitis (hazard ratio: 18.03; 95% confidence interval 1.55-210.05). CRS is useful in risk stratification for the development of subsequent pouchitis in patients with UC undergoing IPAA.


Synthesis and in vitro biocompatibility of injectable polyurethane foam scaffolds.
The development of therapeutics for orthopedic clinical indications exploiting minimally invasive surgical techniques has substantial benefits, especially for treatment of fragility fractures in the distal radius of osteoporotics and vertebral compression fractures. We have designed six formulations of injectable polyurethane foams to address these clinical indications. The polyurethanes were prepared by mixing two liquid components and injecting the reactive liquid mixture into a mold where it hardens in situ. Porous polyurethane foams were synthesized from lysine methyl ester diisocyanate, a poly(epsilon-caprolactone-co-glycolide) triol, a tertiary amine catalyst, anionic and non-ionic stabilizers, and a fatty acid pore opener. The rise time of the foams varied from 8-20 min. The porosity was approximately 95% and the pores varied in size from 100-1000 microm. The polyurethane foams supported attachment of viable (>95%) MG-63 cells under dynamic seeding conditions. We anticipate compelling opportunities will be available as a consequence of the favorable biological and physical properties of the injectable polyurethane foams.


Identification of Hendra virus G glycoprotein residues that are critical for receptor binding.
Hendra virus (HeV) is an emerging paramyxovirus capable of infecting and causing disease in a variety of mammalian species, including humans. The virus infects its host cells through the coordinated functions of its fusion (F) and attachment (G) glycoproteins, the latter of which is responsible for binding the virus receptors ephrinB2 and ephrinB3. In order to identify the receptor binding site, a panel of G glycoprotein constructs containing mutations was generated using an alanine-scanning mutagenesis strategy. Based on a predicted G structure, charged amino acids residing in regions that could be homologous to those in the measles virus H attachment glycoprotein known to be involved in its protein receptor interaction were targeted. Using a coprecipitation-based assay, seven single-amino-acid substitutions in HeV G were identified as having significantly impaired binding to both the ephrinB2 and ephrinB3 viral receptors: D257A, D260A, G439A, K443A, G449A, K465A, and D468A. The impairment of receptor interaction conferred a concomitant diminution in their abilities to promote membrane fusion when coexpressed with F. The G glycoprotein mutants were also recognized by three or more conformation-dependent monoclonal antibodies of a panel of five, were expressed on the cell surface, and retained their abilities to bind and coprecipitate F. Interestingly, some of these mutant G glycoproteins coprecipitated with F more efficiently than wild-type G. Taken together, these data provide strong biochemical and functional evidence that some of these residues could be part of a conformation-dependent, discontinuous, and overlapping ephrinB2 and -B3 binding domain within the HeV G glycoprotein.


A survey of stimulation methods used in SSVEP-based BCIs.
Brain-computer interface (BCI) systems based on the steady-state visual evoked potential (SSVEP) provide higher information throughput and require shorter training than BCI systems using other brain signals. To elicit an SSVEP, a repetitive visual stimulus (RVS) has to be presented to the user. The RVS can be rendered on a computer screen by alternating graphical patterns, or with external light sources able to emit modulated light. The properties of an RVS (e.g., frequency, color) depend on the rendering device and influence the SSVEP characteristics. This affects the BCI information throughput and the levels of user safety and comfort. Literature on SSVEP-based BCIs does not generally provide reasons for the selection of the used rendering devices or RVS properties. In this paper, we review the literature on SSVEP-based BCIs and comprehensively report on the different RVS choices in terms of rendering devices, properties, and their potential influence on BCI performance, user safety and comfort.


Age-related changes in macular vessels and their perfusion densities on optical coherence tomography angiography.
To evaluate age-related changes in macular vessels and their perfusion densities using optical coherence tomography angiography (OCTA). A total of 108 eyes of 54 healthy subjects between the age group of 11 to 60 years having unaided visual acuity of 20/20 were studied on spectral domain OCTS using 3 * 3 mm macula protocol. These subjects were divided into 5 groups; Group 1: 11-20 years, Group 2: 21-30 years, Group 3: 31-40 years, Group 4: 41-50 years, and Group 5: 51-60 years. An early treatment diabetic retinopathy study (ETDRS) grid overlay at the macula was used to calculate changes in different quadrants of the superficial retinal plexus. A total of 98 eyes of 49 patients were considered for the final analysis. The vessel density values decreased from the second to the sixth decade in all four quadrants (except the third decade, where a slight increase was noted). The total vessel density decreased from 168 ± 78 mm-1 (group 1) to 131.47 ± 18.32 mm-1 (group 5). A similar reduction pattern in perfusion density was seen in each quadrant from the second to the sixth decade. The total perfusion density reduced from 309 ± 15.63% (group 1) to 283.05 ± 45.23% (group 5). The foveal avascular zone area was 0.18 ± 0.09 mm2 in group 1, 0.33 ± 0.13 mm2 in group 2, 0.30 ± 0.10 mm2 in group 3, 0.38 ± 0.05 mm2 in group 4, and 0.46 ± 0.06 mm2 in group 5. In our population, macular vessel density appears to decrease noticeably from the fourth decade onwards but a statistically significant decrease was observed only from the fifth decade onwards. However, it was not uniform along with all the quadrants. Similarly, the percentage of perfusion density dropped from the fourth decade but these values also varied among the different quadrants.


A rapid single-step multiplex method for discriminating between Trichogramma (Hymenoptera: Trichogrammatidae) species in Australia.
Inaccurate species identification confounds insect ecological studies. Examining aspects of Trichogramma ecology pertinent to the novel insect resistance management strategy for future transgenic cotton, Gossypium hirsutum L., production in the Ord River Irrigation Area (ORIA) of Western Australia required accurate differentiation between morphologically similar Trichogramma species. Established molecular diagnostic methods for Trichogramma identification use species-specific sequence difference in the internal transcribed spacer (ITS)-2 chromosomal region; yet, difficulties arise discerning polymerase chain reaction (PCR) fragments of similar base pair length by gel electrophoresis. This necessitates the restriction enzyme digestion of PCR-amplified ITS-2 fragments to readily differentiate Trichogramma australicum Girault and Trichogramma pretiosum Riley. To overcome the time and expense associated with a two-step diagnostic procedure, we developed a "one-step" multiplex PCR technique using species-specific primers designed to the ITS-2 region. This approach allowed for a high-throughput analysis of samples as part of ongoing ecological studies examining Trichogramma biological control potential in the ORIA where these two species occur in sympatry.


X-chromosome inactivation in female patients with Fabry disease.
Fabry disease (FD) is an X-linked genetic disorder caused by the deficient activity of lysosomal α-galactosidase (α-Gal). While males are usually severely affected, clinical presentation in female patients may be more variable ranging from asymptomatic to, occasionally, as severely affected as male patients. The aim of this study was to evaluate the existence of skewed X-chromosome inactivation (XCI) in females with FD, its concordance between tissues, and its contribution to the phenotype. Fifty-six females with FD were enrolled. Clinical and biological work-up included two global scores [Mainz Severity Score Index (MSSI) and DS3], cardiac magnetic resonance imaging, measured glomerular filtration rate, and measurement of α-Gal activity. XCI was analyzed in four tissues using DNA methylation studies. Skewed XCI was found in 29% of the study population. A correlation was found in XCI patterns between blood and the other analyzed tissues although some punctual variability was detected. Significant differences in residual α-Gal levels, severity scores, progression of cardiomyopathy and deterioration of kidney function, depending on the direction and degree of skewing of XCI were evidenced. XCI significantly impacts the phenotype and natural history of FD in females.


[Ultrastructure of B-cell tumors of the pancreas (insulinomas - insular carcinoid tumors)].
The subcellular organization of 6 B-cell tumours of the human pancreas was studied. The tumour parenchyma consisted of processed light, dark, and moderately electron dense cells containing insulin granules. The presence of villi in the cytoplasm of tumour cells and intranuclear fibrills was demonstrated. The participation of tumour cells in formation of amyloid-like thin-fiber substance filling the intercellular and perivascular spaces was established. The similarity between endothelial cells of tumour vessels and parenchymatous cells was shown. A hypothesis on neuroectodermal origin of the endocrine tissue of the pancreas is supported.


Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials.
Recent trials have examined the effect of prolonged dual antiplatelet therapy (DAPT) in a variety of patient populations, with heterogeneous results regarding benefit and safety, specifically with regard to cardiovascular and non-cardiovascular mortality. We performed a meta-analysis of randomized trials comparing more than a year of DAPT with aspirin alone in high-risk patients with a history of prior myocardial infarction (MI). A total of 33 435 patients were followed over a mean 31 months among one trial of patients with prior MI (63.3% of total) and five trials with a subgroup of patients that presented with, or had a history of, a prior MI (36.7% of total). Extended DAPT decreased the risk of major adverse cardiovascular events compared with aspirin alone (6.4 vs. 7.5%; risk ratio, RR 0.78, 95% confidence intervals, CI, 0.67-0.90; P = 0.001) and reduced cardiovascular death (2.3 vs. 2.6%; RR 0.85, 95% CI 0.74-0.98; P = 0.03), with no increase in non-cardiovascular death (RR 1.03, 95% CI 0.86-1.23; P = 0.76). The resultant effect on all-cause mortality was an RR of 0.92 (95% CI 0.83-1.03; P = 0.13). Extended DAPT also reduced MI (RR 0.70, 95% CI 0.55-0.88; P = 0.003), stroke (RR 0.81, 95% CI 0.68-0.97; P = 0.02), and stent thrombosis (RR 0.50, 95% CI 0.28-0.89; P = 0.02). There was an increased risk of major bleeding (1.85 vs. 1.09%; RR 1.73, 95% CI 1.19-2.50; P = 0.004) but not fatal bleeding (0.14 vs. 0.17%; RR 0.91, 95% CI 0.53-1.58; P = 0.75). Compared with aspirin alone, DAPT beyond 1 year among stabilized high-risk patients with prior MI decreases ischaemic events, including significant reductions in the individual endpoints of cardiovascular death, recurrent MI, and stroke. Dual antiplatelet therapy beyond 1 year increases major bleeding, but not fatal bleeding or non-cardiovascular death.


Combined Use of Zoledronic Acid Augments Ursolic Acid-Induced Apoptosis in Human Osteosarcoma Cells through Enhanced Oxidative Stress and Autophagy.
Ursolic acid (UA), a naturally occurring pentacyclic triterpene acid found in many medicinal herbs and edible plants, triggers apoptosis in several tumor cell lines but not in human bone cancer cells. Most recently, we have demonstrated that UA exposure reduces the viability of human osteosarcoma MG-63 cells through enhanced oxidative stress and apoptosis. Interestingly, an inhibitor of osteoclast-mediated bone resorption, zoledronic acid (ZOL), also a third-generation nitrogen-containing bisphosphonate, is effective in the treatment of bone metastases in patients with various solid tumors. In this present study, we found that UA combined with ZOL to significantly suppress cell viability, colony formation, and induce apoptosis in two lines of human osteosarcoma cells. The pre-treatment of the antioxidant had reversed the oxidative stress and cell viability inhibition in the combined treatment, indicating that oxidative stress is important in the combined anti-tumor effects. Moreover, we demonstrated that ZOL combined with UA significantly induced autophagy and co-administration of autophagy inhibitor reduces the growth inhibitory effect of combined treatment. Collectively, these data shed light on the pathways involved in the combined effects of ZOL and UA that might serve as a potential therapy against osteosarcoma.


The time of the crime: cognitively induced tonic arousal suppression when lying in a free recall context.
Previous research has shown that suspects in real-life interviews do not display stereotypical signs of nervous behaviours, even though they may be experiencing high detection anxiety. We hypothesised that these suspects may have experienced cognitive load when lying and that this cognitive load reduced their tonic arousal, which suppressed signs of nervousness. We conducted two experiments to test this hypothesis. Tonic electrodermal arousal and blink rate were examined during task-induced (Experiment 1) and deception-induced cognitive load (Experiment 2). Both increased cognitive difficulty and deception resulted in decreased tonic arousal and blinking. This demonstrated for the first time that when lying results in heightened levels of cognitive load, signs of nervousness are decreased. We discuss implications for detecting deception and more wide-ranging phenomena related to emotional behaviour.


Human placentation from nidation to 5 weeks of gestation. Part II: Tools to model the crucial first days.
Human pregnancy is unusual with respect to monthly spontaneous decidualisation as well as the degree of placental invasion and interaction with the decidualised endometrial stroma. This review covers in vivo animal models and in vitro cell culture models that have been used to study the earliest stages of human implantation and placentation from nidation to 5 weeks of gestation. The field has expanded rapidly in recent years due to the generation of human embryonic stem cell lines and the ability of some scientists to culture human blastocysts. These models have enabled researchers to begin to elucidate the interactions involved in human blastocyst apposition, adhesion and implantation. However, we still understand very little about the differentiation processes involved in the formation of the placenta. Continued improvements to current models, including the potential isolation of a human trophoblast stem cell, will significantly enhance our ability to define the molecular and structural events occurring during human implantation and early placental development.


Quantifying weight-bearing by children with cerebral palsy while in passive standers.
Children who are nonambulatory are placed into standers with the goal of providing benefits from weight-bearing. The purpose of this study was to quantify weight-bearing loads by children with cerebral palsy while in standers. Electronic load-measuring footplates were fabricated specifically for this study. Weight-bearing loads were continuously measured in 19 children who were nonambulatory during routine 30-minute standing sessions (3-6 sessions/child, total 110 sessions). Weight-bearing ranged widely (23%-102%) with a mean of 68% of body weight. There was some variation over the course of a session and between different sessions, but more variance was noted between subjects. Actual weight borne in a stander is quite variable, and in some instances only a fraction of actual body weight. Further studies are required to delineate relevant factors and identify ways to maximize weight-bearing loads while in a stander.


Caterpillar- and salivary-specific modification of plant proteins.
Though there is overlap, plant responses to caterpillar herbivory show distinct variations from mechanical wounding. In particular, effectors in caterpillar oral secretions modify wound-associated plant responses. Previous studies have focused on transcriptional and protein abundance differences in response to caterpillar herbivory. This study investigated Spodoptera exigua caterpillar-specific post-translational modification of Arabidopsis thaliana soluble leaf proteins by liquid chromatography/electrospray ionization/mass spectroscopy/mass spectroscopy (LC/ESI/MS/MS). Given that caterpillar labial saliva contains oxidoreductases, such as glucose oxidase, particular attention was paid to redox-associated modifications, such as the oxidation of protein cysteine residues. Caterpillar- and saliva-specific protein modifications were observed. Differential phosphorylation of the jasmonic acid biosynthetic enzyme, lipoxygenase 2, and a chaperonin protein is seen in plants fed upon by caterpillars with intact salivary secretions compared to herbivory by larvae with impaired labial salivary secretions. Often a systemic suppression of photosynthesis is associated with caterpillar herbivory. Of the five proteins modified in a caterpillar-specific manner (a transcription repressor, a DNA-repair enzyme, PS I P700, Rubisco and Rubisco activase), three are associated with photosynthesis. Oxidative modifications are observed, such as caterpillar-specific denitrosylation of Rubisco activase and chaperonin, cysteine oxidation of Rubisco, DNA-repair enzyme, and chaperonin and caterpillar-specific 4-oxo-2-nonenal modification of the DNA-repair enzyme.


Latex-agglutination test for rubella antibody: validity of positive results assessed by response to immunization and comparison with other tests.
A commercial-latex agglutination (LA) assay ( Rubascan , Hynson , Westcott and Dunning, Baltimore, Md) performed on undiluted serum may be more sensitive than is the standard hemagglutination-inhibition assay for the detection of rubella antibody. To investigate whether a positive result of an LA test on undiluted serum was correlated with rubella immunity, we identified 29 persons whose sera produced negative results when initially tested by LA at a 1:10 dilution; 15 of these sera produced positive results and 14 produced negative results when retested undiluted. The immune status of each person for rubella was determined with a test for IgM rubella antibody on serum samples obtained three to five weeks after rubella immunization. None of the 15 persons whose preimmunization sera produced positive results by LA when tested undiluted developed IgM rubella antibody, as compared with 10 of the 14 persons whose preimmunization sera produced negative results (P less than 0.001). Data from this study support the specificity of a positive result of an LA test performed on undiluted serum, but a 1:5 dilution may be optimal for determination of rubella immune status.


Porous organic nanolayers for coating of solid-state devices.
Highly hydrophobic surfaces can have very low surface energy and such low surface energy biological interfaces can be obtained using fluorinated coatings on surfaces. Deposition of biocompatible organic films on solid-state surfaces is attained with techniques like plasma polymerization, biomineralization and chemical vapor deposition. All these require special equipment or harsh chemicals. This paper presents a simple vapor-phase approach to directly coat solid-state surfaces with biocompatible films without any harsh chemical or plasma treatment. Hydrophilic and hydrophobic monomers were used for reaction and deposition of nanolayer films. The monomers were characterized and showed a very consistent coating of 3D micropore structures. The coating showed nano-textured surface morphology which can aid cell growth and provide rich molecular functionalization. The surface properties of the obtained film were regulated by varying monomer concentrations, reaction time and the vacuum pressure in a simple reaction chamber. Films were characterized by contact angle analysis for surface energy and with profilometer to measure the thickness. Fourier Transform Infrared Spectroscopy (FTIR) analysis revealed the chemical composition of the coated films. Variations in the FTIR results with respect to different concentrations of monomers showed the chemical composition of the resulting films. The presented approach of vapor-phase coating of solid-state structures is important and applicable in many areas of bio-nano interface development. The exposure of coatings to the solutions of different pH showed the stability of the coatings in chemical surroundings. The organic nanocoating of films can be used in bio-implants and many medical devices.


trans-Dichlorido-tetra-kis-[(di-methyl-phosphor-yl)methanaminium-κO]cobalt(II) tetra-chloridocobaltate(II).
The asymmetric unit of the title structure, [CoCl2(C3H11NOP)4][CoCl4]2, consists of one half of the trans-dichlorido-tetra-kis-[(di-methyl-phosphor-yl)methanaminium]cobalt(II) tetra-cation lying on an inversion center and one tetra-chloridocobaltate(II) dianion on a general position. Four O-coordinated cationic (di-methyl-phosphor-yl)methanaminium (dpmaH(+)) ligands occupy the equatorial coordination sites, whereas the chloride ligands occupy axial positions of the roughly o-cta-hedral coordination polyhedron of the cobalt metal center. Intra-molecular hydrogen bonds between the aminium groups and the O atom of the phosphoryl groups and additional hydrogen bonds between the aminium groups and the chloride ligands are present. Furthermore, four of the six H atoms not involved in intra-molecular bonding of each cobalt(II) tetra-cation form weak hydrogen bonds to four adjacent tetra-chloridocobaltate(II) counter-anions. By these inter-molecular hydrogen bonds, one-dimensional polymeric strands are formed along the b-axis direction. The hydrogen bonding is analyzed using the graph-set method and the structural similarity with dpmaHCl is discussed.


A phenomenological exploration of the gender transition experience: findings to improve culturally competent nursing care and decrease health disparities.
Most recently, it has been reported that 1.4 million adults in the United States identify as transgender. This number is double what was reported just five years earlier. What little research has been completed on this vulnerable population indicates that people who identify as transgender experience higher rates of depression, suicide, and social stigmatization than the cisgender population. Stigmatization of transgender people and lack of access to quality care is often the root for these disparities. Very few studies have examined the experience of transition. The purpose of this phenomenological study was to explore the experience of transitioning from one gender to another. Non-structured, in-depth interviews were conducted via an online platform with 11 male-to-female transgender adults who gave their informed consent to participate. Through a process of group data analysis, four major themes emerged: (a) Everybody Saw the Mask; (b) A Turning Point; (c) Shedding My Skin; and (d) Navigating the Way. These findings can heighten healthcare personnel's sensitivity to this vulnerable population, as well as guide students and providers to provide culturally appropriate care, which can lead to a decrease in health disparities.


Relatives' experiences with abuse and neglect in Norwegian nursing homes. A qualitative study.
Elder abuse in nursing homes (NH) is a widespread and complex problem. Residents' ability to share their experiences are impeded, due to a high degree of cognitive problems and frailty, and previous studies are thus mainly based on reports from staff. Therefore, we aimed to give voice to the residents by investigating their relatives' experiences with elder abuse in NH. Qualitative individual interviews were conducted with 16 relatives of residents with experience of abuse and/or neglect in NH. Content analysis was used to analyse the data. Relatives perceived neglect as most pervasive and staff-to-resident psychological abuse as a key problem. Physical abuse was mostly related to resident-to-resident aggression. Relatives perceived elder abuse in NH to be related to low competence among staff, low staffing, poor NH leadership, working cultures characterized by fear and loyalty to employer or co-workers, and a lack of individualized care for the residents. Furthermore, relatives themselves experienced maltreatment from NH, which caused them to suffer stress, anxiety and distrust. Relatives also expressed a need to compensate for lack of care. Relatives of NH residents who had experienced abuse reported that neglect of basic care and individual rights was predominant and viewed organizational explanations as most important. Relatives perceive themselves as collaborators in care and are emotionally attached to their family member. Therefore, if relatives experience resident abuse or neglect, it inflicts a feeling of being mistreated themselves, particularly if they are not listened to or their notice of abuse on the part of the resident is ignored or trivialized. Including relatives in a committed partnership with NH in care practices is not only a valuable path to reduce the risk of abuse, but it also leads to a more sustainable healthcare with high standards of quality and safety.


Impact of foetus and mother on IFN-gamma-induced indoleamine 2,3-dioxygenase and inducible nitric oxide synthase expression in murine placenta following Toxoplasma gondii infection.
IFN-gamma production is a hallmark of acute infection with the protozoan parasite Toxoplasma gondii. The tryptophan-catabolising enzyme indoleamine 2,3-dioxygenase (IDO), as well as inducible nitric oxide synthase (NOS2) are induced by IFN-gamma and can play extremely diverse roles in immune regulation, defence against pathogens and physiological homeostasis. We investigated the regulation of these two central enzymes in the placenta during acute infection of pregnant female mice. Using IFN-gamma receptor knockout (IFNgammaR-/-) mice, we showed that IDO is not constitutively expressed in term placentas. In contrast, NOS2 expression was observed, largely dependent on IFN-gamma signalling. Upon infection with the avirulent PRU strain of T. gondii, IDO mRNA expression was induced in an IFNgammaR-dependent manner. Surprisingly, NOS2 mRNA was severely suppressed. Importantly, we showed in crossing experiments of heterozygote (IFNgammaR+/-) mothers with IFNgammaR-/- males and vice versa that IDO expression largely depends on the presence of IFN-gamma receptors on foetal cells, and to a lesser extent on maternal cells. Immunohistochemical analysis localised foetal IDO production to invasive trophoblasts within the maternal part of the placenta. The placental vascular endothelium only stained positive when the mothers possessed functional IFN-gamma receptors. In contrast, placental NOS2 expression, but also its suppression following infection, seems to be largely dependent on IFN-gamma signalling in maternal cells. Neither factor appears to regulate placental T. gondii growth, as we observed no difference in parasite numbers between (+/-) and (-/-) foetuses. Taken together, our results demonstrate the crucial role of the foetus in placental IDO, but not NOS2, production following T. gondii infection.


Construction and validation of questionnaire to assess recreational noise exposure in university students.
Recreational noise exposure and its impact on hearing is a problem to which increasing attention is being paid. In Spanish, it is necessary to have a reliable and valid instrument that is capable of describing the extent of noise exposure. The aim was to create and validate an instrument to determine listening habits and levels of recreational noise exposure in young people. We performed a transversal questionnaire validation study using university students. We assessed the validity of the content and appearance of the "Recreational Hearing Habits Questionnaire" (CHAR in Spanish) through experts' judgment. Then we piloted the administration of semantic adaptation with 30 students. Finally, the instrument was applied to 335 Chilean university students, obtaining with these indicators that demonstrated convergent validity of the construct, criterion and reliability. We used exploratory and confirmatory factor analysis, as well as correlation and agreement tests. It was confirmed that 14 questions in the questionnaire have a good item-test correlation, having also a factorial structure that indicates the existence of three-dimensions. The questionnaire has good internal consistency and convergent validity with the Noise Exposure Questionnaire. In addition, the score obtained in the CHAR is a predictor of the presence of notch at frequencies of 4 kHz in the right ear and 6 kHz in the left. The CHAR is useful for determining listening habits and thereby recreational noise exposure, indicating good psychometric properties.


The effects of the synonymous codon usage and tRNA abundance on protein folding of the 3C protease of foot-and-mouth disease virus.
The 3C protease of foot-and-mouth disease virus (FMDV) has a conserved amino acid sequence and is responsible for most cleavage in the viral polyprotein. The effects of the synonymous codon usage of FMDV 3C gene and tRNA abundance of the hosts on shaping different folding units (α-helix, β-strand and the coil) in the 3C protease were analyzed based on the structural information of the FMDV 3C protease from Protein Data Bank (PDB: 2BHG) and 210 genes of 3C for all serotypes of FMDV. The strong correlation between some codons usage and the specific folding unit in the FMDV 3C protease is found. As for the effect of translation speed caused by tRNA abundance on the formation of folding units, the codon positions with lowly abundant tRNA scatter in the 3C gene and there is the obvious fluctuation of tRNA abundance locating in the transition boundaries from the β-strand to the α-helix and the coil, respectively. However, codon positions with lowly abundant tRNA clustering into these boundaries are not found, suggesting that the adjustment of translation speed is likely also achieved by the single codon position with low tRNA abundance rather than a cluster. The observations can provide the information for insight into the role of the synonymous codon usage in the formation of 3C protease of FMDV and effect of the tRNA abundance of the hosts on this formation of protease.


Residual experiential symptoms mediate the effect of expressive symptoms over the social functioning in remitted schizophrenia.
Impairment in social functioning had been consistently found in remitted schizophrenia; yet, predictors of social dysfunction had been hardly explored and intervention trials had rarely included remitted schizophrenia. 60 subjects with schizophrenia (diagnosed based on DSM5), currently in remission (SAPS and SANS global rating ≤2, for a minimum period of 12 weeks) and 46 age and gender-matched healthy controls were recruited after obtaining informed consent. The socio-demographic details, illness characteristics, depressive symptoms, positive and negative symptoms [using Scale for assessment of positive symptoms (SAPS), and scale for assessment of negative symptoms (SANS)] were assessed. The Theory of Mind (ToM) score was derived from the ToM tasks of a culturally validated tool, Social Cognition Rating Tools in Indian Setting. The social functioning was assessed using Groningen social disabilities schedule II (GSDSSII). The mean SAPS summary and SANS summary scores were 3.01 ± 2.99 and 4.32 ± 2.94, respectively. The social functioning was significantly impaired in remitted schizophrenia when compared to healthy controls. In the hierarchical regression, experiential dimension (β =1.941, t = 6.097, P < 0.001), followed by expressive dimension predicted social functioning (explained 70.5% of variance) after controlling for confounders. On mediation analysis, the effect of expressive dimension over the social functioning was significantly mediated by experiential dimension (E = 1.1821, Boot SE = 0.2895, C.I: 0.6934 to 1.7862). The experiential dimension mediates the effect of expressive dimension over the social dysfunction in remitted schizophrenia. Future studies should focus on targeting the experiential dimension and thereby social functioning.


Analysis of fentanyl analogs and novel synthetic opioids in blood, serum/plasma, and urine in forensic casework.
In recent years an increasing number of novel opioids have appeared on the illicit drug market and have been linked to the growing opioid crisis in the United States. It is suspected that synthetic-opioid-related deaths are underestimated since many laboratories either use a screening method that is not specific and sensitive enough for these compounds or testing is not performed for fentanyl and its related analogs in general. We describe a method for the analysis of 19 of the most current novel opioid drugs quantitatively in whole blood and serum, and 17 analytes qualitatively in urine using solid phase extraction with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The limit of detection was determined to be at a minimum 0.25 ng/mL for beta-hydroxythiofentanyl, 0.05 ng/mL for butyryl/isobutyrylfentanyl, AH-7921, 2-furanylfentanyl, 4-ANPP, and U-47700; 0.025 ng/mL for MT-45, para-methoxybutyrylfentanyl, 4-methylphenethyl acetyl fentanyl, U-50488, acrylfentanyl, valerylfentanyl, and carfentanil; and 0.0125 ng/mL for para-fluorofentanyl, ortho-fluorofentanyl, para-fluorobutyrylfentanyl/FIBF, and alpha-methylfentanyl. The lower limit of quantitation was determined to be 0.1 ng/mL for all analytes except AH-7921, U-47700, U-50488 which were 0.05 ng/mL and beta-hydroxythiofentanyl which was 0.5 ng/mL. The method was validated successfully according to a Scientific Working Group in Forensic Toxicology (SWGTOX) compliant approach. This method was applied to the analysis of 2758 samples between October 2016 and September 2017. It was determined that 4-ANPP, furanylfentanyl, and carfentanil were the 3 most prevalent fentanyl related compounds detected: 56.1% of cases were positive for 4-ANPP, 44.5% were positive for furanylfentanyl, and 25.2% cases were positive for carfentanil.


Satietin; a 50,000 dalton glycoprotein in human serum with potent, long-lasting and selective anorectic activity.
Satietin, a 50,000 dalton anorectic glycoprotein was isolated from human serum. Its isoelectric point is 7.0. It contains 14-15% amino acids and 70-75% carbohydrates. Its biological activity survives digestion with proteases and boiling. Satietin is a highly potent anorectic substance. The intracerebroventricular administration of 10-20 micrograms satietin suppresses food intake in rats during the first day of feeding after deprivation of food for 96 hours to half of the amount eaten by untreated controls (ID50). The onset of the effect can be detected within 30 minutes, the peak effect is reached within an hour. The effect lasts 24-30 hours. Satietin acts both at intravenous and subcutaneous administration (ID50 = 0.5-0.75 mg/kg) in rats deprived of food for 96 hours. The peak effect is reached within an hour and lasts over 24 hours. In contrast to the anorectic drugs in clinical use and to the endogenous anorectic substances (like cholecystokinin and calcitonin) satietin proved to be highly selective in suppressing food intake. Considering that satietin is widely distributed in the world of vertebrates, its concentration in the blood is amazingly high, its site of effect is in the central nervous system and it induces satiety without having any other detectable central or peripheral effect, the hypothesis was forwarded that satietin may play the role of a rate limiting blood-borne satiety signal in the negative feedback of food intake, i.e. serving as the essential chemical link connecting the gastrointestinal tract and the brain in the regulation of feeding.


The archaeon Haloarcula marismortui has few modifications in the central parts of its 23S ribosomal RNA.
Post-transcriptional modifications were mapped in domains II, IV and V of 23S RNA from the archaeon Haloarcula marismortui. The RNA was investigated by two primer extension techniques using reverse transcriptase and three mass spectrometry techniques. One primer extension technique utilized decreasing concentrations of deoxynucleotide triphosphates to detect 2'-O-ribose methylations and other polymerase blocking modifications. In the other, the rRNA was chemically modified, followed by mild alkaline hydrolysis to map pseudo-uridine groups (Psis). RNA fragments for mass spectrometry were isolated from 23S rRNA by site-directed RNase H or mung bean nuclease digestion followed by gel purification. Modified RNase digestion fragments were identified with matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS) and the modifications were further studied by tandem MS. Psis suggested by the primer extension technique were verified by specific cyanoethylation and mass spectrometric detection. A total of only five post-transcriptionally methylated nucleotides and three Psis were detected in the three 23S rRNA domains. One of the methylated nucleotides has not been reported while a dispute about the number of Psis is solved. The limited number of modified nucleotides suggests that H. marismortui does not have special needs for extensive rRNA modifications. We have performed detailed investigations on the three-dimensional location and molecular interactions of the modified nucleotides by computer analysis. Our results show that all the modified positions are at regions with RNA-RNA contacts and all except one are at the surface of the subunit and in functionally important regions.


The influence of endotoxemia on the molecular mechanisms of insulin resistance.
The reduction in the capacity of insulin to reach its biological effects can lead to a chronic hyperglycemia and hyperinsulinemia, assuming an important role in the pathogenesis of metabolic disorders associated to obesity and diabetes. Insulin resistance is associated to chronic subclinical inflammation, which in part can be mediated by increased plasmatic lipopolysaccharide levels, an endotoxin derived from the membrane of gramnegative bacteria that mainly reside in the gut. The aim of this review study is to describe the molecular mechanisms involved in the pathogenesis of insulin resistance due to metabolic endotoxemia and of its connection to obesity and diabetes. Lipopolysaccharide present in the intestinal lumen can reach the circulatory system causing metabolic endotoxemia. When lipopolysaccharide binds to Toll-like receptor 4, inflammation is activated, changing several stages of insulin signaling. It has been shown that chronic exposure to this endotoxin may contribute to weight gain and type 2 diabetes mellitus manifestation. Obese and diabetic people have increased plasmatic lipopolysaccharide levels. The increase in the number of gram-negative bacteria on gut microbiota, the reduction on gut mucosal integrity, and the consumption of high-fat diets increase the plasmatic lipopolysaccharide levels. Therefore, the type of diet consumed may modulate the composition of gut microbiota and improve gut mucosal integrity, decreasing the occurrence of endotoxemia and its postprandial inflammatory effects, leading to adequate insulin signaling. However, there are very few studies that evaluated the influence of nutrients and/or specific food types on metabolic endotoxemia.


Stem rust in Western Siberia - race composition and effective resistance genes.
Stem rust in recent years has acquired an epiphytotic character, causing significant economic damage for wheat production in some parts of Western Siberia. On the basis of a race composition study of the stem rust populations collected in 2016-2017 in Omsk region and Altai Krai, 13 pathotypes in Omsk population and 10 in Altai population were identified. The race differentiation of stem rust using a tester set of 20 North American Sr genes differentiator lines was carried out. The genes of stem rust pathotypes of the Omsk population are avirulent only to the resistance gene Sr31, Altai isolates are avirulent not only to Sr31, but also to Sr24, and Sr30. A low frequency of virulence (10-25 %) of the Omsk population pathotypes was found for Sr11, Sr24, Sr30, and for Altai population - Sr7b, Sr9b, Sr11, SrTmp, which are ineffective in Omsk region. Field evaluations of resistance to stem rust were made in 2016-2018 in Omsk region in the varieties and spring wheat lines from three different sources. The first set included 58 lines and spring bread wheat varieties with identified Sr genes - the so-called trap nursery (ISRTN - International Stem Rust Trap Nursery). The second set included spring wheat lines from the Arsenal collection, that were previously selected according to a complex of economically valuable traits, with genes for resistance to stem rust, including genes introgressed into the common wheat genome from wild cereal species. The third set included spring bread wheat varieties created in the Omsk State Agrarian University within the framework of a shuttle breeding program, with a synthetic wheat with the Ae. tauschii genome in their pedigrees. It was established that the resistance genes Sr31, Sr40, Sr2 complex are effective against stem rust in the conditions of Western Siberia. The following sources with effective Sr genes were selected: (Benno)/6*LMPG-6 DK42, Seri 82, Cham 10, Bacanora (Sr31), RL 6087 Dyck (Sr40), Amigo (Sr24, 1RS-Am), Siouxland (Sr24, Sr31), Roughrider (Sr6, Sr36), Sisson (Sr6, Sr31, Sr36), and Fleming (Sr6, Sr24, Sr36, 1RS-Am), Pavon 76 (Sr2 complex) from the ISRTN nursery; No. 1 BC1F2 (96 × 113) × 145 × 113 (Sr2, Sr36, Sr44), No. 14а F3 (96 × 113) × 145 (Sr36, Sr44), No. 19 BC2F3 (96 × 113) × 113 (Sr2, Sr36, Sr44), and No. 20 F3 (96 × 113) × 145 (Sr2, Sr36, Sr40, Sr44) from the Arsenal collection; and the Omsk State Agrarian University varieties Element 22 (Sr31, Sr35), Lutescens 27-12, Lutescens 87-12 (Sr23, Sr36), Lutescens 70-13, and Lutescens 87-13 (Sr23, Sr31, Sr36). These sources are recommended for inclusion in the breeding process for developing stem rust resistant varieties in the region.


Long-term subjective loneliness in adults after hearing loss treatment.
Objective: While hearing loss is associated with loneliness, the long term impact of hearing loss interventions remains unknown. We investigated levels of loneliness in adults at baseline, 6-months, 1-year and 5-years after receiving a hearing aid (HA) or cochlear implant (CI). Design: In this 5-year follow-up to the Studying Multiple Outcomes after Aural Rehabilitative Treatment study, participants completed the University of California, Los Angeles (UCLA) Loneliness Scale at baseline, 6-months, 1-year, and 5-year time points. Generalized estimating equations modeled the population average UCLA score over time. Study Sample: Analytic cohort of 115 participants (74% of original 156) 50 years or older who received a HA or CI at baseline and completed at least one follow up visit. Results: Loneliness scores were not different at 5 years versus baseline for HA users. CI users showed significantly reduced loneliness at 6-months and 1-year from baseline and with no significant difference at 5 years. Conclusion: Over 5 years, we observed no increase in loneliness from baseline in a cohort of adults receiving HAs and CIs. Short-term reduction in loneliness in CI users was demonstrated. Future randomized trials are needed to definitively assess the impact of treated versus untreated hearing loss on loneliness.


Computational ballistic analysis of the cranial shot to John F. Kennedy.
Almost 60 years after the assassination of President John F. Kennedy in 1963, the majority of Americans are still reluctant to believe official reports presented by the commissions gathered in 1964 and again in 1976 that determined the direction of the shot resulting in the fatal head injury. Long-withheld, confidential government files released in 2017 reignited the controversy. The present investigation computationally simulated projectile-skull-impacts from the direction specified in official reports and from three other directions. Detailed geometric models of the human head and ammunition, as well as known parameters from the assassination site served as the supportive base for analysis. Constitutive mathematical models for the impact of projectile material with skull tissues at supersonic speed were employed to analyze bone and bullet fragmentation mechanics. Simulated fracture characteristics of bone and bullet were compared with photographic and X-ray evidence. The most likely origin of the fatal shot was determined based on the degree of corresponding deformation and fragmentation between simulation and documented evidence. Computational corroboration could be established as physically consistent with high-speed impact from the rear, as established by the official commissions. Simulations of three other speculative shot origins did not correspond with the documented evidence.


The role of APOE in cerebrovascular dysfunction.
The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.


Human small cell lung cancer cell lines expressing the proopiomelanocortin gene have aberrant glucocorticoid receptor function.
Some human small cell lung carcinomas (SCLC) secrete proopiomelanocortin (POMC) derived peptides, but in contrast to the pituitary, glucocorticoids fail to inhibit this hormone production. We have previously described an in vitro model using human SCLC cell lines that express POMC and are resistant to glucocorticoids. We have now identified the glucocorticoid receptor (GR) in the SCLC cell line COR L24 using a whole cell ligand binding assay (Kd = 5.7 nM; Bmax = 11 fmol/million cells), while another cell line, DMS 79, lacked significant glucocorticoid binding. To analyze GR function both positive (GMCO) and negative (TRE)3-tkCAT), glucocorticoid-regulated reporter gene constructs were transfected into COR L24 cells. In the SCLC cell line, neither hydrocortisone nor dexamethasone (500-2,000 nM) significantly induced chloramphenicol acetyltransferase expression from GMCO; in addition, they did not suppress chloramphenicol acetyltransferase expression from (TRE)3-tkCAT. Similar results were obtained with two other POMC-expressing SCLC cell lines. Expression of wild type GR in COR L24 cells restored glucocorticoid signaling, with marked induction of GMCO reporter gene expression by dexamethasone (9,100 +/- 910%; n = 3), and an estimated EC50 of 10 nM. This failure of the GR explains the resistance of the POMC gene to glucocorticoid inhibition and may have implications for cell growth in SCLC.


Cerebral folate deficiency with developmental delay, autism, and response to folinic acid.
The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.


First hyperpolarizability of water at the air-vapor interface: a QM/MM study questions standard experimental approximations.
Surface Second-Harmonic Generation (S-SHG) experiments provide a unique approach to probe interfaces. One important issue for S-SHG is how to interpret the S-SHG intensities at the molecular level. Established frameworks commonly assume that each molecule emits light according to an average molecular hyperpolarizability tensor β(-2ω,ω,ω). However, for water molecules, this first hyperpolarizability is known to be extremely sensitive to their environment. We have investigated the molecular first hyperpolarizability of water molecules within the liquid-vapor interface, using a quantum description with explicit, inhomogeneous electrostatic embedding. The resulting average molecular first hyperpolarizability tensor depends on the distance relative to the interface, and it practically respects the Kleinman symmetry everywhere in the liquid. Within this numerical approach, based on the dipolar approximation, the water layer contributing to the Surface Second Harmonic Generation (S-SHG) intensity is less than a nanometer. The results reported here question standard interpretations based on a single, averaged hyperpolarizability for all molecules at the interface. Not only the molecular first hyperpolarizability tensor significantly depends on the distance relative to the interface, but it is also correlated to the molecular orientation. Such hyperpolarizability fluctuations may impact the S-SHG intensity emitted by an aqueous interface.


Primary and secondary structures of rRNA spacer regions in enterococci.
The 16S-23S and 23S-5S rRNA spacer DNA regions (spacer regions 1 and 2, respectively) from Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus durans and Enterococcus mundtii were amplified by PCR. Their nucleotide sequences were established and a secondary structure model showing the interaction between the two spacer regions was built. Whereas lactococci and Streptococcus sensu stricto are characterized by a single type of spacer region 1, the enterococci show a high degree of variability in this region; thus the spacer regions 1 with and without tRNA(Ala) were characterized. However, as shown for lactococci and Streptococcus sensu stricto, the tRNA(Ala) gene does not encode the 3'-terminal CCA trinucleotide. A putative antitermination signal is found downstream from the tRNA(Ala) gene. Based on comparison with Lactococcus lactis and Streptococcus thermophilus, a double-stranded processing stem is proposed. In E, hirae, one of the three different types of spacer region 1 contains no tRNA(Ala), but displays a 107 nt insertion that forms a long stem-loop structure. A similar insertion (115 nt in length) was found in E. faecium and base compensatory mutations preserve the ability to form the long stem-loop structure. Such insertions may correspond to mobile intervening sequences, as found in the 23S rRNA coding sequences of some Gram-negative bacteria. The spacer regions 1 and 2 from the three subgroups of streptococci were compared, and except for the tRNA(Ala) gene and the double-stranded processing sites, little similarity was found, which opens large possibilities for future development of DNA-based typing methods.