Assessing Different Approaches to Leveraging Historical Smoking Exposure Data to Better Select Lung Cancer Screening Candidates: A Retrospective Validation Study.
There is mounting interest in the use of risk prediction models to guide lung cancer screening. Electronic health records (EHRs) could facilitate such an approach, but smoking exposure documentation is notoriously inaccurate. While the negative impact of inaccurate EHR data on screening practices reliant on dichotomized age and smoking exposure-based criteria has been demonstrated, less is known regarding its impact on the performance of model-based screening. Data were collected from a cohort of 37 422 ever-smokers between the ages of 55 and 74, seen at an academic safety-net healthcare system between 1999 and 2018. The National Lung Cancer Screening Trial (NLST) criteria, PLCOM2012 and LCRAT lung cancer risk prediction models were validated against time to lung cancer diagnosis. Discrimination (area under the receiver operator curve [AUC]) and calibration were assessed. The effect of substituting the last documented smoking variables with differentially retrieved "history conscious" measures was also determined. The PLCOM2012 and LCRAT models had AUCs of 0.71 (95% CI, 0.69 to 0.73) and 0.72 (95% CI, 0.70 to 0.74), respectively. Compared with the NLST criteria, PLCOM2012 had a significantly greater time-dependent sensitivity (69.9% vs. 64.5%, p < .01) and specificity (58.3% vs. 56.4%, p < .001). Unlike the NLST criteria, the performances of the PLCOM2012 and LCRAT models were not prone to historical variability in smoking exposure documentation. Despite the inaccuracies of EHR-documented smoking histories, leveraging model-based lung cancer risk estimation may be a reasonable strategy for screening, and is of greater value compared with using NLST criteria in the same setting. EHRs are potentially well suited to aid in the risk-based selection of lung cancer screening candidates, but healthcare providers and systems may elect not to leverage EHR data due to prior work that has shown limitations in structured smoking exposure data quality. Our findings suggest that despite potential inaccuracies in the underlying EHR data, screening approaches that use multivariable models may perform significantly better than approaches that rely on simpler age and exposure-based criteria. These results should encourage providers to consider using pre-existing smoking exposure data with a model-based approach to guide lung cancer screening practices.


Brownian diffusion of nano-particles in optical traps.
The effect of thermal-induced motion on nano-particles in optical traps is examined theoretically. We derive the steady-state probability density for particles trapped by evanescent waves above a surface. In particular we investigate the enhancement of the gradient force by surface plasmon resonance in a gold film and its application to trapping nano-particles in solution. An expression is derived for the lifetime of nano-particles in the trap in terms of the ratio of the trap energy to the thermal energy. It is shown that this ratio should be 10 or greater for the nano-particles to remain in the trap.


Vaccination Against Amyloidogenic Aggregates in Pancreatic Islets Prevents Development of Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by insulin resistance and insufficient insulin secretion to maintain normoglycemia. The majority of T2DM patients bear amyloid deposits mainly composed of islet amyloid polypeptide (IAPP) in their pancreatic islets. These-originally β-cell secretory products-extracellular aggregates are cytotoxic for insulin-producing β-cells and are associated with β-cell loss and inflammation in T2DM advanced stages. Due to the absence of T2DM preventive medicaments and the presence of only symptomatic drugs acting towards increasing hormone secretion and action, we aimed at establishing a novel disease-modifying therapy targeting the cytotoxic IAPP deposits in order to prevent the development of T2DM. We generated a vaccine based on virus-like particles (VLPs), devoid of genomic material, coupled to IAPP peptides inducing specific antibodies against aggregated, but not monomeric IAPP. Using a mouse model of islet amyloidosis, we demonstrate in vivo that our vaccine induced a potent antibody response against aggregated, but not soluble IAPP, strikingly preventing IAPP depositions, delaying onset of hyperglycemia and the induction of the associated pro-inflammatory cytokine Interleukin 1β (IL-1β). We offer the first cost-effective and safe disease-modifying approach targeting islet dysfunction in T2DM, preventing pathogenic aggregates without disturbing physiological IAPP function.


Results of a quality of life questionnaire in a patch test clinic population.
There has been increasing interest in quality of life outcomes, but there has been little reported on this topic for individuals with contact dermatitis. The objectives of this study were (i) to pilot a dermatology-specific quality of life instrument to assess its acceptability in a patch test clinic population, (ii) to see the effects of contact dermatitis on the patients' lives and (iii) to determine what factors may influence quality of life outcomes in this population. A dermatology-specific quality of life instrument was modified and used for 339 patients undergoing patch testing in a contact dermatitis clinic. The most common effect was pain or itching in 61%. Approximately 1/3 noted embarrassment, interference with work, or sleep disturbance. Other concerns were reported by less than 25% of the population. On multivariate analysis, the key factor influencing most outcomes was hand involvement. The instrument was well accepted by the clinic population and is now being used in a prospective study of outcomes. In the population assessed, it demonstrated the effects of disease. Analysis suggests that a key factor influencing these quality of life outcomes is hand involvement.


Neuromuscular Performance and Training Workload Over an In-Season Mesocycle in Elite Young Soccer Players.
The purpose of this study was to assess neuromuscular performance capabilities over an in-season mesocycle in early-career professional soccer players and examine the relationship with training workload. Neuromuscular performance capabilities (isometric knee extensor: peak force, rate of force development, and peak twitch force) of 12 professional soccer players were assessed weekly over a 6-week period. Training and match workload were also recorded over the same period for each player (high-intensity running distance). Changes in neuromuscular performance and workload variables were analyzed. There was evidence of fluctuations in neuromuscular performance capability over the mesocycle that reached statistical (P < .05) and practical (13.3% [peak-to-peak]) significance alongside interweek heterogeneity in training and match workload (∼17.5% [coefficient of variation], P < .05). Congruence among fluctuating patterns of intramesocycle training load and concomitant neuromuscular performance responses was noted over time for acute training load and acute:chronic workload ratio with peak force and rate of force development. Neuromuscular performance capabilities fluctuate over an in-season mesocycle and are influenced by high-intensity running workload, emphasizing the need for acute monitoring in elite soccer players.


Direct radioimmunoassay of human renin: comparison with renin activity in plasma and amniotic fluid.
Human plasma and amniotic liquid were activated by dialysis at pH 3.3. Then, renin before and after acidification was determined by two methods: enzymatic activity measurement, and direct radioimmunoassay. The identity between nonactivated and activated renin in plasma and amniotic fluid on the one hand, and pure renin on the other, was demonstrated by the dilution curves in radioimmunoassay. After acidification, mean plasma renin activity in 17 patients with high renin activity rose from 26.8 +/- 11.7 pmoles A I ml-1 h-1 to 67.9 +/- 29.3 pmoles A I ml-1 h-1, whereas the mean renin concentration tested by direct radioimmunoassay remained constant at 13.8 +/- 10.5 and 14.8 +/- 11.2 fmol/ml before and after acidification respectively. In amniotic fluid, renin activity increased from 9.7 to 227 pmoles angiotensin I/ml/h, but the renin concentration did not change. Direct radioimmunoassay of renin may therefore be considered as measuring total renin, regardless of its enzymatic activity. In 12 hypertensive patients undergoing bilateral renal-vein catheterization, the direct measurement of renin was very significantly correlated to the non-activated (r = 0.883) and activated renin values (r = 0.963).


Bovine enteroviruses as indicators of fecal contamination.
Surface waters frequently have been contaminated with human enteric viruses, and it is likely that animal enteric viruses have contaminated surface waters also. Bovine enteroviruses (BEV), found in cattle worldwide, usually cause asymptomatic infections and are excreted in the feces of infected animals in large numbers. In this study, the prevalence and genotype of BEV in a closed herd of cattle were evaluated and compared with BEV found in animals in the immediate environment and in environmental specimens. BEV was found in feces from 76% of cattle, 38% of white-tailed deer, and one of three Canada geese sharing the same pastures, as well as the water obtained from animal watering tanks, from the pasture, from streams running from the pasture to an adjacent river, and from the river, which emptied into the Chesapeake Bay. Furthermore, BEV was found in oysters collected from that river downstream from the farm. These findings suggest that BEV could be used as an indicator of fecal pollution originating from animals (cattle and/or deer). Partial sequence analysis of the viral genomes indicates that different viral variants coexist in the same area. The possibility of identifying the viral strains found in the animals and in the contaminated areas by sequencing the RNA genome, could provide a tool to find the origin of the contamination and should be useful for epidemiological and viral molecular evolution studies.


Leveraging the advancements in functional biomaterials and scaffold fabrication technologies for chronic wound healing applications.
Exploring new avenues for clinical management of chronic wounds holds the key to eliminating socioeconomic burdens and health-related concerns associated with this silent killer. Engineered biomaterials offer great promise for repair and regeneration of chronic wounds because of their ability to deliver therapeutics, protect the wound environment, and support the skin matrices to facilitate tissue growth. This mini review presents recent advances in biomaterial functionalities for enhancing wound healing and demonstrates a move from sub-optimal methods to multi-functionalized treatment approaches. In this context, we discuss the recently reported biomaterial characteristics such as bioadhesiveness, antimicrobial properties, proangiogenic attributes, and anti-inflammatory properties that promote chronic wound healing. In addition, we highlight the necessary mechanical and mass transport properties of such biomaterials. Then, we discuss the characteristic properties of various biomaterial templates, including hydrogels, cryogels, nanomaterials, and biomolecule-functionalized materials. These biomaterials can be microfabricated into various structures, including smart patches, microneedles, electrospun scaffolds, and 3D-bioprinted structures, to advance the field of biomaterial scaffolds for effective wound healing. Finally, we provide an outlook on the future while emphasizing the need for their detailed functional behaviour and inflammatory response studies in a complex in vivo environment for superior clinical outcomes and reduced regulatory hurdles.


Red Seaweed-derived Compounds: A Desired Approach for Treating Cancer.
Cancer is a collection of diseases in which aberrant cells grow uncontrolled and invade surrounding tissues. Cancer can be classified as carcinoma, sarcoma, leukemia, or lymphoma. The deadliest cancers are lung, breast, colorectal, pancreatic, and prostate. Chemotherapy, surgery, and radiotherapy are the usual cancer treatments. However, drug resistance poses a significant barrier to cancer treatment. Macroalgae are wellknown producers of bioactive compounds with antimicrobial, antioxidant, anti-inflammatory, and anti-cancer properties. Red algae, in particular, are a prominent source of bioactive substances, such as polysaccharides, phenolic compounds, lipids, sterols, alkaloids, and terpenoids. Therefore, molecules from marine resources could be an appealing way to identify new cancer treatment alternatives. This study aimed to provide a brief overview of what is currently known regarding the potential of red macroalgae in cancer treatment by discussing the primary therapeutic targets of the disease and identifying compounds or extracts with bioactive characteristics against them.


The miR-487b-3p/GRM3/TGFβ signaling axis is an important regulator of colon cancer tumorigenesis.
Molecular targeting is an import strategy to treat advanced colon cancer. The current study demonstrates that expression of GRM3, a metabotropic glutamate receptor mainly expressed in mammalian central nervous system, is significantly upregulated in majority of human colonic adenocarcinomas tested and colon cancer cell lines. Knockdown of GRM3 expression or inhibition of GRM3 activation in colon cancer cells reduces cell survival and anchorage-independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, GRM3 antagonizes TGFβ-mediated activation of protein kinase A and inhibition of Protein kinase B (AKT). In addition, TGFβ signaling increases GRM3 protein stability and knockdown of GRM3 enhances TGFβ-mediated tumor suppressor function. Further studies indicate that miR-487b-3p directly targets GRM3. Overexpression of miR-487b-3p mimics the effects of GRM3 knockdown and suppresses the tumorigenicity of colon cancer cells in vivo. Expression of miR-487b-3p is decreased in colon adenocarcinomas and inversely correlates with GRM3 expression. Taken together, these studies indicate that upregulation of GRM3 expression is a functionally important molecular event in colon cancer, and that GRM3 is a promising molecular target for colon cancer treatment. This is particularly interesting and important from a therapeutic standpoint because numerous metabotropic glutamate receptor antagonists are available, many of which have been found unsuitable for treatment of neuropsychiatric disorders for reasons such as inability to readily penetrate blood brain barriers. As GRM3 is upregulated in colon cancer, but rarely expressed in normal peripheral tissues, targeting GRM3 with such agents would not likely cause adverse neurological or peripheral side effects, making GRM3 an attractive and specific molecular target for colon cancer treatment.


Electronic Cigarettes for Smoking Cessation: A Systematic Review.
Electronic cigarettes (e-cigarettes) have been steadily increasing in popularity among smokers, most of whom report using them to quit smoking. This study systematically reviews the current literature on the effectiveness of e-cigarettes as cessation aids. We searched PubMed, MEDLINE, PsycINFO, CINAHL, ERIC, ROVER, Scopus, ISI Web of Science, Cochrane Library, the Ontario Tobacco Research Unit (OTRU) library catalogue, and various gray literature sources. We included all English-language, empirical quantitative and qualitative papers that investigated primary cessation outcomes (smoking abstinence or reduction) or secondary outcomes (abstinence-related withdrawal symptoms and craving reductions) and were published on or before February 1, 2016. Literature searches identified 2855 references. After removing duplicates and screening for eligibility, 62 relevant references were reviewed and appraised. In accordance with the GRADE system, the quality of the evidence in support of e-cigarettes' effectiveness in helping smokers quit was assessed as very low to low, and the evidence on smoking reduction was assessed as very low to moderate. The majority of included studies found that e-cigarettes, especially second-generation types, could alleviate smoking withdrawal symptoms and cravings in laboratory settings. While the majority of studies demonstrate a positive relationship between e-cigarette use and smoking cessation, the evidence remains inconclusive due to the low quality of the research published to date. Well-designed randomized controlled trials and longitudinal, population studies are needed to further elucidate the role of e-cigarettes in smoking cessation. This is the most comprehensive systematic evidence review to examine the relationship between e-cigarette use and smoking cessation among smokers. This review offers balanced and rigorous qualitative and quantitative analyses of published evidence on the effectiveness of e-cigarette use for smoking abstinence and reduction as well as important outcomes such as withdrawal symptoms and craving to smoke. While inconclusive due to low quality, overall the existing literature suggests e-cigarettes may be helpful for some smokers for quitting or reducing smoking. However, more carefully designed and scientifically sound studies are urgently needed to establish unequivocally the long-term cessation effects of e-cigarettes and to better understand of how and when e-cigarettes may be helpful.


Experimental and Theoretical Brownian Dynamics Analysis of Ion Transport During Cellular Electroporation of E. coli Bacteria.
Escherichia coli bacterium is a rod-shaped organism composed of a complex double membrane structure. Knowledge of electric field driven ion transport through both membranes and the evolution of their induced permeabilization has important applications in biomedical engineering, delivery of genes and antibacterial agents. However, few studies have been conducted on Gram-negative bacteria in this regard considering the contribution of all ion types. To address this gap in knowledge, we have developed a deterministic and stochastic Brownian dynamics model to simulate in 3D space the motion of ions through pores formed in the plasma membranes of E. coli cells during electroporation. The diffusion coefficient, mobility, and translation time of Ca2+, Mg2+, Na+, K+, and Cl- ions within the pore region are estimated from the numerical model. Calculations of pore's conductance have been validated with experiments conducted at Gustave Roussy. From the simulations, it was found that the main driving force of ionic uptake during the pulse is the one due to the externally applied electric field. The results from this work provide a better understanding of ion transport during electroporation, aiding in the design of electrical pulses for maximizing ion throughput, primarily for application in cancer treatment.


More Than 12 % Polarization and 20 Minute Lifetime of 15 N in a Choline Derivative Utilizing Parahydrogen and a Rhodium Nanocatalyst in Water.
Hyperpolarization techniques are key to extending the capabilities of MRI for the investigation of structural, functional and metabolic processes in vivo. Recent heterogeneous catalyst development has produced high polarization in water using parahydrogen with biologically relevant contrast agents. A heterogeneous ligand-stabilized Rh catalyst is introduced that is capable of achieving 15 N polarization of 12.2±2.7 % by hydrogenation of neurine into a choline derivative. This is the highest 15 N polarization of any parahydrogen method in water to date. Notably, this was performed using a deuterated quaternary amine with an exceptionally long spin-lattice relaxation time (T1 ) of 21.0±0.4 min. These results open the door to the possibility of 15 N in vivo imaging using nontoxic similar model systems because of the biocompatibility of the production media and the stability of the heterogeneous catalyst using parahydrogen-induced polarization (PHIP) as the hyperpolarization method.


[In-situ FTIR spectroscopic studies of electro oxidation of ethanol in alkaline media at a nm-Pt/GC electrode].
The electro-oxidation of ethanol on a nm-Pt/GC electrode in alkaline solutions was investigated by using cyclic Voltammetry and in-situ FTIR spectroscopy. The results demonstrated that the main product of ethanol oxidation was CH3COO-, only small quantity of CH3CHO was determined simultaneously. In contrast with the dual path reaction mechanism for the oxidation of ethanol in acid media, the oxidation of ethanol in alkaline media was revealed via the intermediate process of dissociative adsorption.


Mutated otopetrin 1 affects the genesis of otoliths and the localization of Starmaker in zebrafish.
Otoliths in bony fishes and otoconia in mammals are composite crystals consisting of calcium carbonate and proteins. These biominerals are part of the gravity and linear acceleration detection system of the inner ear. Mutations in otopetrin 1 have been shown to result in lack of otoconia in tilted and mergulhador mutant mice. The molecular function of Otopetrin 1, a novel protein that contains ten predicted transmembrane domains, however, has remained elusive. Here we show that a mutation in the orthologous gene in zebrafish is responsible for the complete absence of otoliths in backstroke mutants. We examined the localization of Starmaker, a secreted protein that is highly abundant in otoliths in backstroke mutants. Starmaker protein accumulated within cells of the otic epithelium, indicating a possible defect in secretion. Our data suggest that Otopetrin 1 in zebrafish may be involved in the protein trafficking of components required for formation of biominerals in the ear.


Prevalence of hepatitis E virus (HEV) infection in wild boars (Sus scrofa leucomystax) and pigs in Gunma Prefecture, Japan.
The prevalence of hepatitis E virus (HEV) infection in wild boars and pigs in Gunma Prefecture, Japan, was serologically and genetically examined. The positive detection rates of anti-HEV IgG and HEV RNA in the wild boars were 4.5% (4/89) and 1.1% (1/89), whereas those in the pigs were 74.6% (126/169) and 1.8% (3/169), respectively. The positive rates of anti-HEV IgG and HEV RNA on the 17 pig farms in the present study ranged from 20% to 100%, respectively. One male wild boar approximately 5 years of age was positive for HEV RNA but was negative for anti-HEV IgG. Three pigs from 2 farms were positive for HEV RNA; 2 of these pigs were negative for HEV IgG, and the other was positive. A phylogenetic analysis revealed that all of the HEV ORF1 genes detected in the present study belonged to genotype III. In Gunma Prefecture, HEV is highly prevalent and widespread, and uncooked wild boar and pig meat may have the potential to transmit HEV to humans.


Trends and determinants of immunisation coverage in India.
The 20th century has witnessed many important events in the control of infectious diseases that mostly affect children. In addition to the eradication of smallpox, the interruption of poliomyelitis transmission in many countries with a distinct possibility of its eradication by the turn of this century are some of the major achievements. Also, the rates of other vaccine preventable diseases such as measles, pertussis and diphtheria have gone down significantly. The discovery and use of vaccines have made it possible to save approximately 8 million deaths, annually. This is in addition to the reduction in millions of children's suffering and disability. It is now important to build on these gains through adequate utilisation of other vaccines e.g., hepatitis B, typhoid and Haemophilus influenzae type b that are currently available, but in limited use. But, a high level of coverage for any vaccination programme is a pre-requisite to witness the effective reduction of the specific disease against which child population is vaccinated. This paper reviews the coverage levels by surveys in the last 3 years. It has been observed that vaccination coverage levels are falling. Keeping the promises of immunising every child to fulfill his/her right is the need of the hour. To achieve this the major action points are: (a) The need for organising fixed immunisation sessions at the community, where low proportion of sessions are held; and (b) The need to improve demand generation activities where the coverage is poor despite better service availability at the community level. Therefore, the challenge for the next century is to make sure that the enormous impact of vaccines on the health and well-being of the population is maintained as well as expanded. Vaccines that effectively prevent rotavirus diarrhoea, pneumococcal pneumonia, menigococcal meningitis, if made available, could prevent deaths up to two million a year. Research efforts are currently under progress to develop new vaccines against malaria, tuberculosis, shigella-induced dysentery, and Esch coli-induced diarrhoea.


Viscosity and Rheological Properties of Graphene Nanopowders Nanofluids.
The dynamic viscosity and rheological properties of two different non-aqueous graphene nano-plates-based nanofluids are experimentally investigated in this paper, focusing on the effects of solid volume fraction and shear rate. For each nanofluid, four solid volume fractions have been considered ranging from 0.1% to 1%. The rheological characterization of the suspensions was performed at 20 ∘C, with shear rates ranging from 10-1s-1 to 103s-1, using a cone-plate rheometer. The Carreau-Yasuda model has been successfully applied to fit most of the rheological measurements. Although it is very common to observe an increase of the viscosity with the solid volume fraction, we still found here that the addition of nanoparticles produces lubrication effects in some cases. Such a result could be very helpful in the domain of heat extraction applications. The dependence of dynamic viscosity with graphene volume fraction was analyzed using the model of Vallejo et al.


Endoderm induction for hepatic and pancreatic differentiation of ES cells.
Hepatic and pancreatic differentiation from ES cells is of great interest for the impact that this knowledge could have on the treatment of hepatic and diabetic patients. The liver and pancreas initially develop by budding from the embryonic endoderm. Thus, the development of the endoderm represents an important step and has an integral common role in initiating the early stages of pancreatic and liver development. We know that the development of hepatocytes and insulin-producing pancreatic beta-cells from ES cells represents the culmination of a complex developmental program. However, there has been recent progress in directing ES cells to endoderm and early-stage hepatic and pancreatic progenitor cells. We here discuss the role of the microenvironment, transcriptional factors and cytokines, which have been recognized as important molecules during the major steps of the development of the liver and pancreas. We also present the most recent advances and efforts taken to produce definitive endoderm-committed ES cells for the further differentiation of hepatocyte-like and insulinproducing cells. Recent progress in the search for new sources of hepatocytes and beta-cells has opened up several possibilities for the future of new perspectives for future of new prophylactic and therapeutic possibilities for liver diseases and diabetes.


Simultaneous depth determination of multiple objects by focus analysis in digital holography.
Focus analysis techniques from computer vision are applied to digital holography to determine the depth (range) of multiple objects and their surfaces from a single hologram capture. With this method the depths of objects can be determined from a single hologram capture without the need for manual focusing and without prior information on object location. Variance and the Laplacian of Gaussian are analyzed as focus measures, and techniques are proposed for focus plane determination from the focus measure curves. The algorithm is described in detail and demonstrated through simulation and optical experiment.


Inferior Mesenteric Artery Collaterals to the Uterus during Uterine Artery Embolization: Prevalence, Risk Factors, and Clinical Outcomes.
To evaluate the prevalence of inferior mesenteric artery (IMA) collaterals to the uterus found during uterine artery embolization (UAE), associated risk factors, and clinical outcomes. The records of 559 women who underwent UAE during the period 2008-2011 for uterine fibroids or adenomyosis found on magnetic resonance imaging were retrospectively analyzed. If IMA collaterals to the uterus were suspected on aortography performed after embolization, selective angiography was performed. Risk factors for IMA collaterals to the uterus were analyzed, including the presence of adenomyosis, baseline uterine volume, or prior pelvic surgery. Collaterals to the uterus were found from the ovarian artery (n = 21; 3.8%), IMA (n = 7; 1.3%), round ligament artery (n = 1; 0.2%), and internal pudendal artery (n = 1; 0.2%). IMA collaterals were found in seven patients. Of 185 patients, 6 (3.2%) had adenomyosis, with or without fibroids, which was significantly more frequent than the 1 (0.27%) of 374 patients who had fibroids only (P = .006). On multiple logistic regression analysis, the presence of adenomyosis (odds ratio, 19.556; P = .0168) and uterine volume (odds ratio, 1.003; P = .0069) were independent factors for the presence of IMA collaterals. Of the seven patients with IMA collaterals, embolization was not attempted in six, resulting in clinical failure in four. One patient who underwent IMA embolization with coils experienced clinical improvement. The IMA was the second most common (1.3%) source of collaterals to the uterus. IMA collaterals were more frequent in patients with adenomyosis than in patients with fibroids only, resulting in high frequency of treatment failure.


Inhibition of CARM1-Mediated Methylation of ACSL4 Promotes Ferroptosis in Colorectal Cancer.
Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis-associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis-based antitumor therapy.


Impaired biliary elimination of beta-glucuronidase-resistant "glucuronides" of valproic acid after intravenous administration in the rat. Evidence for oxidative metabolism of the resistant isomers.
A major metabolite of valproic acid (VPA) is its glucuronic acid conjugate (VPA-G). The disposition of VPA-G was compared with that of its intramolecularly rearranged, beta-glucuronidase-resistant isomers (collectively called VPA-G-R) after iv bolus administration to pentobarbitone-anesthetized rats. VPA-G was eliminated from blood more rapidly than VPA-G-R. After administration of dose A (predominantly VPA-G) and dose B (predominantly VPA-G-R) to rats with catheterized bladders and bile ducts, total conjugated VPA in blood declined from 110 micrograms of VPA/ml at 2 min to 1.1 micrograms/ml at 1 and 3 hr, respectively. A role for systemic hydrolysis of VPA-G was demonstrated by blood concentrations of free VPA which increased until 30 min. A minor role for systemic hydrolysis of VPA-G-R may be possible but cannot be proved from the current data. Urinary excretion (57 and 56% of doses A and B, respectively, in 3 hr) was greater than biliary excretion (32 and 10% of the doses, respectively, in 3 hr). The lower biliary elimination of VPA-G-R may be caused in part by impaired transport from blood to hepatocytes and/or hepatocytes to bile, but a role for phase I metabolism of the VPA moiety of VPA-G-R was demonstrated by recovery of 4.4% of dose B as 4-hydroxy-VPA. This latter mechanism was less (or not) applicable to VPA-G since only 0.4% of dose A was recovered as 4-hydroxy-VPA. Other VPA metabolites measured were quantitatively less important. These results were consistent in rats where either or both of the urinary and biliary elimination routes were surgically blocked.


Alcoholic myopathy: vitamin D deficiency is related to muscle fibre atrophy in a murine model.
Chronic myopathy has been described in alcoholics, characterized by atrophy of type II fibres, and vitamin D deficiency. Low serum vitamin D levels are frequent in alcoholics. The possibility exists that serum vitamin D levels are related to muscle changes in a murine experimental model. Histological analysis of the right gastrocnemius muscle was performed in four groups of adult Sprague-Dawley rats, sacrificed after 5 weeks of treatment following the Lieber-DeCarli model. We studied the association between muscle histological changes and the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD) and lipid peroxidation products (malondialdehyde); parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), free testosterone, 1,25 dihydroxyvitamin D3 (vitamin D) and corticosterone; and serum calcium and magnesium. Alcoholic animals showed type IIa and IIb fibre atrophy, especially the low-protein-fed ones, an effect dependent on protein deficiency. A significant relationship was observed between serum vitamin D levels and IIa fibre area (rho = 0.56, P = 0.002), and also, as a trend, between vitamin D and type IIb fibre area (rho = 0.39, p = 0.053); between vitamin D and muscle GPX (rho = 0.40, P = 0.025) and SOD activities (rho = 0.43, P = 0.012). Muscle GPX activity was significantly related with type I fibre area (rho = 0.49, P = 0.01) and muscle SOD, with type IIa fibre area (rho = 0.38, P = 0.045). Serum testosterone was also related with type IIa fibre area (rho = 0.61, P < 0.001). No relation was observed between serum PTH, corticosterone, or IGF-1 and fibre area PTH and antioxidant systems. Multiple regression analysis disclosed that the only parameter independently related with type IIa fibre area was serum vitamin D. Low vitamin D levels are related to muscle fibre atrophy, and altered levels of muscle antioxidant enzymes could play a role in alcoholic myopathy.


Income redistribution predicts greater life satisfaction across individual, national, and cultural characteristics.
The widening income gap between the rich and the poor has important social implications. Governmental-level income redistribution through tax and welfare policies presents an opportunity to reduce income inequality and its negative consequences. The current longitudinal studies examined whether within-region changes in income redistribution over time relate to life satisfaction. Moreover, I examined potential moderators of this relationship to test the strong versus weak hypotheses of income redistribution. The strong hypothesis posits that income redistribution is beneficial to most. The weak hypothesis posits that income redistribution is beneficial to some and damaging to others. Using a nationally representative sample of 57,932 German respondents from 16 German states across 30 years (Study 1) and a sample of 112,876 respondents from 33 countries across 24 years (Study 2), I found that within-state and within-nation changes in income redistribution over time were associated with life satisfaction. The models predicted that a 10% reduction in Gini through income redistribution in Germany increased life satisfaction to the same extent as an 37% increase in annual income (Study 1), and a 5% reduction in Gini through income redistribution increased life satisfaction to the same extent as a 11% increase in GDP (Study 2). These associations were positive across individual, national, and cultural characteristics. Increases in income redistribution predicted greater satisfaction for tax-payers and welfare-receivers, for liberals and conservatives, and for the poor and the rich. These findings support the strong hypothesis of income redistribution and suggest that redistribution policies may play an important role in societal well-being. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Lymphatic aneurysm of the heart.
The Annular Subvalvular Left Ventricular Aneurysm (ASLVA) is a rare entity, which occurs usually in young ethnic groups from Sub-Saharan Africa and South India. These aneurysms are situated immediately beneath the mitral and aortic valves and extend around in the substance of fibrous ring, from which valves arise. Their etiology is still obscure. Fifteen consecutive cases of ASLVA were treated surgically for this heart condition. Their clinical presentations, surgery, histopathology of aneurysmal wall were studied. Infective diseases with associated mediastinal lymphadenopathy were observed in all patients prior to the time the diagnosis of ASLVA was made. Nine patients had also lymphadenopathy in another region. Sinus of Valsalva Aneurysm was an associated finding in three patients. Dense fibrous tissue was the most common histopathological feature of the aneurysmal wall. Endothelium within the structure of the aneurysmal wall, "compressed" myocardium around the ASLVA wall, dilated and deformed heart lymphatics with lymph extravasation, and lymphatic neovascularization were all found in some histopathology specimens. Post-inflammatory destruction of mediastinal lymph nodes may obstruct lymph outflow from the heart, cause backwards lymphostasis, damage lymphatic vessels in the heart, and can lead to aneurysm formation. Increased intravascular shear stress triggers release of endothelial growth factors (bFGF, TGF-beta) and leads to neovascularization and tissue fibrosis, the most common feature of aneurysmal wall.


Large-Area MoS2 Films Grown on Sapphire and GaN Substrates by Pulsed Laser Deposition.
In this paper, we present the preparation of few-layer MoS2 films on single-crystal sapphire, as well as on heteroepitaxial GaN templates on sapphire substrates, using the pulsed laser deposition (PLD) technique. Detailed structural and chemical characterization of the films were performed using Raman spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction measurements, and high-resolution transmission electron microscopy. According to X-ray diffraction studies, the films exhibit epitaxial growth, indicating a good in-plane alignment. Furthermore, the films demonstrate uniform thickness on large areas, as confirmed by Raman spectroscopy. The lateral electrical current transport of the MoS2 grown on sapphire was investigated by temperature (T)-dependent sheet resistance and Hall effect measurements, showing a high n-type doping of the semiconducting films (ns from ~1 × 1013 to ~3.4 × 1013 cm-2 from T = 300 K to 500 K), with a donor ionization energy of Ei = 93 ± 8 meV and a mobility decreasing with T. Finally, the vertical current injection across the MoS2/GaN heterojunction was investigated by means of conductive atomic force microscopy, showing the rectifying behavior of the I-V characteristics with a Schottky barrier height of ϕB ≈ 0.36 eV. The obtained results pave the way for the scalable application of PLD-grown MoS2 on GaN in electronics/optoelectronics.


Lisbon Emoji and Emoticon Database (LEED): Norms for emoji and emoticons in seven evaluative dimensions.
The use of emoticons and emoji is increasingly popular across a variety of new platforms of online communication. They have also become popular as stimulus materials in scientific research. However, the assumption that emoji/emoticon users' interpretations always correspond to the developers'/researchers' intended meanings might be misleading. This article presents subjective norms of emoji and emoticons provided by everyday users. The Lisbon Emoji and Emoticon Database (LEED) comprises 238 stimuli: 85 emoticons and 153 emoji (collected from iOS, Android, Facebook, and Emojipedia). The sample included 505 Portuguese participants recruited online. Each participant evaluated a random subset of 20 stimuli for seven dimensions: aesthetic appeal, familiarity, visual complexity, concreteness, valence, arousal, and meaningfulness. Participants were additionally asked to attribute a meaning to each stimulus. The norms obtained include quantitative descriptive results (means, standard deviations, and confidence intervals) and a meaning analysis for each stimulus. We also examined the correlations between the dimensions and tested for differences between emoticons and emoji, as well as between the two major operating systems-Android and iOS. The LEED constitutes a readily available normative database (available at www.osf.io/nua4x ) with potential applications to different research domains.


Torque generation of Enterococcus hirae V-ATPase.
V-ATPase (V(o)V1) converts the chemical free energy of ATP into an ion-motive force across the cell membrane via mechanical rotation. This energy conversion requires proper interactions between the rotor and stator in V(o)V1 for tight coupling among chemical reaction, torque generation, and ion transport. We developed an Escherichia coli expression system for Enterococcus hirae V(o)V1 (EhV(o)V1) and established a single-molecule rotation assay to measure the torque generated. Recombinant and native EhV(o)V1 exhibited almost identical dependence of ATP hydrolysis activity on sodium ion and ATP concentrations, indicating their functional equivalence. In a single-molecule rotation assay with a low load probe at high ATP concentration, EhV(o)V1 only showed the "clear" state without apparent backward steps, whereas EhV1 showed two states, "clear" and "unclear." Furthermore, EhV(o)V1 showed slower rotation than EhV1 without the three distinct pauses separated by 120° that were observed in EhV1. When using a large probe, EhV(o)V1 showed faster rotation than EhV1, and the torque of EhV(o)V1 estimated from the continuous rotation was nearly double that of EhV1. On the other hand, stepping torque of EhV1 in the clear state was comparable with that of EhV(o)V1. These results indicate that rotor-stator interactions of the V(o) moiety and/or sodium ion transport limit the rotation driven by the V1 moiety, and the rotor-stator interactions in EhV(o)V1 are stabilized by two peripheral stalks to generate a larger torque than that of isolated EhV1. However, the torque value was substantially lower than that of other rotary ATPases, implying the low energy conversion efficiency of EhV(o)V1.


Exploring Idiographic Approaches to Children's Executive Function Performance: An Intensive Longitudinal Study.
Traditional variable-centered research on executive functions (EFs) often infers intraindividual development using group-based averages. Such a method masks meaningful individuality and involves the fallacy of equating group-level data with person-specific changes. We used an intensive longitudinal design to study idiographic executive function fluctuation among ten boys from Grade 4. Each of the participants completed between 33 and 43 measurement occasions (M = 38.8) across approximately three months. Data were collected remotely using a computerized short version of the Dimensional Change Card Sort task. Multi-group analyses of three participant pairs (Participants 5 and 3, 5 and 2, and 5 and 6) demonstrated that Participant 5 differed from Participants 3 and 2 in different ways but Participants 5 and 6 were similar in all comparisons. Dynamic structural equation modeling demonstrated unique individual trajectories, which were not represented by the trajectory of group-averages. Although more than half of the participants showed a negative association between EFs and inattention, two participants showed a positive association between EF and inattention. This study demonstrated meaningful person-specific trajectories of EFs, suggesting that future study should undertake the analysis of individual development before data-aggregation or generalization from aggregate statistics to individuals.


Competitive and noncompetitive antagonists at N-methyl-D-aspartate receptors protect against methamphetamine-induced dopaminergic damage in mice.
The administration of methamphetamine (METH) to experimental animals results in damage to nigrostriatal dopaminergic neurons. We have demonstrated previously that the excitatory amino acids may be involved in this neurotoxicity. For example, several compounds which bind to the phenyclidine site within the ion channel linked to the N-methyl-D-aspartate (NMDA) receptor protected mice from the METH-induced loss of neostriatal tyrosine hydroxylase activity and dopamine content. The present study was conducted to characterize further the role of the excitatory amino acids in mediating the neurotoxic effects of METH. The administration of three or four injections of METH (10 mg/kg) every 2 hr to mice produced large decrements in neostriatal dopamine content (80-84%) and in tyrosine hydroxylase activity (65-74%). A dose-dependent protection against these METH-induced decreases was seen with two noncompetitive NMDA antagonists, ifenprodil and SL 82.0715 (25-50 mg/kg/injection), both of which are thought to bind to a polyamine or sigma site associated with the NMDA receptor complex, and with two competitive NMDA antagonists, CGS 19755 (25-50 mg/kg/injection) and NPC 12626 (150-300 mg/kg/injection). Moreover, an intrastriatal infusion of NMDA (0.1 mumol) produced a slight but significant loss of neostriatal dopamine which was potentiated in mice that also received a systemic injection of METH. The results of these studies strengthen the hypothesis that the excitatory amino acids play a critical role in the nigrostriatal dopaminergic damage induced by METH.


Subglottal pressure and fundamental frequency control in contact calls of juvenile Alligator mississippiensis.
Vocalization is rare among non-avian reptiles, with the exception of the crocodilians, the sister taxon of birds. Crocodilians have a complex vocal repertoire. Their vocal and respiratory system is not well understood but appears to consist of a combination of features that are also found in the extremely vocal avian and mammalian taxa. Anatomical studies suggest that the alligator larynx is able to abduct and adduct the vocal folds, but not to elongate or shorten them, and is therefore lacking a key regulator of frequency, yet alligators can modulate fundamental frequency remarkably well. We investigated the morphological and physiological features of sound production in alligators. Vocal fold length scales isometrically across a wide range of alligator body sizes. The relationship between fundamental frequency and subglottal pressure is significant in some individuals at some isolated points, such as call onset and position of maximum fundamental frequency. The relationship is not consistent over large segments of the call. Fundamental frequency can change faster than expected by pressure changes alone, suggesting an active motor pattern controls frequency and is intrinsic to the larynx. We utilized a two-mass vocal fold model to test whether abduction and adduction could generate this motor pattern. The fine-tuned interplay between subglottal pressure and glottal adduction can achieve frequency modulations much larger than those resulting from subglottal pressure variations alone and of similar magnitude, as observed in alligator calls. We conclude that the alligator larynx represents a sound source with only two control parameters (subglottal pressure and vocal fold adduction) in contrast to the mammalian larynx in which three parameters can be altered to modulate frequency (subglottal pressure, vocal fold adduction and length/tension).


Prevalence of low scores on language tests as a potential factor in misdiagnosis of cognitive impairment in a Spanish-speaking adult population.
In this study, the prevalence of low scores for two neuropsychological tests of language has been determined. In total, N = 5218 healthy adults from 11 countries in Latin America (LA) were administered the Boston Naming Test (BNT) and the Verbal Fluency Test (VFT) as part of a comprehensive neuropsychological evaluation. Z-scores were calculated for BNT Total score, and phonological (letters F, A, S, M) and semantic (Animals, Fruits). Scores were adjusted for age, age2, sex, education, and interaction variables if significant for the given country. Each Z-score was converted to a percentile for each of the seven test-scores. Each participant was categorized based on his/her number of low scoring tests in specific percentile cutoff groups (25th, 16th, 10th, 5th, and 2nd). Between 53% (Paraguay) and 71% (Mexico) of the sample had at least 1-score below the 25th percentile, and between 41% (Paraguay) and 55% (Cuba) scored below the 16th percentile. Between 27% (Paraguay) and 39% (Peru) scored below the 10th percentile on at least 1-score, and between 17% (Chile) and 23% (Argentina) scored below the 5th percentile. Clinicians should use these data to reduce false-positive diagnoses and to improve the neuropsychological assessments in Spanish-speaking individuals from LA countries.


Virucidal or Not Virucidal? That Is the Question-Predictability of Ionic Liquid's Virucidal Potential in Biological Test Systems.
For three decades now, ionic liquids (ILs), organic salts comprising only ions, have emerged as a new class of pharmaceuticals. Although recognition of the antimicrobial effects of ILs is growing rapidly, there is almost nothing known about their possible virucidal activities. This probably reflects the paucity of understanding virus inactivation. In this study, we performed a systematic analysis to determine the effect of specific structural motifs of ILs on three different biological test systems (viruses, bacteria and enzymes). Overall, the effects of 27 different ILs on two non-enveloped and one enveloped virus (P100, MS2 and Phi6), two Gram negative and one Gram positive bacteria (E. coli, P. syringae and L. monocytogenes) and one enzyme (Taq DNA polymerase) were investigated. Results show that while some ILs were virucidal, no clear structure activity relationships (SARs) could be identified for the non-enveloped viruses P100 and MS2. However, for the first time, a correlation has been demonstrated between the effects of ILs on enveloped viruses, bacteria and enzyme inhibition. These identified SARs serve as a sound starting point for further studies.


Prioritizing a research agenda on built environments and physical activity: a twin panel Delphi consensus process with researchers and knowledge users.
The growth of urban dwelling populations globally has led to rapid increases of research and policy initiatives addressing associations between the built environment and physical activity (PA). Given this rapid proliferation, it is important to identify priority areas and research questions for moving the field forward. The objective of this study was to identify and compare research priorities on the built environment and PA among researchers and knowledge users (e.g., policy makers, practitioners). Between September 2022 and April 2023, a three-round, modified Delphi survey was conducted among two independent panels of international researchers (n = 38) and knowledge users (n = 23) to identify similarities and differences in perceived research priorities on the built environment and PA and generate twin 'top 10' lists of the most important research needs. From a broad range of self-identified issues, both panels ranked in common the most pressing research priorities including stronger study designs such as natural experiments, research that examines inequalities and inequities, establishing the cost effectiveness of interventions, safety and injuries related to engagement in active transportation (AT), and considerations for climate change and climate adaptation. Additional priorities identified by researchers included: implementation science, research that incorporates Indigenous perspectives, land-use policies, built environments that support active aging, and participatory research. Additional priorities identified by knowledge users included: built environments and PA among people living with disabilities and a need for national data on trip chaining, multi-modal travel, and non-work or school-related AT. Five common research priorities between the two groups emerged, including (1) to better understand causality, (2) interactions with the natural environment, (3) economic evaluations, (4) social disparities, and (5) preventable AT-related injuries. The findings may help set directions for future research, interdisciplinary and intersectoral collaborations, and funding opportunities.


KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma.
Primary effusion lymphoma (PEL) is a unique form of non-Hodgkin lymphoma (NHL) associated with Kaposi sarcoma-associated herpesvirus (KSHV; HHV-8) that displays a distinct constellation of clinical, morphologic, immunologic, and molecular characteristics. Rare KSHV-containing immunoblastic lymphomas occurring in solid tissues have been described. Whether they represent part of the spectrum of PEL has not been determined. The morphologic, immunophenotypic, and molecular features of KSHV-positive solid lymphomas occurring in 8 HIV+/AIDS patients were systematically investigated and compared with those of 29 similarly analyzed PELs. The 8 KSHV-positive solid lymphomas were virtually indistinguishable from the 29 PELs based on morphology (immunoblastic/anaplastic), immunophenotype (CD45 positive; T cell antigen negative; CD30, EMA, CD138 positive; CD10, CD15, BCL6 negative) and genotype (100% immunoglobulin genes rearranged; no identifiable abnormalities in C-MYC, BCL6, BCL1, BCL2; and uniformly EBV positive). The only identifiable phenotypic difference was that the KSHV-positive solid lymphomas appeared to express B cell-associated antigens (25%) and immunoglobulin (25%) slightly more often than the PELs (<5% and 15%, respectively; P = 0.11 and P = 0.08, respectively). The clinical presentation and course of the patients who develop KSHV-positive solid lymphomas were also similar, except for the lack of an effusion and somewhat better survival (median 11 months vs. 3 months). However, the 3 KSHV-positive solid lymphoma patients alive without disease 11, 25, and 44 months following initial presentation were recently diagnosed patients and, unlike the other patients with KSHV-positive solid lymphomas, received anti-retroviral therapy. These findings strongly suggest that these decidedly rare KSHV-positive solid lymphomas belong to the spectrum of PEL. Therefore, we propose that the KSHV-positive solid lymphomas be designated extra-cavitary PELs.


Biological and ecological evidences suggest Stipa krylovii (Pooideae), contributes to optimal growth performance and population distribution of the grasshopper Oedaleus asiaticus.
Oedaleus asiaticus Bey. Bienko is a significant grasshopper pest species occurring in north Asian grasslands. Outbreaks often result in significant loss in grasses and economic losses. Interestingly, we found this grasshopper was mainly restricted to Stipa-dominated grassland. We suspected this may be related to the dominant grasses species, Stipa krylovii Roshev, and hypothesized that S. krylovii contributes to optimal growth performance and population distribution of O. asiaticus. A 4 year investigation showed that O. asiaticus density was positively correlated to the above-ground biomass of S. krylovii and O. asiaticus growth performance variables (survival rate, size, growth rate) were significantly higher in Stipa-dominated grassland. A feeding trial also showed that O. asiaticus had a higher growth performance when feeding exclusively on S. krylovii. In addition, the choice, consumption and the efficiency of conversion of ingested food (ECI) by O. asiaticus was highest for S. krylovii compared with other plant species found in the Asian grasslands. These ecological and biological traits revealed why O. asiaticus is strongly associated with Stipa-dominated grasslands. We concluded that the existence of S. krylovii benefited the growth performance and explained the distribution of O. asiaticus. These results are useful for improved pest management strategies and developing guidelines for the monitoring of grasshopper population dynamics against the background of vegetation succession and changing plant communities in response to activities such as grazing, fire and climate change.


Explaining public resistance to genetically modified corn: an analysis of the distribution of benefits and risks.
Genetically modified (GM) crops have met with widespread approval among scientists and policy makers in the United States, but public approval of GM crops, both domestically and abroad, is progressing much more slowly. An underlying cause of public wariness may be that both nations and individual consumers do not perceive significant benefits to themselves from GM crops, while fearing the risks they may incur. In this study, an economic analysis is conducted to determine whether the benefits of one type of GM corn, Bt corn (genetically modified to resist damage from the ECB and Southwestern corn borer), outweigh the potential risks; and who the "winners" and "losers" are among stakeholder groups that may be affected by Bt corn. It is found that Bt corn growers, consumers, and industry all benefit from Bt corn adoption, though the purported health and environmental benefits of reducing chemical pesticide usage through Bt corn are negligible. Though the aggregated public benefit is large, the welfare gain to individual consumers is small and may not make up for perceived risks. While environmental and health risks of Bt corn are unlikely, the potential market risks-impacting both the organic corn market and total U.S. corn exports-are found to be significant. Currently, distributional analysis is not a part of regulatory decision making of Bt corn in the United States; yet it may help to explain why decision makers at both the government and individual-consumer levels have failed to embrace Bt corn and other GM crops.


Use of a parathyroid hormone peptide (PTH(1-34))-enriched fibrin hydrogel for the treatment of a subchondral cystic lesion in the proximal interphalangeal joint of a warmblood filly.
To describe the treatment of a subchondral bone cyst in the proximal phalanx with parathyroid hormone peptide-enriched fibrin hydrogel in a warmblood filly. The cyst was localized with computer-assisted orthopaedic surgery, then curetted and finally filled with parathyroid hormone fragment peptide 1-34 (PTH(1-34)) covalently attached to a fibrin hydrogel. The cyst healed quickly without any complications. This result supports the hypothesis that PTH(1-34) delivered locally in a fibrin hydrogel may improve the postoperative prognosis of surgical management of subchondral bone cysts in horses. Subchondral bone cysts are fairly common in horses. Especially in older horses, the prognosis is poor, even after surgical curettage. Therefore, different management protocols have been investigated in conjunction with surgical curettage to improve prognosis. Locally delivered PTH(1-34) seems to be a new method in the treatment of subchondral bone cysts.


The effect of temperature on the rate of conversion of p,p-DDT to p,p-DDE in brook trout (Salvelinus fontinalis).
Brook trout (Salvelinus fontinalis) were maintained in flowing fresh water at 2, 10, and 18 degrees C and injected intramuscularly with p,p-[-14C]DDT. Fish were killed at intervals up to 16 weeks after injection, and analyzed by a combination of thin-layer chromatography, gas-liquid chromatography, and liquid-scintillation counting. Only one labelled metabolite, p,p-DDE, was detected during the experimental period. Its rate of production varied with temperature; after 16 weeks, about 9, 13, and 19 percent of the original p,p-DDT in fish maintained at 2, 10, and 18 degrees C, respectively, had been converted.


Negative impact of immunoparesis in response to anti-SARS-CoV-2 mRNA vaccination of patients with multiple myeloma.
Multiple myeloma reduces cellular and humoral immunity. Optimal prediction of antibody response to anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in patients with MM and related disorders is essential to prevent coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 pandemic. This study analyzed the humoral response to the anti-SARS-CoV-2 messenger ribonucleic acid (mRNA) vaccine and its associated factor in 83 patients from June to November 2021 at seven member institutions of the Kyoto Clinical Hematology Study Group. SARS-CoV-2 neutralizing antibody (nAb) was measured from 12 to 210 days. The result revealed that 40 (48.2%) patients with MM and 59 (100%) healthy controls became seropositive after vaccination. Receiver operating characteristic curve analysis identified serum immunoglobulin (Ig) M of > 18 mg/dL at vaccination as the optimal threshold level associated with seropositivity in the whole cohort. Moreover, the multivariate analysis identified serum IgM of > 18 mg/dL as the independent predictor for a favorable response. Serum IgA level was positively associated with vaccine response in a sub-cohort. Our findings indicate a significant association between immunoparesis and impaired humoral response against mRNA vaccination, including that against SARS-CoV-2, and that serum non-M-protein Ig levels can serve as surrogate biomarkers of nAb production ability.


Background-free search for neutrinoless double-β decay of 76Ge with GERDA.
Many extensions of the Standard Model of particle physics explain the dominance of matter over antimatter in our Universe by neutrinos being their own antiparticles. This would imply the existence of neutrinoless double-β decay, which is an extremely rare lepton-number-violating radioactive decay process whose detection requires the utmost background suppression. Among the programmes that aim to detect this decay, the GERDA Collaboration is searching for neutrinoless double-β decay of 76Ge by operating bare detectors, made of germanium with an enriched 76Ge fraction, in liquid argon. After having completed Phase I of data taking, we have recently launched Phase II. Here we report that in GERDA Phase II we have achieved a background level of approximately 10-3 counts keV-1 kg-1 yr-1. This implies that the experiment is background-free, even when increasing the exposure up to design level. This is achieved by use of an active veto system, superior germanium detector energy resolution and improved background recognition of our new detectors. No signal of neutrinoless double-β decay was found when Phase I and Phase II data were combined, and we deduce a lower-limit half-life of 5.3 × 1025 years at the 90 per cent confidence level. Our half-life sensitivity of 4.0 × 1025 years is competitive with the best experiments that use a substantially larger isotope mass. The potential of an essentially background-free search for neutrinoless double-β decay will facilitate a larger germanium experiment with sensitivity levels that will bring us closer to clarifying whether neutrinos are their own antiparticles.


Extinction of oscillating populations.
Established populations often exhibit oscillations in their sizes that, in the deterministic theory, correspond to a limit cycle in the space of population sizes. If a population is isolated, the intrinsic stochasticity of elemental processes can ultimately bring it to extinction. Here we study extinction of oscillating populations in a stochastic version of the Rosenzweig-MacArthur predator-prey model. To this end we develop a WKB (Wentzel, Kramers and Brillouin) approximation to the master equation, employing the characteristic population size as the large parameter. Similar WKB theories have been developed previously in the context of population extinction from an attracting multipopulation fixed point. We evaluate the extinction rates and find the most probable paths to extinction from the limit cycle by applying Floquet theory to the dynamics of an effective four-dimensional WKB Hamiltonian. We show that the entropic barriers to extinction change in a nonanalytic way as the system passes through the Hopf bifurcation. We also study the subleading pre-exponential factors of the WKB approximation.


Inhibition of human brain pyruvate kinase and hexokinase by phenylalanine and phenylpyruvate: possible relevance to phenylketonuric brain damage.
In phenylketonuria high levels of L-phenylalanine are present along with increased levels of phenylpyruvic acid. The present work shows that L-phenylalanine is a competitive inhibitor of human brain pyruvate kinase and phenylpyruvic acid is an inhibitor of human brain hexokinase. The enzymes have approximately the same K(i) for these inhibitors in adult and in fetal human brain. However, in the fetal human brain the absolute activities for both enzymes are less than 10 per cent of those found in the adult. Thus, the fetal brain enzymes may be more vulnerable to inhibition by these compounds in the phenylketonurics. The inhibition of human brain pyruvate kinase and hexokinase by L-phenylalanine and phenylpyruvic acid may have a role in the brain damage in phenylketonurics.


Synthesis of High-Quality Graphene and Hexagonal Boron Nitride Monolayer In-Plane Heterostructure on Cu-Ni Alloy.
Graphene/hexagonal boron nitride (h-BN) monolayer in-plane heterostructure offers a novel material platform for both fundamental research and device applications. To obtain such a heterostructure in high quality via controllable synthetic approaches is still challenging. In this work, in-plane epitaxy of graphene/h-BN heterostructure is demonstrated on Cu-Ni substrates. The introduction of nickel to copper substrate not only enhances the capability of decomposing polyaminoborane residues but also promotes graphene growth via isothermal segregation. On the alloy surface partially covered by h-BN, graphene is found to nucleate at the corners of the as-formed h-BN grains, and the high growth rate for graphene minimizes the damage of graphene-growth process on h-BN lattice. As a result, high-quality graphene/h-BN in-plane heterostructure with epitaxial relationship can be formed, which is supported by extensive characterizations. Photodetector device applications are demonstrated based on the in-plane heterostructure. The success will have important impact on future research and applications based on this unique material platform.


Dissipative electron transfer dynamics in mixed valence dimers: microscopic approach to the solid state problem.
We propose a microscopic analytical approach to the description of the low-temperature dissipative intracluster electron transfer dynamics in centrosymmetric one-electron mixed-valence (MV) dimers. The dissipative system (bath) is supposed to consist of the acoustic phonons of the crystal surrounding that are coupled to the delocalized electron(s) of a MV dimer. Although the concept of the bath is the spin-boson model is more generic, the present consideration is relevant, for example, to a MV bi-center impurity in an ionic crystal. The model allows us to develop an approximate microscopic approach within which the relaxation processes are explicitly taken into account without additional assumption regarding spectral function of the bath. It is assumed that initially the extra electron is localized on a certain center and then the time-dependent localization probability (averaged value of the electron dipole moment) is evaluated with the emphasis on the damping of the amplitude of the Rabi oscillations. The approach assumes the following conditions: (i) the vibrational spectrum of the crystal does not show the presence of local modes; (ii) the itinerant electron is weakly coupled to the long-waves acoustic phonons which is peculiar to fully delocalized Robin and Day class III MV systems; (iii) the Debye energy ℏωD exceeds the electronic resonance energy gap 2β (β is the electron transfer parameter). We have demonstrated that the dissipation in this case is super-ohmic with the low-frequency spectral function J(ω) ∝ ω(5). The time dependences of the localization probabilities show nearly picosecond damped oscillations. The longitudinal relaxation time T1 has been shown to be two times shorter than the decoherence time T2 thus giving the upper bound for T2, T2 ≤ 2T1.


Resumption of puberty in girls and boys following removal of the histrelin implant.
To determine time to menarche in girls and testicular volume increase in boys after removal of a histrelin implant, which causes profound hypothalamic-pituitary-gonadal axis suppression. Medical records of patients treated with a histrelin implant were reviewed. Seventy-one patients (56 girls) treated with the histrelin implant were identified, of these patients, 37 explanted girls (68% naïve) and 6 explanted boys (83% naïve) were included in the analysis. Time to menarche after explantation in girls and time to testicular volume increase after explantation in boys were determined. Additional variables investigated included indication for and duration of treatment, history of menarche (girls), previous therapy, and age at beginning and end of histrelin treatment. Of the girls, 30 were treated for central precocious puberty (CPP), 26 had menarche at an average of 12.75 months after explantation. Of the 30, 7 were treated for other indications, of whom 6 had reached menarche. In girls with CPP, older age at explantation correlated with sooner menarche (P = .04). All boys achieved spontaneous testicular enlargement within 1 year of explantation. This study documented resumption of puberty after histrelin explantation in treatment naïve and non-naïve boys and girls with and without CPP. Menarche in girls with CPP occurs within a similar timeframe to that observed after other treatment approaches.


Thyroid hormone receptor beta2 is strongly up-regulated at all levels of the hypothalamo-pituitary-thyroidal axis during late embryogenesis in chicken.
In this study, we tried to elucidate the changes in thyroid hormone (TH) receptor beta2 (TRbeta2) expression at the different levels of the hypothalamo-pituitary-thyroidal (HPT) axis during the last week of chicken embryonic development and hatching, a period characterized by an augmented activity of the HPT axis. We quantified TRbeta2 mRNA in retina, pineal gland, and the major control levels of the HPT axis - brain, pituitary, and thyroid gland - at day 18 of incubation, and found the most abundant mRNA content in retina and pituitary. Thyroidal TRbeta2 mRNA content increased dramatically between embryonic day 14 and 1 day post-hatch. In pituitary and hypothalamus, TRbeta2 mRNA expression rose gradually, in parallel with increases in plasma thyroxine concentrations. Using in situ hybridization, we have demonstrated the presence of TRbeta2 mRNA throughout the diencephalon and confirmed the elevation in TRbeta2 mRNA expression in the hypophyseal thyrotropes. In vitro incubation with THs caused a down-regulation of TRbeta2 mRNA levels in embryonic but not in post-hatch pituitaries. The observed expression patterns in pituitary and diencephalon may point to substantial changes in TRbeta2-mediated TH feedback active during the perinatal period. The strong rise in thyroidal TRbeta2 mRNA content could be indicative of an augmented modulation of thyroid development and/or function by THs toward and after hatching. Finally, THs proved to exert an age-dependent effect on pituitary TRbeta2 mRNA expression.


Biliary cancer: gateway to comprehensive molecular profiling.
Cholangiocarcinoma is a rare malignancy with a poor prognosis. The majority of tumors present at an advanced stage, and relapse often occurs after surgery conducted with curative intent. In both of these cases, standard treatment is a combination of cisplatin and gemcitabine. The use of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) in second-line treatment improves survival, but outcomes remain dismal. Studies have shown that cholangiocarcinoma possesses a wide spectrum of genetic aberrations. Clinical trials evaluating targeted therapies in patients with FGFR2 fusions, IDH1 mutations, and BRAF mutations have yielded very promising results, and the agents were generally well tolerated. Several FGFR2 fusion-targeted agents have achieved response rates between 20.7% and 35.5%, with disease stability rates ranging between 76% and 82%. Agents targeting FGFR2 fusions also have produced median progression-free survival (PFS) ranging from 5.7 to 6.9 months and median overall survival (OS) ranging from 12.5 to 21.1 months. Ivosidenib in patients with an IDH1/2 mutation has produced a response rate of 2% and a disease stability rate of 51%, with median PFS of 2.7 months and median OS of 10.8 months. In patients with a BRAF mutation, a combination of dabrafenib and trametinib led to an overall response rate of 51% and disease stability in another 40% of patients. Median PFS and OS were 9 and 14 months, respectively. Patients should be encouraged to participate in clinical trials.


Modeling the late steps in HIV-1 retroviral integrase-catalyzed DNA integration.
Model oligodeoxyribonucleotide substrates representing viral DNA integration intermediates with a gap and a two-nucleotide 5' overhang were used to examine late steps in human immunodeficiency virus, type 1 (HIV-1) retroviral integrase (IN)-catalyzed DNA integration in vitro. HIV-1 or avian myeloblastosis virus reverse transcriptase (RT) were capable of quantitatively filling in the gap to create a nicked substrate but did not remove the 5' overhang. HIV-1 IN also failed to remove the 5' overhang with the gapped substrate. However, with a nicked substrate formed by RT, HIV-1 IN removed the overhang and covalently closed the nick in a disintegration-like reaction. The efficiency of this closure reaction was very low. Such closure was not stimulated by the addition of HMG-(I/Y), suggesting that this protein only acts during the early processing and joining reactions. Addition of Flap endonuclease-1, a nuclease known to remove 5' overhangs, abolished the closure reaction catalyzed by IN. A series of base pair inversions, introduced into the HIV-1 U5 long terminal repeat sequence adjacent to and/or including the conserved CA dinucleotide, produced no or only a small decrease in the HIV-1 IN-dependent strand closure reaction. These same mutations caused a significant decrease in the efficiency of concerted DNA integration by a modified donor DNA in vitro, suggesting that recognition of the ends of the long terminal repeat sequence is required only in the early steps of DNA integration. Finally, a combination of HIV-1 RT, Flap endonuclease-1, and DNA ligase is capable of quantitatively forming covalently closed DNA with these model substrates. These results support the hypothesis that cellular enzyme(s) may catalyze the late steps of retroviral DNA integration.


Team physician #7. A comparative study of functional bracing in the anterior cruciate deficient knee.
We evaluated the ability of three functional knee braces, (CTI, OTI, and TS7) to control anterolateral rotary instability of the knee. Fourteen subjects, none of elite athletic status, with arthroscopically proven anterior cruciate deficient knees were selected. The subjects evaluated each brace after one-month periods, and then underwent testing with physical examinations, KT-1000 arthrometry, and timed running events. All braces reduced subjective symptoms of knee instability. Different subjects preferred different braces. KT-1000 testing showed a reduction in anterior tibial displacement for all braces; however, this reduction did not increase as forces increased. A timed figure-of-eight running event did not show any functional advantage of bracing. Five subluxation events occurred in four subjects while braced. Functional braces appear to have a role in the anterior cruciate deficient knee, but only in conjunction with activity modification.


Red Fluorescent Protein Variant with a Dual-Peak Emission of Fluorescence.
The marine environment is a rich reservoir of diverse biological entities, many of which possess unique properties that are of immense value to biotechnological applications. One such example is the red fluorescent protein derived from the coral Discosoma sp. This protein, encoded by the DsRed gene, has been the subject of extensive research due to its potential applications in various fields. In the study, a variant of the red fluorescent protein was generated through random mutagenesis using the DsRed2 gene as a template. The process employed error-prone PCR (epPCR) to introduce random mutations, leading to the isolation of twelve gene variants. Among these, one variant stood out due to its unique spectral properties, exhibiting dual fluorescence emission at both 480 nm (green) and 550 nm (red). This novel variant was expressed in both Escherichia coli and zebrafish (Danio rerio) muscle, confirming the dual fluorescence emission in both model systems. One of the immediate applications of this novel protein variant is in ornamental aquaculture. The dual fluorescence can serve as a unique marker or trait, enhancing the aesthetic appeal of aquatic species in ornamental settings.


Massive gas embolisms in diving fatalities visualized by radiology and neuropathology.
Massive vascular gas embolism is a feared and often lethal symptom of decompression illness, resulting from diving accidents. The aim of this case report was to correlate post-mortem computed tomography scan (PMCT) findings with autopsy in cases of massive vascular gas embolism. Two cases of fatal diving accidents were retrospectively selected from a forensic radiological pathological database. The PMCT results were initially shared with the forensic pathologist prior to autopsy, enabling a more accurate overall assessment. Both cases were in retrospect thoroughly studied to compare the PMCT findings with the autopsy results. In general, intra- and extra-vascular gas collections are easily detected on PMCT in all body regions. We focused on abundant intravascular gas collections, mainly in the large brain vessels. General autopsy findings are described in both cases, and in one case we elaborate on specific intracerebral changes found at autopsy. Both cases were diagnosed as pulmonary barotrauma with subsequent vascular gas embolisms. We conclude that PMCT excels in the detection of macroscopic gas collections in the body, whereas microscopic gas collections identified at autopsy aid in the differentiation between decompression sickness and pulmonary barotrauma followed by vascular gas embolism. The presented cases highlight the advantages of using both PMCT and autopsy in the post-mortem evaluation of fatal diving accidents.


Automated detection of COVID-19 cough.
Easy detection of COVID-19 is a challenge. Quick biological tests do not give enough accuracy. Success in the fight against new outbreaks depends not only on the efficiency of the tests used, but also on the cost, time elapsed and the number of tests that can be done massively. Our proposal provides a solution to this challenge. The main objective is to design a freely available, quick and efficient methodology for the automatic detection of COVID-19 in raw audio files. Our proposal is based on automated extraction of time-frequency cough features and selection of the more significant ones to be used to diagnose COVID-19 using a supervised machine-learning algorithm. Random Forest has performed better than the other models analysed in this study. An accuracy close to 90% was obtained. This study demonstrates the feasibility of the automatic diagnose of COVID-19 from coughs, and its applicability to detecting new outbreaks.


Biosynthesis of the oxygenated diterpene nezukol in the medicinal plant Isodon rubescens is catalyzed by a pair of diterpene synthases.
Plants produce an immense diversity of natural products (i.e. secondary or specialized metabolites) that offer a rich source of known and potentially new pharmaceuticals and other desirable bioproducts. The Traditional Chinese Medicinal plant Isodon rubescens (Lamiaceae) contains an array of bioactive labdane-related diterpenoid natural products. Of these, the ent-kauranoid oridonin is the most prominent specialized metabolite that has been extensively studied for its potent antimicrobial and anticancer efficacy. Mining of a previously established transcriptome of I. rubescens leaf tissue identified seven diterpene synthase (diTPSs) candidates. Here we report the functional characterization of four I. rubescens diTPSs. IrTPS5 and IrTPS3 were identified as an ent-copalyl diphosphate (CPP) synthase and a (+)-CPP synthase, respectively. Distinct transcript abundance of IrTPS5 and the predicted ent-CPP synthase IrTPS1 suggested a role of IrTPS5 in specialized ent-kaurene metabolism possibly en route to oridonin. Nicotiana benthamiana co-expression assays demonstrated that IrTPS4 functions sequentially with IrTPS3 to form miltiradiene. In addition, IrTPS2 converted the IrTPS3 product (+)-CPP into the hydroxylated tricyclic diterpene nezukol not previously identified in I. rubescens. Metabolite profiling verified the presence of nezukol in I. rubescens leaf tissue. The proposed IrTPS2-catalyzed reaction mechanism proceeds via the common ionization of the diphosphate group of (+)-CPP, followed by formation of an intermediary pimar-15-en-8-yl+ carbocation and neutralization of the carbocation by water capture at C-8 to yield nezukol, as confirmed by nuclear magnetic resonance (NMR) analysis. Oxygenation activity is rare for the family of class I diTPSs and offers new catalysts for developing metabolic engineering platforms to produce a broader spectrum of bioactive diterpenoid natural products.


Preserving elemental content in adherent mammalian cells for analysis by synchrotron-based x-ray fluorescence microscopy.
Trace metals play important roles in biological function, and x-ray fluorescence microscopy (XFM) provides a way to quantitatively image their distribution within cells. The faithfulness of these measurements is dependent on proper sample preparation. Using mouse embryonic fibroblast NIH/3T3 cells as an example, we compare various approaches to the preparation of adherent mammalian cells for XFM imaging under ambient temperature. Direct side-by-side comparison shows that plunge-freezing-based cryoimmobilization provides more faithful preservation than conventional chemical fixation for most biologically important elements including P, S, Cl, K, Fe, Cu, Zn and possibly Ca in adherent mammalian cells. Although cells rinsed with fresh media had a great deal of extracellular background signal for Cl and Ca, this approach maintained cells at the best possible physiological status before rapid freezing and it does not interfere with XFM analysis of other elements. If chemical fixation has to be chosen, the combination of 3% paraformaldehyde and 1.5 % glutaraldehyde preserves S, Fe, Cu and Zn better than either fixative alone. When chemically fixed cells were subjected to a variety of dehydration processes, air drying was proved to be more suitable than other drying methods such as graded ethanol dehydration and freeze drying. This first detailed comparison for x-ray fluorescence microscopy shows how detailed quantitative conclusions can be affected by the choice of cell preparation method.


Expression of the antimicrobial peptide cecropin fused with human lysozyme in Escherichia coli.
Lysozyme is an abundant, cationic antimicrobial protein that plays an important role in host defense. It targets the beta (1-4) glycosidic bond between N-acetylglucosamine and N-acetylmuramic residues that make up peptidoglycan, making lysozyme highly active against Gram-positive bacteria. However, lysozyme alone is inactive against Gram-negative bacteria because it cannot reach the peptidoglycan layer. Cecropins are cationic molecules with a wide range of antimicrobial activities. The main target for these peptides is the cytoplasmic membrane. We resume that cecopin may disrupt the outer membrane, giving the enzyme access to the peptidoglycan in cell wall. So in the present study, novel hybrid protein combining Musca domestica cecropin (Mdc) with human lysozyme (Hly) was designed. The DNA sequence encoding recombination fusion protein Mdc-hly was cloned into the pET-32a vector for protein expression in Escherichia coli strain BL21 (DE3). The protein was expressed as a His-tagged fusion protein, and the Mdc-hly was released from the fusion by enterokinase cleavage and separated from the carrier thioredoxin. Antimicrobial activity assays showed that the recombinant fusion protein Mdc-hly has improved in vitro antimicrobial activity and action spectrum compared to Mdc and hly. Mdc-hly may have important potential application as a future safely administered human drug and food additive.


The C-terminal region Mesd peptide mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells.
While Mesd was discovered as a specialized molecular endoplasmic reticulum chaperone for the Wnt co-receptors LRP5 and LRP6, recombinant Mesd protein is able to bind to mature LRP5 and LRP6 on the cell surface and acts as a universal antagonist of LRP5/6 modulators. In our previous study, we found that the C-terminal region of Mesd, which is absent in sequences from invertebrates, is necessary and sufficient for binding to mature LRP6 on the cell surface. In the present studies, we further characterized the interaction between the C-terminal region Mesd peptide and LRP5/6. We found that Mesd C-terminal region-derived peptides block Mesd binding to LRP5 at the cell surface too. We also showed that there are two LRP5/6 binding sites within Mesd C-terminal region which contain several positively charged residues. Moreover, we demonstrated that the Mesd C-terminal region peptide, like the full-length Mesd protein, blocked Wnt 3A- and Rspodin1-induced Wnt/β-catenin signaling in LRP5- and LRP6- expressing cells, suppressed Wnt/β-catenin signaling in human breast HS578T cells and prostate cancer PC-3 cells, and inhibited cancer cell proliferation, although the full-length Mesd protein is more potent than its peptide. Finally, we found that treatment of the full-length Mesd protein and its C-terminal region peptide significantly increased chemotherapy agent Adriamycin-induced cytotoxicity in HS578T and PC-3 cells. Together, our results suggest that Mesd C-terminal region constitutes the major LRP5/6-binding domain, and that Mesd protein and its C-terminal region peptide have a potential therapeutic value in cancer.


The effects of hypohydration and fatigue on neuromuscular activation performance.
This study investigated the effects of hypohydration by fluid restriction on voluntary and evoked indices of neuromuscular performance at a functional joint angle. Measures of static volitional peak force (2-3-s maximal muscle actions) and evoked peak twitch force, electromechanical delay, and rate of force development were obtained from the knee extensors (30° knee flexion) of 10 males (age, 24 (4) years; height, 1.76 (0.10) m; body mass, 78.7 (9.13) kg (mean (SD))) prior to and immediately following 24 h of (i) euhydration (EU) and (ii) hypohydration (HYP). Neuromuscular performance was also assessed in response to a fatiguing task (3 × 30-s maximal static knee extensions) following each condition. Repeated-measures ANOVAs showed that HYP was associated with a significant 2.1% loss in body mass (p < 0.001) and a 7.8% reduction in volitional peak force (p < 0.05). Following fatigue, data indicated statistically similar levels of impairment to volitional peak force (11.6%, p < 0.01) and rate of force development (21.0%, p < 0.01) between conditions (EU; HYP). No changes to any other indices of performance were observed. The substantive hypohydration-induced deficits to muscle strength at this functional joint angle might convey a decreased performance capability and should be considered by the hypohydrated athlete. Whilst hypohydration did not affect fatigue-related performance of the knee extensors, the additive changes associated with lower baseline levels of strength performance (7.8%) and fatigue (11.6%) coupled with slower rate of muscle force production (from 0-100 ms) following fatigue may present significant challenges to the maintenance of dynamic knee joint stability, particularly at this vulnerable joint position.


Tracking Fast and Slow Changes in Synaptic Weights From Simultaneously Observed Pre- and Postsynaptic Spiking.
Synapses change on multiple timescales, ranging from milliseconds to minutes, due to a combination of both short- and long-term plasticity. Here we develop an extension of the common generalized linear model to infer both short- and long-term changes in the coupling between a pre- and postsynaptic neuron based on observed spiking activity. We model short-term synaptic plasticity using additive effects that depend on the presynaptic spike timing, and we model long-term changes in both synaptic weight and baseline firing rate using point process adaptive smoothing. Using simulations, we first show that this model can accurately recover time-varying synaptic weights (1) for both depressing and facilitating synapses, (2) with a variety of long-term changes (including realistic changes, such as due to STDP), (3) with a range of pre and postsynaptic firing rates, and (4) for both excitatory and inhibitory synapses. We then apply our model to two experimentally recorded putative synaptic connections. We find that simultaneously tracking fast changes in synaptic weights, slow changes in synaptic weights, and unexplained variations in baseline firing is essential. Omitting any one of these factors can lead to spurious inferences for the others. Altogether, this model provides a flexible framework for tracking short- and long-term variation in spike transmission.


Effects of asymmetric dispersal on the coexistence of competing species.
The global biodiversity crisis has made a priority of understanding biodiversity maintenance in ecological communities. It is increasingly apparent that dispersal patterns can have important effects on such maintenance processes. Nevertheless, most competition theory has focused on a small subset of the possible dispersal patterns in nature. Here, we show that spatially asymmetric dispersal, i.e. the disproportionate transport of propagules towards or away from particular habitat patches in a metacommunity, when it differs between species, can promote the coexistence of competing species even in the absence of environmental heterogeneity among habitat patches. Moreover, when asymmetric dispersal is present, changes in the self-recruitment of competitive dominants and subordinates have important, but fundamentally different, effects on species coexistence. Our results underscore the importance of the interplay between species interactions and dispersal patterns for understanding the effects of habitat fragmentation and for designing regional-scale conservation strategies, such as networks of protected areas.


Atypical compression of the deep branch of the ulnar nerve in Guyon's canal by a ganglion. Case report.
A 61-year-old woman with an ulnar claw-finger deformity but no sensory loss had a cystic lesion excised from Guyon's canal. The ganglion was in zone 1 of the canal, which is associated with both motor and sensory deficit, but on this occasion it caused motor dysfunction alone.


Micro-RNA-143 inhibits proliferation and promotes apoptosis of thymocytes by targeting CXCL13 in a myasthenia gravis mouse model.
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder, affecting the quality of life of millions of people worldwide. The present study aims to determine the relationship between micro-RNA-143 (miR-143) and C-X-C motif chemokine 13 (CXCL13) and whether it influences the pathogenesis of myasthenia gravis (MG). Thymus specimens were resected from patients with thymic hyperplasia combined with MG and then infused into normal mouse cavities to establish MG mouse models. Immunohistochemistry, reverse transcription-quantitative PCR, in situ hybridization detection, and Western blot analysis were employed to identify the expression of miR-143 and CXCL13 in MG and normal mice. The obtained thymocytes were cultured in vitro and transfected with a series of miR-143 mimic, miR-143 inhibitor, overexpression of CXCL13, or siRNA against CXCL13. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and flow cytometry assays were employed to assess cell viability, cycle entry, and apoptosis of the thymocytes. Dual-luciferase reporter assay provided verification, confirming that CXCL13 was the target gene of miR-143. Low miR-143 expression in the thymus tissues of the MG mice was detected, which presented with a reciprocal relationship with the expression rate of CLCX13. Observations in relation to the interactions between miR-143 mimic or siRNA-CXCL13 exposure showed reduced cell viability, with a greater number of cells arrested at the G0/G1 phase and a greater rate of induced apoptosis. Furthermore, overexpression of CXCL13 rescued miR-143 mimic-induced apoptosis. The findings have identified the potential role of miR-143 as a MG development mediator by targeting CXCL13. The key results obtained provide a promising experimental basis for targeted intervention treatment with miR-143.


HMG box-activating factors 1 and 2, two HMG box transcription factors that bind the human Ig heavy chain enhancer.
We present the isolation of two cDNAs that encode distinct, yet related, proteins that bind the HE2 region of the human Ig heavy chain (IgH) enhancer. Designated HMG box-activating factors (HAF) 1 and 2, the two proteins are new members of the HMG box family of DNA binding proteins. Both are potent transcription activators when expressed 1) as GAL4 fusions targeted to promoters containing GAL4 operators, or 2) as intact proteins targeted to minimal promoters containing binding sites derived from the IgH enhancer. HAF-1 and HAF-2 mRNAs are apparently expressed in both B cells and non-B cells. However, activity generated by the isolated HE2 region in B cells is dependent on both an intact HAF-1/HAF-2 binding site and at least one additional site that has been reported previously to bind a B cell-restricted protein. Our results suggest a collaborative role for either or both HAF-1 and HAF-2 in establishing the B cell activity of the human IgH enhancer.


Potential of genetically engineered hybrid poplar for pyrolytic production of bio-based phenolic compounds.
Wild-type and two genetically engineered hybrid poplar lines were pyrolyzed in a micro-pyrolysis (Py-GC/MS) and a bench scale setup for fast and intermediate pyrolysis studies. Principal component analysis showed that the pyrolysis vapors obtained by micro-pyrolysis from wood of caffeic acid O-methyltransferase (COMT) and caffeoyl-CoA O-methyltransferase (CCoAOMT) down-regulated poplar trees differed significantly from the pyrolysis vapors obtained from non-transgenic control trees. Both fast micro-pyrolysis and intermediate pyrolysis of transgenic hybrid poplars showed that down-regulation of COMT can enhance the relative yield of guaiacyl lignin-derived products, while the relative yield of syringyl lignin-derived products was up to a factor 3 lower. This study indicates that lignin engineering via genetic modifications of genes involved in the phenylpropanoid and monolignol biosynthetic pathways can help to steer the pyrolytic production of guaiacyl and syringyl lignin-derived phenolic compounds such as guaiacol, 4-methylguaiacol, 4-ethylguaiacol, 4-vinylguaiacol, syringol, 4-vinylsyringol, and syringaldehyde present in the bio-oil.


Development and validation of the Patient's Health Belief Questionnaire on Psychiatric Treatment.
Our previous studies with regard to adherence to psychiatric medications measured pharmacophobia, psychological reactance, and locus of control using a 42-item questionnaire requiring ~1.5 hours for completion. This study aims to develop the Patient's Health Belief Questionnaire on Psychiatric Treatment, a 17-item inventory which requires only 15 minutes to complete. Our new questionnaire with five subscales was based on 17 items from three previously validated scales (on pharmacophobia, psychological reactance, and locus of control). In 588 consecutive Spanish psychiatric outpatients taking 1,114 psychiatric medications, we studied the responses to the questionnaire; to validate it, medication adherence was assessed by the Sidorkiewicz tool. Validation of the construct was addressed by performing two exploratory factor analyses independent of each other (one for the eight-item section measuring the attitudes of patients toward psychotropic drugs and one for the nine-item section measuring perceived health locus of control [HLOC]), which led to five subscales that were called Positive and Negative Aspects of Medications, Doctor-HLOC, Internal-HLOC, and Psychological Reactance. The five subscales showed better internal consistency when corrected by number of items than the original 17-item scale. Logistic regression models of the continuous scores, dichotomized subscales, and Chi-squared Automatic Interaction Detector (CHAID) analysis indicated that all five subscales help in predicting adequate adherence, although the various subscales behave differently in different analyses. Future studies need to verify and further extend the preliminary findings of this study that the questionnaire may have construct and predictive validity.