Patient-Clinician Decision Making for Stable Angina: The Role of Health Literacy.
Stable angina patients have difficulty understanding the tradeoffs between treatment alternatives. In this analysis, we assessed treatment planning conversations for stable angina to determine whether inadequate health literacy acts as a barrier to communication that may partially explain this difficulty. We conducted a descriptive analysis of patient questionnaire data from the PCI Choice Trial. The main outcomes were the responses to the Decisional Conflict Scale and the proportion of correct responses to knowledge questions about stable angina. We also conducted a qualitative analysis on recordings of patient-clinician discussions about treatment planning. The recordings were coded with the OPTION12 instrument for shared decision-making. Two analysts independently assessed the number and types of patient questions and expressions of preferences. Patient engagement did not differ by health literacy level and was generally low for all patients with respect to OPTION12 scores and the number of questions related to clinical aspects of treatment. Patients with inadequate health literacy had significantly higher decisional conflict. However, the proportion of knowledge questions answered correctly did not differ significantly by health literacy level. Patients with inadequate health literacy had greater decisional conflict but no difference in knowledge compared to patients with adequate health literacy. Inadequate health literacy may act as a barrier to communication, but gaps were found in patient engagement and knowledge for patients of all health literacy levels. The recorded patient-clinician encounters and the health literacy measure were valuable resources for conducting research on care delivery.


Identifying physical activity information needs and preferred methods of delivery of people with multiple sclerosis.
The purpose of this study was to examine the preferred sources and methods for acquiring physical activity information of individuals with multiple sclerosis (MS) using the Comprehensive Model of Information Seeking. A secondary objective was to explore the barriers and facilitators to physical activity information seeking. Twenty-one participants diagnosed with MS participated in focus groups or telephone interviews. A direct content analysis of the transcripts revealed that individuals appeared to generally prefer receiving physical activity information during period of relapse and remission. Participants also had positive beliefs toward physical activity and a clear preference for a time when physical activity messages would be relevant. Receiving physical activity information from credible sources such as the MS Society of Canada, healthcare professionals and peers with MS was also deemed important. The Internet was a preferred source to receive information due to its accessibility, but it often was considered to lack credibility. The lack of physical activity information specific to MS is the greatest barrier for individuals with MS to learn about physical activity. Healthcare professionals, National MS Societies, and peers should work together to deliver specific and relevant physical activity messages the MS population. People with MS want more physical activity information from credible sources. Multiple vehicles of physical activity information delivery (i.e. healthcare providers, peers, MS Society) should be utilized. Physical activity information should be tailored to the individual with MS.


Persistent predominance of the Victoria lineage of influenza B virus during COVID-19 epidemic in Nanchang, China.
The sentinel hospital-based influenza-like illness (ILI) surveillance network was established in China since the 2009 H1N1 pandemic. This network plays important roles in monitoring influenza virus variation and identifying novel respiratory pathogens. In this study, we characterized the pathogen spectrum pattern (PSP) of ILI based on three sentinel hospitals and analyzed the significant change of PSP during the COVID-19 epidemic. The notable change of influenza virus spectrum was observed since the beginning of COVID-19 outbreak, and we found persistent domination of Victoria lineage of influenza B virus and "extinction" of A/H1N1, A/H3N2, and B/Yamagata during the dynamic Zero-COVID-19 pandemic in Nanchang, China. However, these strains intermittently co-circulated before the COVID-19.


Polydispersity analysis of Taylor dispersion data: the cumulant method.
Taylor dispersion analysis is an increasingly popular characterization method that measures the diffusion coefficient, and hence the hydrodynamic radius, of (bio)polymers, nanoparticles, or even small molecules. In this work, we describe an extension to current data analysis schemes that allows size polydispersity to be quantified for an arbitrary sample, thereby significantly enhancing the potentiality of Taylor dispersion analysis. The method is based on a cumulant development similar to that used for the analysis of dynamic light scattering data. Specific challenges posed by the cumulant analysis of Taylor dispersion data are discussed, and practical ways to address them are proposed. We successfully test this new method by analyzing both simulated and experimental data for solutions of moderately polydisperse polymers and polymer mixtures.


Clinical Outcome Prediction Using Single-Cell Data.
Single-cell technologies like flow cytometry (FCM) provide valuable biological data for knowledge discovery in complex cellular systems like tissues and organs. FCM data contains multi-dimensional information about the cellular heterogeneity of intricate cellular systems. It is possible to correlate single-cell markers with phenotypic properties of those systems. Cell population identification and clinical outcome prediction from single-cell measurements are challenging problems in the field of single cell analysis. In this paper, we propose a hybrid learning approach to predict clinical outcome using samples' single-cell FCM data. The proposed method is efficient in both i) identification of cellular clusters in each sample's FCM data and ii) predict clinical outcome (healthy versus unhealthy) for each subject. Our method is robust and the experimental results indicate promising performance.


LncRNA DCST1-AS1 drives the malignant progression of pediatric acute myeloid leukemia via regulating p53 methylation.
To uncover the biological role of lncRNA DCST1-AS1 in the process of pediatric AML and its regulatory effect on p53 methylation. Serum level of DCST1-AS1 in AML children and healthy participants was detected by qRT-PCR. The role of DCST1-AS1 in mediating biological functions of AML193 and U937 cells was assessed by functional experiments. p53 methylation level was examined. Through BSP, MSP and dual-luciferase reporter assay, the regulatory effect of DCST1-AS1 on p53 methylation was explored. The correlation between DCST1-AS1 and p53 in the serum of AML children was assessed. Serum level of DCST1-AS1 was higher in AML children than in healthy subjects. Knockdown of DCST1-AS1 decreased proliferative and migratory rates in AML193 and U937 cells. DCST1-AS1 was able to induce methylation of p53 promoter. P53 was markedly upregulated by the knockdown of DCST1-AS1, presenting a negative correlation. LncRNA DCST1-AS1 drives the malignant progression of pediatric AML through inducing methylation of the p53 promoter.


[Practice guideline for diagnosis and treatment of hepatocellular carcinoma].
Hepatocellular carcinoma (HCC) is the 3rd most common cancer. The annual incidence is over 10,000 cases in Korea. While hepatitis B virus is major cause of Korean HCC, the impact of alcoholic liver disease is a rising trend. The 5-year survival rate of HCC is only 9.6%, mainly due late diagnosis, tumor biology and underlying chronic liver diseases. Because almost eighty percent of HCC is diagnosed in late, not early stages, a nationwide surveillance program to screen high risk groups (HBV or HCV carriers or liver cirrhosis, over 40 years old) was launched last year and a practice guideline, with special emphasis on advanced stage HCC was formulated. Forty-five experts from KLCSG and the National Cancer Center participated in a special committee to develop a practice guideline for HCC. Based on scientific evidence, the consensus was made for diagnosis and treatment strategy after considering the medico-social situation in Korea. Required and optional tests and clinical (non-invasive) diagnosis criteria for HCC are identified. The first decision, based on both Child-Pugh score and modified UICC tumor staging, is to determine operability. The second decision, to determine resectability, is based on localization of the tumor and residual liver function. Chemoembolization or local ablation therapy is allowed for resectable tumors in certain conditions, such as at borderline risk or non-invasively diagnosed. Unresectable tumors are classified into either a group with inadequate residual liver functions or the another group with extensive or macrovascular invasion or distant metastases. Indications of liver transplantation, chemoembolization, local ablation, radiation therapy and chemotherapy for unresectable HCC are presented. This guideline is expected to be useful for clinical management of, and research for HCC patients.


Parallel excitation-emission multiplexed fluorescence lifetime confocal microscopy for live cell imaging.
We present a novel excitation-emission multiplexed fluorescence lifetime microscopy (FLIM) method that surpasses current FLIM techniques in multiplexing capability. The method employs Fourier multiplexing to simultaneously acquire confocal fluorescence lifetime images of multiple excitation wavelength and emission color combinations at 44,000 pixels/sec. The system is built with low-cost CW laser sources and standard PMTs with versatile spectral configuration, which can be implemented as an add-on to commercial confocal microscopes. The Fourier lifetime confocal method allows fast multiplexed FLIM imaging, which makes it possible to monitor multiple biological processes in live cells. The low cost and compatibility with commercial systems could also make multiplexed FLIM more accessible to biological research community.


LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations.
To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤ 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥ 20 ng/l. The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations.


Ion-exchange high-performance liquid-chromatography steps in peptide purifications.
Ion-exchange high-performance liquid chromatography (HPLC; on Ultropac TSK DEAE and CM) is compared with conventional soft-gel ion-exchange chromatography in identical peptide purifications. The results show that separating properties are similar, but as expected, ion-exchange HPLC has a much higher resolving capacity and a higher sensitivity, and allows a considerably shorter total separation time. The same buffer systems as for conventional ion-exchange chromatography can be used, including urea to solubilize large peptides, if care is taken not to exceed the pH limits set by the column matrix. A complete purification scheme by HPLC in the nanomolar range, utilizing exclusion, ion-exchange, and reverse-phase chromatographies, is given with a complex peptide mixture from a digest of a large protein. Similar steps as in conventional soft-gel schemes can be utilized. It is concluded that ion-exchange HPLC is a suitable complement to commonly used reverse-phase HPLC steps and that it permits high speed and sensitivity over wide ranges of peptide sizes and amounts.


Patients benefit--partners suffer? The impact of heart transplantation on the partner relationship.
Terminal heart disease affects not only the patient, but also members of the patient's family, and especially the spouse. The aim of this prospective study of 26 couples was to collect information about the impact of heart transplantation on the partner relationship. Data were collected from patients and spouses when the patients were placed on the waiting list for transplantation, 1 year postoperatively, and 5 years postoperatively. The Family Assessment Measure (FAM III), a self-report instrument that provides quantitative indices of family functioning on seven interacting dimensions, was used. In the course of the transplant process, both patients and spouses reported a significant deterioration in the partner relationship in general. While patients perceived only one clear-cut point of conflict communication about emotions - as crucial, the spouses reported a significant worsening in role performance, communication, emotional involvement, and values and norms. These changes were discernible 1 year after transplantation and persisted for at least 5 years. We conclude that heart transplantation has a significant negative impact on the partner relationship 1-5 years after transplantation. Consequently, more attention should be paid to all aspects of the partner relationship in a holistic approach to the treatment of heart transplant recipients and their partners.


Reprint of: Air travel and COVID-19 prevention in the pandemic and peri-pandemic period: A narrative review.
Air travel during the COVID-19 pandemic is challenging for travellers, airlines, airports, health authorities, and governments. We reviewed multiple aspects of COVID peri-pandemic air travel, including data on traveller numbers, peri-flight prevention, and testing recommendations and in-flight SARS-CoV-2 transmission, photo-epidemiology of mask use, the pausing of air travel to mass gathering events, and quarantine measures and their effectiveness. Flights are reduced by 43% compared to 2019. Hygiene measures, mask use, and distancing are effective, while temperature screening has been shown to be unreliable. Although the risk of in-flight transmission is considered to be very low, estimated at one case per 27 million travellers, confirmed in-flight cases have been published. Some models exist and predict minimal risk but fail to consider human behavior and airline procedures variations. Despite aircraft high-efficiency filtering, there is some evidence that passengers within two rows of an index case are at higher risk. Air travel to mass gatherings should be avoided. Antigen testing is useful but impaired by time lag to results. Widespread application of solutions such as saliva-based, rapid testing or even detection with the help of "sniffer dogs" might be the way forward. The "traffic light system" for traveling, recently introduced by the Council of the European Union is a first step towards normalization of air travel. Quarantine of travellers may delay introduction or re-introduction of the virus, or may delay the peak of transmission, but the effect is small and there is limited evidence. New protocols detailing on-arrival, rapid testing and tracing are indicated to ensure that restricted movement is pragmatically implemented. Guidelines from airlines are non-transparent. Most airlines disinfect their flights and enforce wearing masks and social distancing to a certain degree. A layered approach of non-pharmaceutical interventions, screening and testing procedures, implementation and adherence to distancing, hygiene measures and mask use at airports, in-flight and throughout the entire journey together with pragmatic post-flight testing and tracing are all effective measures that can be implemented. Ongoing research and systematic review are indicated to provide evidence on the utility of preventive measures and to help answer the question "is it safe to fly?".


Total robotic pancreaticoduodenectomy: a systematic review of the literature.
Pancreaticoduodenectomy (PD) is a complex operation with high perioperative morbidity and mortality, even in the highest volume centers. Since the development of the robotic platform, the number of reports on robotic-assisted pancreatic surgery has been on the rise. This article reviews the current state of completely robotic PD. A systematic literature search was performed including studies published between January 2000 and July 2016 reporting PDs in which all procedural steps (dissection, resection and reconstruction) were performed robotically. Thirteen studies met the inclusion criteria, including a total of 738 patients. Data regarding perioperative outcomes such as operative time, blood loss, mortality, morbidity, conversion and oncologic outcomes were analyzed. No major differences were observed in mortality, morbidity and oncologic parameters, between robotic and non-robotic approaches. However, operative time was longer in robotic PD, whereas the estimated blood loss was lower. The conversion rate to laparotomy was 6.5-7.8%. Robotic PD is feasible and safe in high-volume institutions, where surgeons are experienced and medical staff are appropriately trained. Randomized controlled trials are required to further investigate outcomes of robotic PD. Additionally, cost analysis and data on long-term oncologic outcomes are needed to evaluate cost-effectiveness of the robotic approach in comparison with the open technique.


Complement C3a receptor-mediated vascular dysfunction: a complex interplay between aging and neurodegeneration.
Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR-mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1-/-) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.


Examination of the role of obesity in the association between childhood trauma and inflammation during pregnancy.
Childhood trauma is associated with negative perinatal health outcomes including mood disorders and shorter gestation. However, effects of early life exposures on maternal biology are poorly delineated. This study examined associations between childhood trauma and inflammation, as well as the mediating role of obesity in this relationship. This study examined a racially diverse sample of 77 pregnant women assessed in early, mid, and late pregnancy. Assessments included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, serum CRP, IL-6, and TNF-α, and prepregnancy BMI. Per linear mixed models, while no direct relationships were observed between childhood trauma with IL-6 or TNF-α, physical (95% CI: 0.007, 0.080) and emotional (95% CI: 0.005, 0.046) abuse as well as emotional neglect (95% CI: 0.010, 0.051) predicted elevated CRP. Effects remained after adjustment for race, income, education, smoking status, medical conditions, and depressive symptoms. PROCESS analyses showed BMI mediated the relationship between physical abuse and both serum CRP (95% CI: 0.014, 0.062) and IL-6 (95% CI: 0.009, 0.034). Exposure to childhood trauma, particularly emotional abuse, physical abuse, and emotional neglect, is associated with inflammation in pregnant women. Obesity served as 1 pathway by which physical abuse contributed to elevations in serum CRP and IL-6. Interventions targeting maternal obesity prior to pregnancy may help mitigate the effects of childhood trauma on perinatal health. These findings have relevance for understanding biological and behavioral pathways by which early life exposures contribute to maternal health. (PsycINFO Database Record


Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils.
Remoxipride is an atypical antipsychotic displaying selective binding to the dopamine D2 receptor. Several cases of aplastic anemia led to the withdrawal of remoxipride from the market in December 1993. The remoxipride metabolite NCQ-344 is a hydroquinone while the structural isomer NCQ-436 is a catechol, both of which have been suggested to be capable of forming a reactive para- and ortho-quinone, respectively. Recently, these two remoxipride metabolites were shown to induce apoptosis in human bone marrow progenitor cells. Furthermore, NCQ-344 also caused necrosis of these cells unlike NCQ-436. Although NCQ-344 has been detected in plasma of humans dosed with remoxipride, to date, no experimental evidence for the formation of the corresponding para-quinone has been obtained. Here, we report the detection of three glutathione (GSH) conjugates of NCQ-344 in vitro that were formed following a chemical reaction and characterized by tandem mass spectrometry and for a cyclized conjugate additionally with derivatization and deuterium exchange. In contrast, NCQ-436 did not form a GSH conjugate. Hypochlorous acid oxidized NCQ-344 to the para-quinone while NCQ-436 was resistant to oxidation. Upon incubation with NCQ-344, stimulated human neutrophils produced from 2- to 5-fold greater amounts of glutathione conjugates than unstimulated neutrophils. Ab initio calculations on these remoxipride metabolites indicated that the reaction leading to the respective quinone was spontaneous for the para-quinone (e.g., from NCQ-344) while ortho-quinone (e.g., from NCQ-436) formation was not. These results demonstrate that NCQ-344 is capable of facile formation of a reactive para-quinone capable of reacting with GSH and may rationalize previous findings regarding the biological effects observed in vitro with these two remoxipride metabolites.


Sequence similarity is more relevant than species specificity in probabilistic backtranslation.
Backtranslation is the process of decoding a sequence of amino acids into the corresponding codons. All synthetic gene design systems include a backtranslation module. The degeneracy of the genetic code makes backtranslation potentially ambiguous since most amino acids are encoded by multiple codons. The common approach to overcome this difficulty is based on imitation of codon usage within the target species. This paper describes EasyBack, a new parameter-free, fully-automated software for backtranslation using Hidden Markov Models. EasyBack is not based on imitation of codon usage within the target species, but instead uses a sequence-similarity criterion. The model is trained with a set of proteins with known cDNA coding sequences, constructed from the input protein by querying the NCBI databases with BLAST. Unlike existing software, the proposed method allows the quality of prediction to be estimated. When tested on a group of proteins that show different degrees of sequence conservation, EasyBack outperforms other published methods in terms of precision. The prediction quality of a protein backtranslation methis markedly increased by replacing the criterion of most used codon in the same species with a Hidden Markov Model trained with a set of most similar sequences from all species. Moreover, the proposed method allows the quality of prediction to be estimated probabilistically.


Longitudinal Relationships Among Fear of COVID-19, Smartphone Online Self-Disclosure, Happiness, and Psychological Well-being: Survey Study.
Given that governmental prevention measures restricted most face-to-face communications, online self-disclosure via smartphones emerged as an alternative coping strategy that aimed at reducing the impact of the COVID-19 pandemic on people's psychological health. Prepandemic research demonstrated that online self-disclosure benefits people's psychological health by establishing meaningful relationships, obtaining social support, and achieving self-acceptance, particularly in times of crisis. However, it is unclear whether these dynamics transition well to lockdown conditions where online self-disclosure must stand almost entirely on its own. Longitudinal investigations are needed to gain insights into the psychological functionalities of online self-disclosure during the COVID-19 pandemic. This study aimed to determine the temporal associations between smartphone online self-disclosure (as a communicative behavior) and critical indicators of psychological health (including psychopathological, as well as hedonic and eudaimonic states) during the first COVID-19 lockdown in Austria. We conducted a representative 2-wave panel survey between late March/April 2020 and May 2020. A total of 416 participants completed both waves (43.1% attrition rate, given n=731 participants who completed the first wave). A partially metric measurement invariant overtime structural equation model was used to determine the temporal associations among online self-disclosure, fear of COVID-19, happiness, and psychological well-being. The analysis revealed that fear of COVID-19 significantly predicted online self-disclosure over time (b=0.24, P=.003) and happiness over time (b=-0.14, P=.04), but not psychological well-being (b=0.03, P=.48), that is, stronger COVID-19 fears at T1 prompted more online self-disclosure and less happiness at T2. Online self-disclosure, on the other hand, significantly predicted happiness (b=0.09, P=.02), but neither fear of COVID-19 (b=-0.01, P=.57) nor psychological well-being (b=-0.01, P=.57) over time. Participants who engaged more strongly in online self-disclosure at T1 felt happier at T2, but they did not differ from less-disclosing participants concerning COVID-19 fears and psychological well-being at T2. Importantly, happiness and psychological well-being were significantly related over time (happiness T1 → psychological well-being T2: b=0.11, P<.001; psychological well-being T1 → happiness T2: b=0.42, P<.001). Our findings suggest that online self-disclosure might play a pivotal role in coping with pandemic stressors. With restrictions on their options, individuals increasingly turn to their smartphones and social media to disclose their feelings, problems, and concerns during lockdown. While online self-disclosure might not alleviate fears or improve psychological well-being, our results demonstrate that it made people experience more happiness during this crisis. This psychological resource may help them withstand the severe psychological consequences of the COVID-19 crisis over longer timeframes.


Redirecting photosynthetic electron flow into light-driven synthesis of alternative products including high-value bioactive natural compounds.
Photosynthesis in plants, green algae, and cyanobacteria converts solar energy into chemical energy in the form of ATP and NADPH, both of which are used in primary metabolism. However, often more reducing power is generated by the photosystems than what is needed for primary metabolism. In this review, we discuss the development in the research field, focusing on how the photosystems can be used as synthetic biology building blocks to channel excess reducing power into light-driven production of alternative products. Plants synthesize a large number of high-value bioactive natural compounds. Some of the key enzymes catalyzing their biosynthesis are the cytochrome P450s situated in the endoplasmic reticulum. However, bioactive compounds are often synthesized in low quantities in the plants and are difficult to produce by chemical synthesis due to their often complex structures. Through a synthetic biology approach, enzymes with a requirement for reducing equivalents as cofactors, such as the cytochrome P450s, can be coupled directly to the photosynthetic energy output to obtain environmentally friendly production of complex chemical compounds. By relocating cytochrome P450s to the chloroplasts, reducing power can be diverted toward the reactions catalyzed by the cytochrome P450s. This provides a sustainable production method for high-value compounds that potentially can solve the problem of NADPH regeneration, which currently limits the biotechnological uses of cytochrome P450s. We describe the approaches that have been taken to couple enzymes to photosynthesis in vivo and to photosystem I in vitro and the challenges associated with this approach to develop new green production platforms.


Optimum in the thermoelectric efficiency of nanostructured Nb-doped TiO2 ceramics: from polarons to Nb-Nb dimers.
Rutile is the most common and stable polymorph form of titanium oxide TiO2 at all temperatures. The doping of rutile TiO2 with a small amount of niobium is reknown for being responsible for a large increase of the electrical conductivity by several orders of magnitude, broadening its technological interest towards new emerging fields such as the thermoelectric conversion of waste heat. The electronic conduction has been found to be of a polaronic nature with strongly localized charges around the Ti3+ centers while, on the other side, the relatively high value of the thermal conductivity implies the existence of lattice heat carriers, i.e. phonons, with large mean free paths which makes the nanostructuration relevant for optimizing the thermoelectric efficiency. Here, the use of a high-pressure and high-temperature sintering technique has allowed to vary the grain size in rutile TiO2 pellets from 300 to 170 nm, leading to a significant reduction of the lattice thermal conductivity. The thermoelectric properties (electrical conductivity, Seebeck coefficient and thermal conductivity) of Nb-doped rutile nanostructured ceramics, namely NbxTi1-xO2 with x varying from 1 to 5%, are reported from room temperature to ∼900 K. With the incorporation of Nb, an optimum in the thermoelectric properties together with an anomaly on the tetragonal lattice constant c are observed for a concentration of ∼2.85%, which might be the fingerprint of the formation of short Nb dimers.


Ca2+-tolerant adult canine myocytes: preparation and response to anoxia/acidosis.
A procedure is described for the production of large numbers of Ca2+-tolerant adult canine ventricular myocytes. Gentle tissue dissociation is achieved in Spinner flasks using 320 mosM enzyme buffer containing collagenase hyaluronidase, and trypsin in the presence of millimolar levels of Ca2+. The technique allows for the complete removal of erythrocytes, the gentle removal of closely adhering nonmuscle cells (less than 3% contamination), and the selective removal of damaged from nondamaged myocytes. Total myocyte yields averaged 4-6 x 10(6)/g wet wt; 61.0 +/- 6.5% of the cells have rod-shaped morphology and are "viable" based on trypan blue exclusion. Only 3.9 +/- 1.1% of the rod-shaped cells beat spontaneously when challenged with 2 mM Ca2+. Exposure to 2 mM Ca2+ at 37 degrees C results in minimal loss of viability (2.1 +/- 1.3%/h) based on both trypan blue uptake and creatine kinase release. Simulation of cellular (i.e., membrane) injury in vitro is performed by the separate application of the perturbations of anoxia, acidosis, and low glucose to the canine myocyte suspensions; the data suggest that these myocytes are affected independently by these perturbations and are in good agreement with the results obtained by others using the isolated rat myocyte system.


Dissecting the subcellular compartmentation of proteins and metabolites in arabidopsis leaves using non-aqueous fractionation.
Non-aqueous fractionation is a technique for the enrichment of different subcellular compartments derived from lyophilized material. It was developed to study the subcellular distribution of metabolites. Here we analyzed the distribution of about 1,000 proteins and 70 metabolites, including 22 phosphorylated intermediates in wild-type Arabidopsis rosette leaves, using non-aqueous gradients divided into 12 fractions. Good separation of plastidial, cytosolic, and vacuolar metabolites and proteins was achieved, but cytosolic, mitochondrial, and peroxisomal proteins clustered together. There was considerable heterogeneity in the fractional distribution of transcription factors, ribosomal proteins, and subunits of the vacuolar-ATPase, indicating diverse compartmental location. Within the plastid, sub-organellar separation of thylakoids and stromal proteins was observed. Metabolites from the Calvin-Benson cycle, photorespiration, starch and sucrose synthesis, glycolysis, and the tricarboxylic acid cycle grouped with their associated proteins of the respective compartment. Non-aqueous fractionation thus proved to be a powerful method for the study of the organellar, and in some cases sub-organellar, distribution of proteins and their association with metabolites. It remains the technique of choice for the assignment of subcellular location to metabolites in intact plant tissues, and thus the technique of choice for doing combined metabolite-protein analysis on a single tissue sample.


Multiple causes of high extinction risk in large mammal species.
Many large animal species have a high risk of extinction. This is usually thought to result simply from the way that species traits associated with vulnerability, such as low reproductive rates, scale with body size. In a broad-scale analysis of extinction risk in mammals, we find two additional patterns in the size selectivity of extinction risk. First, impacts of both intrinsic and environmental factors increase sharply above a threshold body mass around 3 kilograms. Second, whereas extinction risk in smaller species is driven by environmental factors, in larger species it is driven by a combination of environmental factors and intrinsic traits. Thus, the disadvantages of large size are greater than generally recognized, and future loss of large mammal biodiversity could be far more rapid than expected.


The role of STEP in Alzheimer's disease.
Amyloid beta (Aβ), the putative causative agent in Alzheimer's disease, is known to affect glutamate receptor trafficking. Previous studies have shown that Aβ downregulates the surface expression of N-methyl D-aspartate type glutamate receptors (NMDARs) by the activation of STriatal-Enriched protein tyrosine Phosphatase 61 (STEP₆₁). More recent findings confirm that STEP₆₁ plays an important role in Aβ-induced NMDAR endocytosis. STEP levels are elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The increase in STEP₆₁ levels and activity contribute to the removal of GluN1/GluN2B receptor complexes from the neuronal surface membranes. The elevation of STEP₆₁ is due to disruption in the normal degradation of STEP₆₁ by the ubiquitin proteasome system. Here, we briefly discuss additional studies in support of our hypothesis that STEP₆₁ contributes to aspects of the pathophysiology in Alzheimer's disease. Exogenous application of Aβ-enriched conditioned medium (7PA2-CM) to wild-type cortical cultures results in a loss of GluN1/GluN2B subunits from neuronal membranes. Abeta-mediated NMDAR internalization does not occur in STEP knock-out cultures, but is rescued by the addition of active TAT-STEP to the cultures prior to Aβ treatment.


Topological mapping of unique epitopes on the dengue-2 virus NS1 protein using monoclonal antibodies.
Monoclonal antibodies were produced against two distinct Thai dengue-2 (DEN-2) virus strains isolated in 1980 from dengue haemorrhagic fever patients. Nine of 36 hybridomas produced monoclonal IgG antibodies which reacted in radioimmune precipitation assays with the NS1 non-structural protein (42,000 mol. wt.) from DEN-2-infected C6/36 (Aedes albopictus) cells. The virus specificity of NS1-reactive monoclonal antibodies was determined by indirect immunofluorescence assays using LLC-MK2 cells infected with either the Thai 1980 DEN-2 isolates, prototype DEN viruses (four serotypes), Japanese encephalitis (JE), Murray Valley encephalitis, West Nile, Wesselbron or Tembusu viruses. Eight of the monoclonal antibody preparations were DEN-2-serotype specific. One preparation defined a special serological relationship between DEN-2 and JE viruses. Four preparations had detectable complement fixation titres using Thai DEN-2 virus antigen. Six spatially unique epitopes were identified using competitive binding assays.


Gross structure of the atriums: more than an anatomic curiosity?
Despite the extensive literature concerning atrial arrhythmias, there are relatively few articles on the anatomy of the atrial chambers. Since electrophysiological mapping and interventional treatments of atrial arrhythmias involve entering the chambers, this article reviews the gross structures to provide a better understanding of the atriums, the septum, and the connecting great veins. In addition, based on the human heart, differences between porcine and canine hearts are highlighted. The right and left atriums are characterized by morphologically distinct appendages. The right atrium contains prominent muscular bundles and an extensive array of pectinate muscles. The distal ramifications of the terminal crest lead to the "flutter" isthmus. By contrast, the left atrium has relatively smooth walls. The atrial septum is limited to the valve of the oval fossa and its immediate muscular rim. Atrial musculature extends beyond the veno-atrial junctions to the outside of the pulmonary veins. The longest sleeves are around the upper pulmonary veins, and similar sleeves are seen around the superior caval vein. The structure of the atrium is more than an anatomic curiosity. It has practical implicationsfor mapping and interventional procedures.


Neighborhood disorder and juvenile drug arrests: a preliminary investigation using the NIfETy instrument.
Disordered neighborhood environments are associated with crime, drug use, and poor health outcomes. However, research utilizing objective instruments to characterize the neighborhood environment is lacking. This investigation examines the relationship between objective measures of neighborhood disorder and juvenile drug arrests (JDAs) in an urban locale. The neighborhood disorder scale was developed using indicators from the Neighborhood Inventory for Environmental Typology (NIfETy) instrument; a valid and reliable tool that assesses physical and social disorder. Data on 3146 JDAs from 2006 were obtained from the police department. Negative binomial regression models revealed a significant association between neighborhood disorder and the count of JDAs in the neighborhood (β == .34, p < .001). The relationship between neighborhood disorder and JDAs remained significant after adjusting for percent African-Americans in the neighborhood (β == .24, p < .001). This preliminary investigation identified a positive and statistically significant relationship between an objective measure of neighborhood disorder and JDAs. Future investigations should examine strategies to reduce drug-related crime by addressing the larger neighborhood and social context in which drug involvement and crime occurs.


Computed tomographic analysis of calvarial hyperostosis in captive lions.
Osseous malformations in the skull and cervical vertebrae of lions in captivity are believed to be caused by hypovitaminosis A. These often lead to severe neurologic abnormalities and may result in death. We describe the characterization of these abnormalities based on computed tomography (CT). CT images of two affected and three healthy lions were compared with define the normal anatomy of the skull and cervical vertebrae and provide information regarding the aforementioned osseous malformations. Because bone structure is influenced by various factors other than the aforementioned disease, all values were divided by the skull width that was not affected. The calculated ratios were compared and the most pronounced abnormalities in the affected lions were, narrowing of the foramen magnum, thickening of the tentorium osseus cerebelli and thickening of the dorsal arch of the atlas. CT is useful for detection of the calvarial abnormalities in lions and may be useful in further defining this syndrome.


Causal influences in primate cerebral cortex during visual pattern discrimination.
Anatomical studies of the visual cortex demonstrate the existence of feedforward, feedback and lateral pathways among multiple cortical areas. Yet relatively little evidence has previously been available to show the causal influences of these areas on one another during visual information processing. We simultaneously recorded event-related local field potentials (LFPs) from surface-to-depth bipolar electrodes at six sites in the ventral region of the right hemisphere visual cortex in a highly trained macaque monkey during performance of a visual pattern discrimination task. Applying a new statistical measure, the short-time directed transfer function (STDTF), to the LFP data set, we charted the changing strength and direction of causal influence between these cortical sites on a fraction-of-a-second time scale. We present results showing, for the first time, the dynamics of distinct feedforward, feedback and lateral influences in the ventral portion of the primate visual cortex during visual pattern processing.


Treatment of rats with dexamethasone or thyroxine reverses zinc deficiency-induced intestinal damage.
Structural and functional damage to the intestine and the potential beneficial effects of dexamethasone (Dex) and thyroxine (T4) were examined in zinc-deficient rats. Rats were assigned to zinc deficient (ZD), control (C) or pair-fed (PF ) groups and fed for 40 d a zinc deficient (1 mg/kg) diet (ZD rats) or a similar diet supplemented with 50 mg Zn/kg (C and PF rats). Some rats of the ZD group were treated for the last 10 d with low (250 mg/kg) or high (5 mg/kg) doses of Dex or with T4 (100 mg/kg). Serum corticosterone of T4-treated ZD rats did not differ from untreated ZD rats. Serum T4 of T4-treated ZD rats did not differ from C rats. ZD rats developed ulcerations, inflammation and edema in the small intestine, particularly in the jejunum. PF rats did not show mucosal changes relative to C rats. ZD rats showed significantly lower crypt cell production rate (CCPR) and labeling index (LI) in the three intestinal regions, and lower cell migration rate and higher turnover time in the duodenum relative to C rats. Sucrase and maltase activities of ZD rats were significantly lower than C rats in the three mucosal regions. Treatment with the low dose of Dex resulted in fewer ulcerations compared with ZD rats. In rats administered the high dose of Dex or T4, all morphological alterations disappeared; the CCPR, LI, cell migration rate, cell turnover time and disaccharidase activities did not differ from C rats. In conclusion, Dex and T4 exert beneficial effects on zinc deficiency-induced intestinal alterations in rats.


Working together for success.
Administrators and Directors of Nursing usually believe they are doing the right thing when they begin to implement an ergonomic program such as safe resident handling. However, as time goes by, and the program fades, they may wonder where they went wrong. The commitment, planning, and follow through between "management" and "employees" when a safe resident handling/minimal lift program is implemented is an essential, but often overlooked, part of an effective ergonomic program. The best of programs can fail unless there is an ongoing effort by both to insure that the following goals are achieved: (1) safety for the caregivers, (2) safety for the residents, and (3) improvement or maintenance of mobility of the residents.


It Is Time to Prioritize Education and Well-Being Over Workforce Needs in Residency Training.
Residents inhabit an ambiguous world. They are no longer medical students but are still learners. They are not yet attendings but are still paid employees. This ambiguity leads to a misalignment of departmental incentives and trainee expectations. Trainees expect their learning and well-being to be prioritized, while departments are under pressure to meet staffing needs and cut costs. This sets up a fundamental disconnect between the "formal" Accreditation Council for Graduate Medical Education (ACGME) message of well-being and the dominant "hidden" workplace forces that pull in the opposite direction, possibly contributing to the epidemic of burnout in trainees. It is critical that all parties-health systems, graduate medical education (GME) programs, the ACGME, and residents-recognize this disconnect and collaborate to meaningfully implement current ACGME requirements to decompress work intensity and address well-being. Real change will require more than general directives. The ACGME will likely need to take the lead and consider taking a design-thinking approach to structuring regulations governing how and when residents work and how they are supported. It would also be worthwhile to revisit the Institute of Medicine recommendations on GME from 2014 related to funds flow and transformation initiatives. Taking a more comprehensive approach to residents as people, workers, and vital health care professionals is the right thing to do and may well improve retention, reduce burnout, decrease medical errors, and improve care.


Clinical, pharmacokinetic, and pharmacogenetic determinants of clopidogrel resistance in Korean patients with acute coronary syndrome.
Clopidogrel has been widely used to prevent recurrent ischemia in patients with acute coronary syndrome (ACS). However, inter-individual variability in response to clopidogrel has been a problem in the clinical setting. The aim of the present study was to investigate the frequency of clopidogrel resistance and to determine the clinical, pharmacokinetic, and pharmacogenetic factors for clopidogrel resistance in Korean patients with ACS. Clinical information, such as the underlying diseases and concurrent medications, of 114 patients with ACS who received clopidogrel therapy was studied. The degree of inhibition of platelets was assessed using the VerifyNow assay (Accumetrics, USA). The patients who showed less than 20% inhibition of platelets were defined as non-responders to clopidogrel treatment. Steady state plasma concentrations of clopidogrel were measured using HPLC/tandem mass spectrometry. CYP2C19 genotyping was also performed. A wide inter-individual variability was observed in platelet inhibition (0-76%); 56 patients (49%) showed less than 20% inhibition. There were no differences between the patients' history of diabetes mellitus and concurrent medications as well as the plasma concentrations of clopidogrel of the responders and non-responders. CYP2C19 variants, including CYP2C19*2 and CYP2C19*3, were more commonly observed in the non-responders than in the responders (P value < 0.0001). The response to clopidogrel was highly variable in Korean patients with ACS. The results of the present study confirmed that the genetic polymorphism of CYP2C19 could be important in clopidogrel response. However, further studies are required to investigate other likely factors involved in clopidogrel resistance.


Cancer incidence and mortality in a Swedish rubber tire manufacturing plant.
A classification of 12 work categories was used to evaluate the cancer incidence and mortality among a cohort of Swedish rubber tire workers. Cancer incidence and mortality in the cohort was compared with expected values from national rates. Standardized incidence and mortality ratios were calculated for the total cohort, for sub-cohorts and with the inclusion of a latency requirement. Among men, increased incidence and mortality risks were found for cancer in the larynx; SIR=2.10; 95% confidence intervals (95% CI): 1.05-3.76, SMR=2.08; 95% CI: 0.42-6.09. Increased risks were also seen for cancer in the trachea, bronchus, and lung; SIR=1.62; 95% CI: 1.28-2.02, SMR=1.54; 95% CI: 1.21-1.94, the incidence risk was highest among those with the longest exposure duration and among workers in compounding/mixing, milling, and maintenance. Decreased incidence risks were seen for cancer of the prostate (SIR=0.74; 95% CI: 059-0.92) and skin (SIR=0.57; 95% CI: 0.36-0.84). The finding of an excess of tumors in the respiratory system is in agreement with earlier findings in other studies on rubber tire workers. The results on other cancer types are compared to earlier findings and related to work processes and chemical exposures of possible causal importance.


Short-chain fatty acids stimulate dendrite elongation in dendritic cells by inhibiting histone deacetylase.
Dendritic cells activate immune responses by presenting pathogen-derived molecules. The dendrites of dendritic cells contribute to the incorporation of foreign antigens or presenting antigens to T cells. Short-chain fatty acids (SCFAs), such as acetic, propionic, butyric and valeric acids, have many effects on immune responses by activating specific receptors or inhibiting a histone deacetylase (HDAC), although their effect on dendrite formation in dendritic cells is unknown. In the present study, we aimed to investigate the effect of SCFAs on dendrite elongation using a dendritic cell line (DC2.4 cells) and mouse bone marrow-derived dendritic cells. We found that SCFAs induced dendrite elongation. The elongation was reduced by inhibitors of Src family kinase (SFK), phosphatidylinositol-3 kinase (PI3K), Rho family GTPases (Cdc42, Rac1) or actin polymerization, indicating that SCFAs promote dendrite elongation by activating actin polymerization via the SFK/PI3K/Rho family GTPase signaling pathway. We showed that agonists for SCFA receptors GPR43 and GPR109a did not promote dendrite elongation. By contrast, HDAC inhibitors, including trichostatin A, promoted dendrite elongation in DC2.4 cells, and the promoting activity of trichostatin A was decreased by inhibiting the SFK/PI3K/Rho family GTPase signaling pathway or actin polymerization. Furthermore, DC2.4 cells treated with valeric acid showed enhanced uptake of soluble proteins, insoluble beads and Staphylococcus aureus. We also found that treatment with valeric acid enhanced major histocompatibility complex class II-mediated antigen presentation in bone marrow-derived dendritic cells. These results suggest that SCFAs promote dendrite elongation by inhibiting HDAC, stimulating the SFK/PI3K/Rho family pathway and activating actin polymerization, resulting in increased antigen uptake and presentation in dendritic cells.


Cross-linked polyelectrolyte multilayers for marine antifouling applications.
A polyionic multilayer film was fabricated by layer-by-layer (LbL) sequential deposition followed by cross-linking under mild conditions on a substrate surface to inhibit marine fouling. A novel polyanion, featuring methyl ester groups for an easy cross-linking was used as a generic solution for stabilization of LbL films in a harsh environment. Covalent cross-linking was confirmed by FTIR and XPS spectroscopy. AFM was used to observe film morphology and its variation because of cross-linking, as well as to measure the thickness of the LbL films. Cross-linking improved the stability of the LbL film when it was immersed in artificial seawater, natural seawater, and in a polar organic solvent (DMSO). No changes in the thickness and topography of the film were observed in these media. The LbL films prevented settlement of Amphibalanus amphitrite barnacle cyprids and reduced adhesion of the benthic diatom Amphora coffeaeformis. Assay results indicated that the cross-linking process did not weaken the antifouling effect of LbL films. The high stability and low degree of fouling make these coatings potentially promising candidates in marine applications.


Differential effects of over-expressed neural cell adhesion molecule isoforms on myoblast fusion.
We have used a transfection based approach to analyze the role of neural cell adhesion molecule (NCAM) in myogenesis at the stage of myoblast fusion to form multinucleate myotubes. Stable cell lines of myogenic C2 cells were isolated that express the transmembrane 140- or 180-kD NCAM isoforms or the glycosylphosphatidylinositol (GPI) linked isoforms of 120 or 125 kD. We found that expression of the 140-kD transmembrane isoform led to a potent enhancement of myoblast fusion. The 125-kD GPI-linked NCAM also enhanced the rate of fusion but less so when a direct comparison of cell surface levels of the 140-kD transmembrane form was carried out. While the 180-kD transmembrane NCAM isoform was effective in promoting C2 cell fusion similar to the 140-kD isoform, the 120-kD isoform did not have an effect on fusion parameters. It is possible that these alterations in cell fusion are associated with cis NCAM interactions in the plane of the membrane. While all of the transfected human NCAMs (the transmembrane 140- and 180-kD isoforms and the 125- and 120-kD GPI isoforms) could be clustered in the plane of the plasma membrane by species-specific antibodies there was a concomitant clustering of the endogenous mouse NCAM protein in all cases except with the 120-kD human isoform. These studies show that different isoforms of NCAM can undergo specific interactions in the plasma membrane which are likely to be important in fusion. While the transmembrane and the 125-kD GPI-anchored NCAMs are capable of enhancing fusion the 120-kD GPI NCAM is not. Thus it is likely that interactions associated with NCAM intracellular domains and also the muscle specific domain (MSD) region in the extracellular domain of the GPI-linked 125-kD NCAM are important. In particular this is the first role ascribed to the O-linked carbohydrate containing MSD region which is specifically expressed in skeletal muscle.


Identifying and overcoming implementation challenges: Experience of 59 noninstitutional long-term services and support pilot programs in the Veterans Health Administration.
From 2010 to 2013, the Department of Veterans Affairs (VA) funded a large pilot initiative to implement noninstitutional long-term services and supports (LTSS) programs to support aging Veterans. Our team evaluated implementation of 59 VA noninstitutional LTSS programs. The specific objectives of this study are to (a) examine the challenges influencing program implementation comparing active sites that remained open and inactive sites that closed during the funding period and (b) identify ways that active sites overcame the challenges they experienced. Key informant semistructured interviews occurred between 2011 and 2013. We conducted 217 telephone interviews over four time points. Content analysis was used to identify emergent themes. The study team met regularly to define each challenge, review all codes, and discuss discrepancies. For each follow-up interview with the sites, the list of established challenges was used as a priori themes. Emergent data were also coded. The challenges affecting implementation included human resources and staffing issues, infrastructure, resources allocation and geography, referrals and marketing, leadership support, and team dynamics and processes. Programs were able to overcome challenges by communicating with team members and other areas in the organization, utilizing information technology solutions, creative use of staff and flexible schedules, and obtaining additional resources. This study highlights several common challenges programs can address during the program implementation. The most often mentioned strategy was effective communication. Strategies also targeted several components of the organization including organizational functions and processes (e.g., importance of coordination within a team and across disciplines to provide good care), infrastructure (e.g., information technology and human resources), and program fit with priorities in the organization (e.g., leadership support). Anticipating potential pitfalls of program implementation for future noninstitutional LTSS programs can improve implementation efficiency and program sustainability. Staff at multiple levels in the organization must fully support noninstitutional LTSS programs to address these challenges.


2,2'-Dipyridyl diselenide (Py2Se2) induces G1 arrest and apoptosis in human lung carcinoma (A549) cells through ROS scavenging and reductive stress.
Organo-diselenides are well documented for pro-oxidant effects in tumor cells. However, the present study demonstrated that 2,2'-dipyridyl diselenide (Py2Se2) induced cytotoxicity in human non-small cell lung carcinoma (A549) cells through reductive stress marked by a significant decrease in the basal level of reactive oxygen species and a concurrent decrease in the ratio of oxidised (GSSG) and reduced (GSH) glutathione. The IC50 (concentration inducing 50% cytotoxicity) of Py2Se2 in A549 and human normal lung fibroblast (WI38) cells was ∼8.5 μM and ∼5.5 μM, respectively, indicating that Py2Se2 did not exhibit selective toxicity towards cancer cells. Cell free studies indicated that Py2Se2 acted as a substrate of thioredoxin reductase (TrxR) and accordingly it was proposed that TrxR mediated reduction of Py2Se2 within cells might be generating intermediates leading to a reductive environment. Despite generating a reducing environment, Py2Se2 caused significant DNA damage, G1 phase arrest and apoptosis. The mechanistic investigation revealed that Py2Se2 induced G1 arrest was mediated through up-regulation of p21 transcript in a p53 independent manner. Further, the apoptotic effect of Py2Se2 was associated with the increase in the levels of unfolded protein response markers like BiP and CHOP, mitochondrial permeability (JC1) and apoptotic markers such as cleaved caspase-3 and poly (ADP-ribose) polymerase. Finally, pre-treatment with N-acetylcysteine (a stimulator of GSH biosynthesis) or l-buthionine sulfoximine (an inhibitor of GSH biosynthesis) increased and decreased the Py2Se2 mediated apoptosis, respectively. This confirmed that the cytotoxicity of Py2Se2 in A549 cells was triggered through reductive stress.


Is the warfarin saga over?
Warfarin is the most widely used oral anticoagulant and has been available for more than 65 years. The last decade has brought a host of new orally available anticoagulants with promising features to clinical trials and some have already been approved for limited indications. As patients are starting to be switched to these new agents there is a need to gain understanding of the subsets of patients that will benefit the most from the new alternatives and whether warfarin is still the best choice for some subpopulations. With this knowledge we will provide the individual patient with the drug that has the best benefit/risk ratio at the same time as we conserve drug expenditures. This review discusses the directions we could follow in such a tailored anticoagulation approach, referring to the limited evidence when available.


Information diffusion backbones in temporal networks.
Progress has been made in understanding how temporal network features affect the percentage of nodes reached by an information diffusion process. In this work, we explore further: which node pairs are likely to contribute to the actual diffusion of information, i.e., appear in a diffusion trajectory? How is this likelihood related to the local temporal connection features of the node pair? Such deep understanding of the role of node pairs is crucial to tackle challenging optimization problems such as which kind of node pairs or temporal contacts should be stimulated in order to maximize the prevalence of information spreading. We start by using Susceptible-Infected (SI) model, in which an infected (information possessing) node could spread the information to a susceptible node with a given infection probability β whenever a contact happens between the two nodes, as the information diffusion process. We consider a large number of real-world temporal networks. First, we propose the construction of an information diffusion backbone GB(β) for a SI spreading process with an infection probability β on a temporal network. The backbone is a weighted network where the weight of each node pair indicates how likely the node pair appears in a diffusion trajectory starting from an arbitrary node. Second, we investigate the relation between the backbones with different infection probabilities on a temporal network. We find that the backbone topology obtained for low and high infection probabilities approach the backbone GB(β → 0) and GB(β = 1), respectively. The backbone GB(β → 0) equals the integrated weighted network, where the weight of a node pair counts the total number of contacts in between. Finally, we explore node pairs with what local connection features tend to appear in GB(β = 1), thus actually contribute to the global information diffusion. We discover that a local connection feature among many other features we proposed, could well identify the (high-weight) links in GB(β = 1). This local feature encodes the time that each contact occurs, pointing out the importance of temporal features in determining the role of node pairs in a dynamic process.


Sequential power analysis framework in assessing social forestry outcomes.
We extend the Actor-Centred Power framework to consider dimensions beyond the life of community natural resource management partnership initiatives by examining social forestry partnership projects in Indonesia. We do this by examining how power constellations realign across the temporal phases that operationalize project partnerships. We propose a sequential power analysis framework that examines power in three parts. The framework first proposes a method for historicizing actors into their power background. Second, we present mode for examining the arrival of a partnership scheme, which we call the power delivery phase. Third, we highlight approaches for examining the way power relations are adjusted, whether reinforced or reconfigured, by introducing an approach for examining programmatic outcomes of social forestry partnership schemes. This article thus provides broadly applicable but targeted guide for the researchers collecting data and seeking to make sense of power relations on community forest partnership schemes in various contexts. This framework is particularly useful for analysing equity and justice dimensions by highlighting who benefits and who loses.•Sequential Power Analysis (SPA) methodology is rooted in interest based and historical power framework.•SPA is consisted of three parts: power background, power delivery, and power adjustment•SPA framing provides a protocol for researchers to collect data.


Thyroid cancer in black thyroid glands: the effect of age and race.
Black thyroid pigmentation is a rare entity. The risk of malignancy is higher in black thyroid compared to non-black thyroid glands. We aimed to examine the effect of age and race on the risk of malignancy in black thyroid glands. We identified a series of consecutive patients who underwent thyroidectomy at an academic institution between January 1998 and May 2013. Patient demographics, clinical characteristics, and histopathology data were reviewed. Among 925 patients who underwent thyroidectomy, 112 (12.1%) patients with black thyroid glands were identified. The incidence of thyroid cancer was 55.4% in black thyroid glands compared to 32.8% in non-black thyroid glands (p < 0.0001). The incidence of papillary thyroid cancer among the black and non-black thyroid glands was 34.8 and 20%, respectively (p < 0.001). The mean age (± SD) for patients with black thyroid glands and those with non-black thyroid was 54.3 ± 12.8 and 51.2 ± 15.7 years, respectively (p = 0.05). Black thyroid glands were also associated with a higher incidence of microcarcinomas (76 vs. 59%, p = 0.02). Among patients with black thyroid glands, Caucasians had a higher malignancy rate (63.4%) than African-Americans (37%; p = 0.03). The incidence of malignancy is higher in black thyroid compared to non-black thyroid glands, specifically in Caucasians.


Modulation of immune responses by histone deacetylase inhibitors.
Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases.


Recombinant human platelet-derived growth factor: biology and clinical applications.
The abilities of bone to remodel, fractures to repair, and bone grafts to incorporate are all fundamental reflections of the bone remodeling cycle. This process is characterized by the recruitment and differentiation of osteoblastic and osteoclastic cell populations, whose cellular activities are coordinated and regulated by an elaborate system of growth factors and cytokines. One of the crucial biological factors responsible for reparative osseous activity is platelet-derived growth factor (PDGF). The potent stimulatory effects of PDGF as a chemoattractant and mitogen for mesenchymal cells (including osteogenic cells), along with its ability to promote angiogenesis, have been demonstrated in a variety of preclinical models predicting maxillofacial, spine and appendicular skeletal, and soft-tissue applications. The biological profile of PDGF, including its ability to recruit osteoprogenitor cells, makes it particularly suited to address the skeletal defects that are seen with comorbid conditions such as osteoporosis, diabetes, and the effects of smoking. The clinical success and safety that have been demonstrated with use of recombinant human PDGF (rhPDGF) in the repair of periodontal defects have led to U.S. Food and Drug Administration (FDA) approval of rhPDGF for this indication. Ongoing pilot and pivotal trials in the United States and internationally will continue to clarify the promising role of PDGF in the treatment of challenging skeletal disorders.


Structural differences between human and rat lungs: implications for Monte Carlo modeling of aerosol deposition.
The geometrical structure of the lung is one of the main factors governing inhaled particle deposition; structural differences among different species are, therefore, of great importance for extrapolation modeling. A statistical analysis of morphometric data for the human and rat tracheobronchial tree reveals significant interspecies differences in airway branching patterns: compared to the relatively dichotomous and symmetric structure of the human lung, the rat lung displays a more monopodial airway branching pattern. Thus, for the rat lung, we recommend characterizing the properties of a given airway, i.e., its size, physiologic function, and distance from the trachea, by its diameter rather than by a theoretically assigned generation number. A Monte Carlo method is used to construct an airway geometry along each inhaled particle's path by randomly selecting airway parameters from their frequency distributions and the correlations among them. While the airway geometry is selected randomly, particle deposition in individual airways is calculated analytically. These stochastic deposition calculations allow for structural differences between the human and rat lung, and the variability of the airway system within each species.


The impact of selective amygdala, orbital frontal cortex, or hippocampal formation lesions on established social relationships in rhesus monkeys (Macaca mulatta).
Social dominance, personality ratings, and frequency, duration, and timing of social behaviors were measured pre- and postsurgically in 6 groups of rhesus monkeys (Macaca mulatta), each consisting of 1 sham-operated control and 1 monkey each with a selective amygdala, hippocampal, or orbital frontal cortex lesion. Unlike previous reports, none of the operated groups showed changes in social dominance postsurgery, although changes in other measures varied by lesion site. Although sham-operated monkeys displayed heightened avoidant, anxious, and aggressive behaviors, those with hippocampal lesions also showed increased exploration and excitability, along with reduced responses to affiliative signals. Amygdala lesions yielded several personality changes that precluded positive social interactions (increased exploration and excitability, decreased affiliation and popularity) and altered responses to threatening social signals. By contrast, monkeys with orbital frontal lesions were involved in more aggressive interactions and responded differently to both affiliative and threatening signals. Although several findings differ from earlier nonhuman primate studies, they are largely in agreement with human data and emphasize the context-specific nature of social behavior studies. Interpretation of results in relation to cognitive processes mediated by each structure is discussed.


Separation in distinct subpopulations by elutriation of liver cells following exposure of rats to N-nitrosomorpholine.
N-Nitrosomorpholine, administered with drinking water to SD rats at the daily dose of 2.4 mg/kg for 7 weeks, induces persisting changes in the hepatocytes as shown by electron microscopy and cytochemistry. In situ, the hepatocytes exhibit a heterogeneous reaction for glucose-6-phosphatase activity. Cells of large diameter, frequently deficient in this enzyme, contain a well-developed rough and/or smooth endoplasmic reticulum. Adult rat hepatocytes from control and N-nitrosomorpholine-treated rats were isolated by enzymatic perfusion. Isolated cell populations in both experimental models were composed of a few contaminating sinusoidal cells; small, intermediate, and large hepatocytes; and doublets or triplets of undissociated cells. Five distinct hepatic subpopulations were separated by elutraition or counterflow centrifugation and analyzed by morphological, morphometric, and cytophotometric methods. Fraction I is composed of small (16 to 18 micrometers) diploid hepatocytes; Fractions II and III consist of homogeneous populations of tetraploid cells (mean diameters, 20.5 and 22.4 micrometers); Fraction IV is enriched with large octoploid cells whose mean diameters reach 25.2 micrometers; and Fraction V contains large cells and cell aggregates. The counterflow centrifugation shows the higher proportion of hypertrophied and polyploid hepatocytes, obtained after carcinogen treatment, in the elutriated Fractions IV and V. The structural integrity of hepatocytes is not affected by the process of elutriation. Large hepatocytes, up to 30 micrometers in diameter, exhibit an abundant smooth endoplasmic reticulum, frequently disposed at the periphery of the cell where it forms a network of anastomosing tubules. Moreover, some of these cells present well-developed rough endoplasmic cisternae, closely associated in large fields. Under the scanning electron microscope, elutriated hepatocytes from control rats show numerous regularly distributed microvilli covering the entire cell surface, whereas hypertrophic hepatocytes from N-nitrosomorpholine-treated rats offer heterogeneous cell surfaces, characterized by the presence of patches of short, closely packed microvilli.


Cardiovascular response to closed-loop intraneural stimulation of the right vagus nerve: a proof-of-concept study.
Vagus nerve stimulation (VNS) is an FDA-approved technique for the neuromodulation of the autonomic nervous system. There are many therapeutic applications where VNS could be used as a therapy, such as cardiovascular diseases, epilepsy, depression, and inflammatory conditions. Cardiovascular applications are particularly relevant, since cardiovascular diseases are the top causes of death worldwide. VNS clinical trials have been performed in the last 15 years for the treatment of heart failure (HF), achieving controversial results. Typically VNS is applied with a cuff electrode placed around the nerve, in an open-loop or cardiac synchronized design. The effectiveness of this approach is hindered by the multifunctional nature of the VN, which is involved in a variety of homeostatic controls. When a high current is applied, adverse effects arise from the stimulation of undesired fibers. An alternative strategy is represented by intraneural stimulation, which can guarantee higher selectivity. Moreover, closed-loop modalities allow the delivery of electrical current inside the nerves only if needed, with a reduced risk of untargeted nerve activation and lower energy consumption. Here we propose a closed-loop intraneural stimulation of the right cervical VN in a clinically relevant animal model. The intraneural was designed according to the internal structure of the VN. A threshold-based closed-loop algorithm was developed using HR as a control variable to produce a chronotropic effect.Clinical Relevance-This work analyzes the closed-loop intraneural VNS for the treatment of cardiovascular disorders, and supports the possibility of developing fully implantable devices with a high degree of selectivity in stimulation and prolonged lifespan.


Genome-wide annotation and expression profiling of cell cycle regulatory genes in Chlamydomonas reinhardtii.
Eukaryotic cell cycles are driven by a set of regulators that have undergone lineage-specific gene loss, duplication, or divergence in different taxa. It is not known to what extent these genomic processes contribute to differences in cell cycle regulatory programs and cell division mechanisms among different taxonomic groups. We have undertaken a genome-wide characterization of the cell cycle genes encoded by Chlamydomonas reinhardtii, a unicellular eukaryote that is part of the green algal/land plant clade. Although Chlamydomonas cells divide by a noncanonical mechanism termed multiple fission, the cell cycle regulatory proteins from Chlamydomonas are remarkably similar to those found in higher plants and metazoans, including the proteins of the RB-E2F pathway that are absent in the fungal kingdom. Unlike in higher plants and vertebrates where cell cycle regulatory genes have undergone extensive duplication, most of the cell cycle regulators in Chlamydomonas have not. The relatively small number of cell cycle genes and growing molecular genetic toolkit position Chlamydomonas to become an important model for higher plant and metazoan cell cycles.


[Encephalopathy by hyperammonemia in teenagers].
Hyperammonemia causes several alterations, mainly in the central nervous system. If hepatic failure is not its etiology, other less frequent causes must be investigated in the search for a definitive diagnosis. We report the case of a 16 year old patient admitted for acute encephalopathy and hyperammonemia. After analysis, brain CT, ultrasound and abdominal Doppler, we began empirical treatment of hyperammonemia secondary to disorders of the urea cycle. We treated the brain edema and eliminated ammonia but we did not obtain favourable results and the patient died four days later. The complex management of hyperammonemia and the high morbidity and mortality involved require a multidisciplinary approach. Only early treatment and identification of the hyperammonemia's etiology can avoid high morbidity and mortality in these patients.


The effect of autologous activated platelet rich plasma (AA-PRP) injection on pattern hair loss: clinical and histomorphometric evaluation.
To investigate the safety and clinical efficacy of AA-PRP injections for pattern hair loss. AA-PRP, prepared from a small volume of blood, was injected on half of the selected patients' scalps with pattern hair loss. The other half was treated with placebo. Three treatments were given for each patient, with intervals of 1 month. The endpoints were hair re-growth, hair dystrophy as measured by dermoscopy, burning or itching sensation, and cell proliferation as measured by Ki-67 evaluation. At the end of the 3 cycles of treatment, the patients presented clinical improvement in the mean number of hairs, with a mean increase of 18.0 hairs in the target area, and a mean increase in total hair density of 27.7 ( number of hairs/cm(2)) compared with baseline values. Microscopic evaluation showed the increase of epidermis thickness and of the number of hair follicles two weeks after the last AA-PRP treatment compared to baseline value (P < 0.05). We also observed an increase of Ki67(+) keratinocytes of epidermis and of hair follicular bulge cells and a slight increase of small blood vessels around hair follicles in the treated skin compared to baseline (P < 0.05).


Farnesoid X receptor enhances epithelial ACE2 expression and inhibits virally induced IL-6 secretion: implications for intestinal symptoms of SARS-CoV-2.
Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The angiotensin converting enzyme 2 (ACE2) receptor plays a key role in SARS-CoV-2 pathogenesis, facilitating entry of the virus into epithelial cells, while also regulating mucosal inflammatory responses. Here, we investigated roles for the nuclear bile acid receptor farnesoid X receptor (FXR) in regulating ACE2 expression and virally mediated inflammatory responses in intestinal epithelia. Human colonic or ileal enteroids and cultured T84 and Caco-2 monolayers were treated with the FXR agonists, obeticholic acid (OCA) or GW4064, or infected with live SARS-CoV-2 (2019-nCoV/USA_WA1/2020). Changes in mRNA, protein, or secreted cytokines were measured by qPCR, Western blotting, and ELISA. Treatment of undifferentiated colonic or ileal enteroids with OCA increased ACE2 mRNA by 2.1 ± 0.4-fold (n = 3; P = 0.08) and 2.3 ± 0.2-fold (n = 3; P < 0.05), respectively. In contrast, ACE2 expression in differentiated enteroids was not significantly altered. FXR activation in cultured epithelial monolayers also upregulated ACE2 mRNA, accompanied by increases in ACE2 expression and secretion. Further experiments revealed FXR activation to inhibit IL-6 release from both Caco-2 cells infected with SARS-CoV-2 and T84 cells treated with the viral mimic, polyinosinic:polycytidylic acid, by 46 ± 12% (n = 3, P < 0.05) and 35 ± 6% (n = 8; P < 0.01), respectively. By virtue of its ability to modulate epithelial ACE2 expression and inhibit virus-mediated proinflammatory cytokine release, FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2.NEW & NOTEWORTHY Activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), specifically upregulates ACE2 expression in undifferentiated colonic epithelial cells and inhibits virus-induced proinflammatory cytokine release. By virtue of these actions FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2 infection.


Sleep quality and its correlates in patients with chronic kidney disease: a cross-sectional design.
Since sympathovagal imbalance influences clinical phenomena, such as hypertension, diabetes mellitus, chronic kidney disease (CKD) and sleeping problems, there should be correlations between these conditions. We hypothesized that sleep quality would be correlated with estimated glomerular filtration rate (eGFR), blood pressure and the presence of diabetes. We included 303 CKD patients in this study. We employed the Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI) and Short Form 36 Quality of Life Health Survey Questions (SF-36) to screen sleeping disturbances, depression and quality of life, respectively. A chart review was performed for the patients' demographics, diagnoses and certain laboratory parameters--including blood glucose, hemoglobin, albumin, calcium, phosphate, parathyroid hormone and eGFR. Multivariate logistic regression models were employed to estimate odds ratios with 95% confidence intervals. We included 303 patients in this cross-sectional study. A total of 101 patients were on dialysis. In the univariate models, gender, calcium and mental component summary scores (MCS) reached a significant level of 0.1, and those covariates were included in the multivariate analysis. The reduced models included gender and MCS categories. Female gender increases the risk for poor sleep quality. In our report, evidence suggests MCS domain scores are inversely related to the risk for impaired sleep. Our results indicated a high burden of sleep disturbances in kidney patients. In addition, female gender and having low MCS scores may influence sleep quality in kidney patients.


Diagnostic capability of Fourier-Domain optical coherence tomography in early primary open angle glaucoma.
Optical coherence tomography (OCT) is a high resolution noncontact imaging modality which can quantitatively detect the optic disc and retinal structure. This study was designed to evaluate the diagnostic capability of parameters of the optic disc, retinal nerve fiber layer thickness, and ganglion cell complex (GCC) using a new technology called Fourier-domain OCT (FD-OCT) for early primary open angle glaucoma (POAG) patients. Two groups of patients, early perimetric damage POAG and normal subjects were included in this observational cross-sectional study. All patients underwent FD-OCT and visual field examination in addition to full ophthalmic examinations. Receiver operating characteristic curves (ROC) were studied for all parameters. The sensitivity and specificity for distinguishing between normal and early glaucomatous eyes, the areas under the receiver operating characteristic curves (AROC) and positive, negative likelihood ratios were evaluated for all the single parameters and selected combined parameters using arbitrary cutoffs. Thirty-four eyes of 34 early POAG patients and 42 eyes of 42 normal subjects were analyzed. Cup/disc (C/D) vertical ratio presented the best sensitivity and positive likelihood ratio for selected specificities (95% and 85%) which were 79.4% and 88.2%, 33.4 and 7.4, respectively. Among all single parameters, the C/D vertical ratio demonstrated the highest AROC which was at 0.930. The average thickness of circumpapillary RNFL on 3.45 mm showed the highest AROC among all of the peripapillary RNFL parameters. The sensitivity at selected specificity and AROC of GCC were not as high as C/D vertical ratio and RNFL AT on 3.45 mm. When the C/D vertical ratio, RNFL AT on 3.45 mm, and rim area were combined using a logistical diagnostic model, the AROC was raised to 0.949 but not significantly different from the top single parameter, C/D vertical ratio. The key parameters obtained by FD-OCT were able to show the significant differences of optic discs, thickness of RNFL and GCC between POAG patients and normal subjects. According to sensitivity, specificity, likelihood ratio and AROC, the top three parameters from FD-OCT for early diagnosis of POAG were C/D vertical ratio, RNFL AT on 3.45 mm, and the rim area.


Differentiating biliary atresia from other causes of infantile cholestasis: An appraisal of the histomorphological changes on liver biopsy.
Cholestatic disorders are a significant cause of morbidity and mortality in infants. Characterization of these disorders and differentiating biliary atresia (BA) from other causes of intrahepatic cholestasis is an age-old problem. To study the spectrum of different infantile cholestatic disorders in our population, to differentiate BA from other causes of neonatal cholestasis (NC) on a liver biopsy, and validation of the available scoring system for the characterization of these disorders. This is an observational cross-sectional study performed over a period of 3 years between 2018 and 2021, done on neonates and infants presenting with cholestatic jaundice. The changes on liver biopsy were evaluated by different histological parameters and available scoring systems to differentiate BA from non-BA causes. Correlation with clinical, biochemical, and imaging findings was done in all cases. This study included 87 cases of NC, of which BA comprised 28 cases (32%), whereas idiopathic neonatal hepatitis (INH) comprised only 12 cases (14%). Portal neutrophilic inflammation (P = 0.000053), ductal cholestasis (P < 0.001), neoductular bile plugs (P < 0.001) and bile ductular proliferation (P < 0.0001) were significantly more in BA, whereas lobular lymphocytic inflammation (P = 0.001) and giant cell transformation of hepatocytes (P = 0.0024) were more frequent in the non-BA group. Using the Lee and Looi scoring system, a histologic score ≥7 was helpful in identifying BA with 85.7% sensitivity, 92.6% specificity, and 90.6% accuracy. BA is the commonest cause of NC in neonates, whereas the frequency of INH is declining. Detailed histomorphologic analysis of liver biopsy, aided with IHC, is the cornerstone for the diagnosis of these disorders.


Detection of subtle gait disturbance and future fall risk in early multiple sclerosis.
To test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS). Persons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall data. Patients performed worse on higher challenge balance, but not gait, tasks compared with healthy controls. Worse patient-reported gait disturbance was associated with worse performance on all tasks, but only dynamic balance was sensitive to mild patient-reported gait difficulty. Balance tasks were more correlated with MRI metrics than were walking tasks or EDSS score. Thirty percent of patients reported either a fall or near fall after 1 year, with poor dynamic balance as the only task independently predicting falls. Balance plays a leading role in gait dysfunction early in MS. Clinically feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers, and risk of future falls, highlighting potential to advance functional outcomes in clinical practice and trials.


Dietary Magnesium Intake Affects the Vitamin D Effects on HOMA-β and Risk of Pancreatic β-Cell Dysfunction: A Cross-Sectional Study.
Some studies have shown that, the circulating vitamin D (Vit D) concentration in the body exerts a crucial role in regulating the pancreatic β-cell function. Meanwhile, the role of magnesium is important in the synthesis of Vit D, since it is an essential element for activating Vit D. Nevertheless, there remains insufficient studies concerning whether dietary Magnesium intake influences the association between Vit D and risk of pancreatic β-cell dysfunction. Hence, this cross-sectional study aimed to assess the effect of Magnesium intake alterations on the association between serum Vit D levels and the risk of pancreatic β-cell dysfunction. This large-scale cross-sectional study involves four cycles of National Health and Nutrition Examination Survey (NHANES) (2007-2014), with totally 4,878 participants. Groups were divided depending on the median daily intake of Magnesium, namely, the low intake group (Magnesium intake <267 Magnesium/d) and the high intake group (Magnesium intake ≥ 267 Magnesium/d). By constructing multiple multivariate linear and logistics regression models, the associations between serum Vit D levels and HOMA-β, as well as between serum Vit D levels and the risk of pancreatic β-cell dysfunction were explored at different Magnesium intakes. In this cross-sectional study, the serum Vit D level is independently correlated with the HOMA-β index [β: 0.65 (0.40-0.90)] and the risk of pancreatic β-cell dysfunction [OR: 0.95 (0.92-0.98)]. Moreover, such correlations are affected by different dietary Magnesium intakes (P for interaction < 0.001). According to the results of this study, the dietary Magnesium intake influences the associations of serum Vit D levels with HOMA-β index and pancreatic β-cell dysfunction. Besides, the finding requires validation through more RCT or cohort studies.


Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy.
Pathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants. Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy. A homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here. This report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.


Glucagon-like peptide 2: a nutrient-responsive gut growth factor.
Glucagon-like peptide 2 (GLP-2) is a 33-amino acid peptide derived from the tissue-specific, post-translational processing of the proglucagon gene expressed in the intestinal enteroendocrine L-cell. The primary stimulus for GLP-2 secretion is nutrient intake, and involves direct luminal stimulation of the L-cell as well as indirect enteroendocrine and neural mechanisms. The biological activity of GLP-2 in circulation is regulated by the proteolytic cleavage of the N-terminus by dipeptidylpeptidase IV. Several studies have shown that GLP-2 has specific trophic effects on the small and large intestine, which are mediated by stimulation of cell proliferation and inhibition of apoptosis and proteolysis. GLP-2 also has been shown to suppress gastric motility and acid secretion, increase hexose transport activity and suppress food intake, specifically when infused centrally. The actions of GLP-2 are mediated by a G-protein-linked, membrane receptor (GLP-2R) that is localized largely to the gastrointestinal tract, but also is found in the brain. The secretion of GLP-2 and expression of the GLP-2R are present in the late gestation fetus. However, the developing intestine does not become responsive to the trophic effect of GLP-2 until after birth. Based on its efficacy in preventing atrophy and stimulating growth in the neonatal gut, GLP-2 may be a promising therapeutic adjuvant for treatment of infants with compromised gut function.


Atypical Film-Forming Behavior of Soluble Tetra-3-Nitro-Substituted Copper Phthalocyanine.
Thin films of metal phthalocyanines (MPc) are known to exhibit excellent physical properties but poorly controlled morphologies. Therefore, the present work seeks to understand the film growth mechanism of a model compound for potentially usable MPc, specifically, copper tetra(3-nitro-5-tert-butyl)phthalocyanine (CuPc*). The Langmuir-Schaefer (LS) technique was applied to prepare a series of CuPc* films under different processing conditions. The film growth was examined by Brewster angle microscopy (BAM) on the water surface and small-angle X-ray scattering (SAXS) from the solid films. Neutron reflectometry (NR) measurements of the water uptake into the films and computer simulation of hydrated CuPc* were performed to substantiate an idea of colloidal MPc-water aggregates as nanoscale precursors of smooth solid films. This idea appears fruitful in terms of materials chemistry.


Activity Dependent and Independent Determinants of Synaptic Size Diversity.
The extraordinary diversity of excitatory synapse sizes is commonly attributed to activity-dependent processes that drive synaptic growth and diminution. Recent studies also point to activity-independent size fluctuations, possibly driven by innate synaptic molecule dynamics, as important generators of size diversity. To examine the contributions of activity-dependent and independent processes to excitatory synapse size diversity, we studied glutamatergic synapse size dynamics and diversification in cultured rat cortical neurons (both sexes), silenced from plating. We found that in networks with no history of activity whatsoever, synaptic size diversity was no less extensive than that observed in spontaneously active networks. Synapses in silenced networks were larger, size distributions were broader, yet these were rightward-skewed and similar in shape when scaled by mean synaptic size. Silencing reduced the magnitude of size fluctuations and weakened constraints on size distributions, yet these were sufficient to explain synaptic size diversity in silenced networks. Model-based exploration followed by experimental testing indicated that silencing-associated changes in innate molecular dynamics and fluctuation characteristics might negatively impact synaptic persistence, resulting in reduced synaptic numbers. This, in turn, would increase synaptic molecule availability, promote synaptic enlargement, and ultimately alter fluctuation characteristics. These findings suggest that activity-independent size fluctuations are sufficient to fully diversify glutamatergic synaptic sizes, with activity-dependent processes primarily setting the scale rather than the shape of size distributions. Moreover, they point to reciprocal relationships between synaptic size fluctuations, size distributions, and synaptic numbers mediated by the innate dynamics of synaptic molecules as they move in, out, and between synapses.SIGNIFICANCE STATEMENT Sizes of glutamatergic synapses vary tremendously, even when formed on the same neuron. This diversity is commonly thought to reflect the outcome of activity-dependent forms of synaptic plasticity, yet activity-independent processes might also play some part. Here we show that in neurons with no history of activity whatsoever, synaptic sizes are no less diverse. We show that this diversity is the product of activity-independent size fluctuations, which are sufficient to generate a full repertoire of synaptic sizes at correct proportions. By combining modeling and experimentation we expose reciprocal relationships between size fluctuations, synaptic sizes and synaptic counts, and show how these phenomena might be connected through the dynamics of synaptic molecules as they move in, out, and between synapses.