Deletion of 3p25.3 in a patient with intellectual disability and dysmorphic features with further definition of a critical region.
Several recent reports of interstitial deletions at the terminal end of the short arm of chromosome 3 have helped to define the critical region whose deletion causes 3p deletion syndrome. We report on an 11-year-old girl with intellectual disability, obsessive-compulsive tendencies, hypotonia, and dysmorphic facial features in whom a 684 kb interstitial 3p25.3 deletion was characterized using array-CGH. This deletion overlaps with interstitial 3p25 deletions reported in three recent case reports. These deletions share a 124 kb overlap region including only three RefSeq annotated genes, THUMPD3, SETD5, and LOC440944. The current patient had phenotypic similarities, including intellectual disability, hypotonia, depressed nasal bridge, and long philtrum, with previously reported patients, while she did not have the cardiac defects, seizures ormicrocephaly reported in patients with larger deletions. Therefore, this patient furthers our knowledge of the consequences of 3p deletions, while suggesting genotype-phenotype correlations.


Assessment of idiopathic inflammatory myopathy using a deep learning method for muscle T2 mapping segmentation.
To investigate the utility of an automatic deep learning (DL) method for segmentation of T2 maps in patients with idiopathic inflammatory myopathy (IIM) against healthy controls, and also the association of quantitative T2 values in patients with laboratory and pulmonary findings. Structural MRI and T2 mapping of bilateral thigh muscles from patients with IIM and healthy volunteers were segmented using dedicated software based on a pre-trained convolutional neural network. Incremental and federated learning were implemented for continuous adaptation and improvement. Muscle T2 values derived from DL segmentation were compared between patients and healthy controls, and T2 values of patients were further analyzed with serum muscle enzymes, and interstitial lung disease (ILD) which was diagnosed and graded based on chest HRCT. Overall, 64 patients (27 patients with dermatomyositis, 29 with polymyositis, and 8 with antisynthetase syndrome (ASS)) and 10 healthy controls were included. By using DL-based muscle segmentation, T2 values generated from T2 maps accurately differentiated patients from those of controls (p < 0.001) with a cutoff value of 36.4 ms (sensitivity 96.9%, and specificity 100%). In patients with IIM, muscle T2 values positively correlated with all the serum muscle enzymes (all p < 0.05). ILD score of patients with ASS was markedly higher than that of those without ASS (p = 0.011), while dissociation between the severity of muscular involvement and ILD was observed (p = 0.080). Automatic DL could be used to segment thigh muscles and help quantitatively assess muscular inflammation of IIM through T2 mapping. • Muscle T2 mapping automatically segmented by deep learning can differentiate IIM from healthy controls. • T2 value, an indicator of active muscle inflammation, positively correlates with serum muscle enzymes. • T2 mapping can detect muscle disease in patients with normal muscle enzyme levels.


The Neurobiology of Mammalian Navigation.
Mammals have evolved specialized brain systems to support efficient navigation within diverse habitats and over varied distances, but while navigational strategies and sensory mechanisms vary across species, core spatial components appear to be widely shared. This review presents common elements found in mammalian spatial mapping systems, focusing on the cells in the hippocampal formation representing orientational and locational spatial information, and 'core' mammalian hippocampal circuitry. Mammalian spatial mapping systems make use of both allothetic cues (space-defining cues in the external environment) and idiothetic cues (cues derived from self-motion). As examples of each cue type, we discuss: environmental boundaries, which control both orientational and locational neuronal activity and behaviour; and 'path integration', a process that allows the estimation of linear translation from velocity signals, thought to depend upon grid cells in the entorhinal cortex. Building cognitive maps entails sampling environments: we consider how the mapping system controls exploration to acquire spatial information, and how exploratory strategies may integrate idiothetic with allothetic information. We discuss how 'replay' may act to consolidate spatial maps, and simulate trajectories to aid navigational planning. Finally, we discuss grid cell models of vector navigation.


Opportunities to Improve Tobacco Control for State Agency Employees.
The aim of the study is to explore tobacco-related knowledge and perceptions at Washington State (WA) agencies. The study used a cross-sectional employee survey and qualitative focus groups with managers/supervisors. We produced descriptive statistics to examine differences in awareness and perceptions of tobacco-control efforts among employees and conducted a rapid thematic analysis of focus group data. Of employees, only 18% with a history of tobacco use had used their agency's cessation benefits. Employees who did not use tobacco and who had higher education had more favorable attitudes toward tobacco-control efforts. In the focus groups, manager/supervisors described limited tobacco cessation promotion at their agency, barriers to tobacco control implementation, and concerns about the perceived effectiveness of additional tobacco-control efforts. State agencies should increase promotion of tobacco control policies and programs to increase awareness and reduce disparities in tobacco use.


Successfully treated lingual tonsillar metastasis from bronchial adenocarcinoma.
Tonsillar metastasis from neoplasms, including lung cancer, are extremely rare, and the prognosis for patients with tonsillar metastases is rather poor. We herein describe a case of long-term survival following radiation for lingual tonsillar metastasis from a bronchial adenocarcinoma. A 39-year-old male was diagnosed with adenocarcinoma of the right lung and was surgically treated. Four months after surgery, a mass arising from the lingual tonsil was noted at the root of the tongue and was pathologically diagnosed as metastasis from lung cancer. In addition, a computed tomography scan revealed a jugular lymphadenopathy, which was considered to be a metastasis from the tonsillar tumor. The tonsillar mass and jugular lymphadenopathy disappeared after external radiotherapy (50 Gy). The patient is alive without recurrence more than 8 years after treatment for tonsillar metastasis. This is the first report of successfully treated tonsillar metastasis from a malignant tumor.


The transport and metabolism of alanine by Giardia intestinalis.
The transport and metabolism of L-alanine by Giardia intestinalis trophozoites was characterised. G. intestinalis formed 14CO2 from L-[1-14C]alanine (1 mM) at a rate of 4.8 nmol min-1 (mg protein)-1 at 30 degrees C. The system was saturable, with an apparent Km of 0.29 mM for alanine, and a maximal rate of 6.1 nmol min-1 (mg protein)-1. L-cycloserine inhibited the metabolism, as did a number of amino acids including glycine, serine and threonine. D-alanine and 2-aminoisobutyrate had no effect. G. intestinalis was shown to have a functional transport system for L-alanine. The transporter was saturable with a Km of 1.5 mM and a maximal velocity of 6.1 nmol min-1 (mg protein)-1 at 23 degrees C. It was temperature dependent, with a Q10 of 2.2 and activation energy of 15.9 kcal mol-1. It was not inhibited by potential inhibitors of energy dependent transport. Glycine, L-serine and L-threonine potently inhibited L-alanine transport, whereas D-alanine, beta-alanine and 2-aminoisobutyrate had no effect. L-serine competitively inhibited L-alanine influx. In trophozoites preloaded with [3H]alanine, rapid exchange occurred with external L-alanine and L-serine, but not with D-alanine confirming that L-alanine and L-serine share a common transport site. These observations indicate that G. intestinalis has a functional alanine transporter, which may be an antiport catalysing the exchange of alanine, serine, glycine and threonine.


The long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy combined with radical cystectomy versus radical cystectomy alone for bladder cancer: a propensity-score matching study.
Bladder cancer is a complex disease associated with high morbidity and mortality. Management of bladder cancer before radical cystectomy continues to be controversial. We compared the long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy (IAC) versus no IAC (NIAC) before radical cystectomy (RC) for bladder cancer. We performed a retrospective review of patients who underwent either one-shot IAC or NIAC before RC between October 2006 and November 2015. A propensity-score matching (1:3) was performed based on key characters. The Kaplan-Meier method was utilized to estimate survival probabilities, and the log-rank test was used to compare survival outcomes between different groups. A multivariable Cox proportional hazard model was used to estimate survival outcomes. Twenty-six patients were treated using IAC before RC, and 123 NIAC patients also underwent RC. After matching, there was no significant difference between groups in baseline characteristics, perioperative variables, complication outcomes or tumor characteristics. Compared with clinical tumor stages, pathological tumor stages demonstrated a significant decrease (P = 0.002) in the IAC group. There was no significant difference in overall survival (OS, p = 0.354) or cancer-specific survival (CSS, p = 0.439) between the groups. Among all patients, BMI significantly affected OS (p = 0.004), and positive lymph nodes (PLN) significantly affected both OS (p<0.001) and CSS (p = 0.010). One-shot neoadjuvant IAC before RC shows safety and tolerability and provides a significant advantage in pathological downstaging but not in OS or CSS. Further study of neoadjuvant combination therapeutic strategies with RC is needed.


A novel 3D printed bioactive scaffolds with enhanced osteogenic inspired by ancient Chinese medicine HYSA for bone repair.
Some traditional Chinese medicine (TCM) has been applied in bone repair, however, hydroxy-safflower yellow A (HYSA), one composition of safflower of the typical invigorating the circulation of TCM, has little been studied in orthopedics field for osteogenesis and angiogenesis clinically. Herein, we hypothetically speculated that the synthetic bioactive glasses (BG, 1393) scaffolds carried HYSA by a 3D print technique could enhance osteogenic repair properties. Notably, scaffolds coating chitosan/sodium alginate endowed with excellent drug control release ability, and significantly improved the BG mechanical strength. HYSA was loaded into BG scaffolds by coating chitosan/sodium alginate film, and the osteogenesis and angiogenesis of the HYSA/scaffolds were evaluated in vitro and in vivo. In vitro the cell culture results exhibited that the high dose of HYSA (0.5 mg/ml) loaded scaffolds can promote the proliferation of bone marrow stromal cells (rBMSCs) and migration, tubule formation of human umbilical vein endothelial cells (HUVECs). The active alkaline phosphatase (ALP) of rBMSCs can also be improved by the high dose of HYSA/scaffolds. Results of qRT-PCR and Western blot indicated that the high dose of HYSA/scaffolds can up-regulate ALP, OCN, OPN and RUNX-2 expression and relative protein secretion of the HIF-1α and BMP-2. In the animal experiment, the high dose of HYSA/scaffolds has a significantly better capacity to promote new bone formation than the undoped scaffolds at 8 weeks post-surgery. Thus, our results claimed that the novel HYSA/scaffolds hold the substantial potential to be further developed as effective and safe bone tissue engineering biomaterials for bone regeneration by combining enhanced osteogenesis and angiogenesis.


The effectiveness of a health education intervention to reduce anxiety in quarantined COVID-19 patients: a randomized controlled trial.
The COVID-19 pandemic is regarded as a serious public health concern that boosts levels of stress and anxiety which could be explained by several reasons, including social isolation. In this regard, we aimed to assess the impact of health education on the anxiety level of COVID-19 patients during the isolation period. This is a randomized controlled trial conducted between February 2021 and June 2021. Patients tested positive for Covid-19 with mild to moderate forms were randomized to Education (n = 267) or control (n = 269). The education group received a phone health education session on day 1 (D1) following the diagnosis. The three components of the health education intervention were an explanation of the coronavirus disease, what to do in the event of complications, and the recommended preventive measures. The two groups received a telephone evaluation of their Hospital Anxiety and Depression scores on D1 and day seven D7 following the positive diagnosis. The primary outcome was the rate of anxiety reduction in each group on D7 based on a HAD-A score ≥ 8. Secondary outcomes were the rate of anxiety reduction on D7 based on a HAD-A score ≥ 11, the percentage of people complying with isolation and the scores of adherences to preventive measures during the isolation in each group. Hundred and ninety-six patients in the intervention group and 206 patients in the control group completed the study. The sociodemographic, clinical, and initial anxiety level features of the intervention and control groups were comparable at baseline (p ≥ 0.05). On D7, the education group's anxiety level (HAD-A ≥ 8) decreased from 26 to 16.3% (p = 0.013) while in the control group it increased from 19.4 to 22.8% (p = 0.37). Thus, the percentage change in anxiety between D1 and D7 (delta D7 - D1) was - 9.7% in the Education group and + 3.4% in the Control group. Using the HAD-A ≥ 11 thresholds, the percentage of anxiety decreased from 15.3 to 11.2% (p = 0.26) between D1 and D7, while it increased in the control group from 9.7 to 15.7% (p = 0.045). Thus, the education group's change in anxiety (delta D7 - D1) was - 4.1%, while the control group's change was + 6%. During an outbreak, providing health education to quarantined patients may be beneficial to reduce the psychological impact of the disease. ClinicalTrials.gov Identifier: NCT05715593, retrospectively registered on 8/02/2023 https://clinicaltrials.gov/ct2/results?term=NCT05715593&Search=Search .


Disproportionate effect on child admissions of the change in Medicines and Healthcare Products Regulatory Agency guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland.
The aim of the present study was to assess the effects of the changes in the management of paracetamol overdose recommended by the UK Commission for Human Medicines on rates of hospital admission. An interrupted time series analysis was carried out on data for hospital admissions for paracetamol poisoning for England between January 2010 and June 2014, and for Scotland between January 2010 and Sept. 2014. The main outcome measure was admissions to hospital with paracetamol poisoning (T39.1), as defined by first position coding in children and adults. The time series analysis (Jan 2010 to June 2014) showed that admission rates for paracetamol poisoning were steady from 2010 to the date of change (September 2012), with an estimated 269 [95% confidence interval (CI) 252.5, 285.5] child (0-14 years) and 3541 (95% CI 3454, 3628) adult admissions per month. In September 2013, 12 months after the change, there were an estimated additional 116 [37.3% (95% CI 17.2-67.4)] child and 426 [12.5% (95% CI 4.5-19.6)] adult admissions. Thus, in the year before the change (September 2011 to August 2012) there were 45,181 (3500 child and 41,681 adult) admissions, and in the year after (September 2012 to August 2013) there were 50,198 (4779 child and 45,419 adult) admissions. The overall proportion of child admissions was significantly greater after the change (Chi-square 32.486, P < 0.001), emphasizing the disproportionate effect in children. Changes to the management guidelines for paracetamol poisoning in September 2012 were rapidly implemented but have particularly increased paediatric hospital admissions for paracetamol poisoning. This impact in children, who are at low risk of mortality from paracetamol toxicity, appears excessive.


UV-mediated thiol-ene click reactions for the synthesis of drug-loadable and degradable gels based on copoly(2-oxazoline)s.
An 80-membered library of gels composed of monofunctional 2-ethyl-2-oxazoline and 2-nonyl-2-oxazoline and one of four selected difunctional 2-oxazolines (containing either ether or ester bonds) were synthesized by microwave-assisted ring-opening polymerizations. The difunctional 2-oxazolines were prepared from the thiol-ene reaction of glycol dimercaptoacetate or 2,2'-(ethylenedioxy)diethanethiol and 2-but-3'-enyl-2-oxazoline or 2-dec-9'-enyl-2-oxazoline. 53 of the gels exhibited glass-transition temperatures, which ranged from -5.9 to 45.3 °C. 13 Derivatives exhibited glass-transition temperatures in the range from 20 to 30 °C, which renders them stiff at room temperature and flexible at body temperature. The gels that did not contain any 2-ethyl-2-oxazoline acted as lipogels, whereas the gels that did not contain any 2-nonyl-2-oxazoline acted as hydrogels; all other gels may be classified as amphigels. The swelling degrees were measured by gravimetry and maximum swelling degrees of 6 (in water) were observed for the gels with the lowest degrees of crosslinking. In a second approach, the synthesis of crosslinked networks had been achieved by performing the polymeranalogous thiol-ene reaction of copoly(2-oxazoline)s containing olefinic side-chains and glycol dimercaptoacetate. This soft strategy enabled the straightforward loading of such gels with active pharmaceutical ingredients without altering them. This method delivered gels with selected composition exhibiting a targeted disc-shape and loaded with active pharmaceutical ingredients from one-step syntheses. The maximum swelling degrees of these specimens were found to be in accordance with the ones from the first route investigated. Preliminary degradation studies were performed at 25 °C; these types of gels were found to be degraded in alkaline media as well as by esterases.


A CT study of the femoral and sciatic nerve periacetabular moving in different hip positions.
Femoral and sciatic nerves could be damaged during various stages of the periacetabular osteotomy. Changing the position of the hip could be the most effective way of preventing nerve injuries. The purpose of the present study was to investigate the distances of the nerves to various bony landmarks with different hip positions in computerized pelvic scanograms of healthy adults. Fifteen healthy male adults (30 hips) (age 30 ± 6) were included. Scans were performed at three different hip positions measured by goniometer (neutral "N," flexion (30-45°) + abduction (30-45°) + external rotation (20°) "F" and neutral+ abduction (30-45°) + external rotation (20°) (Nabext) at three different levels (sourcil "1," the middle of the femoral head "2," and lower border of triradiate cartilage "3." At the sourcil level, the femoral nerve was found to be the furthest distance from the anterior acetabulum in the neutral position compared to flexion or neutral plus abduction, external rotation (p < 0.001). For the sciatic nerve, at level 2, hip flexion resulted in a greater distance than in the neutral position (p = 0.001). For level 3, hip flexion caused a decrease in the distance of the sciatic nerve to the acetabulum compared to both neutral positions (N or Nabex) (p = 0.001). During a pubic cut of the osteotomy, the femoral nerve moves closer to the anterior acetabulum wall with hip flexion or abduction plus external rotation. During an ischial cut, the sciatic nerve gets closer to the ischium with hip flexion while it moves away from the bone during retroacetabular cut. Level-III Study.


Unhydrolyzed and hydrolyzed konjac glucomannans modulated cecal and fecal microflora in Balb/c mice.
The prebiotic role of intact konjac glucomannan (KGM) is contradictory. Short-chain glucomannan may cause a greater or faster effect on colonic microflora compared with KGM. Therefore, time-course and dose-dependent studies were conducted to examine and compare effects of unhydrolyzed KGM with those of acid-hydrolyzed glucomannan (KH) on cecal and fecal microflora. Short-chain fatty acid concentrations in cecal content were also determined. Seven-week-old male Balb/c mice were fed 5% (w/w) cellulose and KGM or KH diets for 2 or 4 wk in a time-course study. Cecal total anaerobes, bifidobacteria, Clostridium perfringens and Escherichia coli counts, and short-chain fatty acid concentrations were determined. In a subsequent dose-dependent study, Balb/c mice were fed AIN-93 fiber-free diets supplemented with 2.5%, 5%, or 7.5% of KGM or KH for 4 wk. Anaerobes, bifidobacteria, C. perfringens, and E. coli were enumerated in the cecal content and feces. KGM and KH significantly increased cecal anaerobes and bifidobacteria counts at weeks 2 and 4, respectively, compared with cellulose. In contrast, KGM and KH significantly decreased cecal C. perfringens counts only at week 4. Acetate and propionate concentrations in cecal contents were increased by KGM and KH diets at weeks 2 and 4, respectively. In the dose-dependent study, KH increased cecal bifidobacteria counts only at the 2.5% level but increased fecal bifidobacteria count and suppressed C. perfringens counts at each dose level as compared with KGM. Hydrolyzed glucomannan exerts a greater prebiotic effect than does KGM in Balb/c mice.


Costs of Laparoscopic cholecystectomy. Analysis of potential savings.
Despite the growing acceptance of laparoscopic cholecystectomy the costs remain unclear. Therefore, a detailed cost analysis was performed to determine potential savings. As part of a continuing audit, data of 508 consecutive laparoscopic cholecystectomies have been prospectively collected. Pre-, intra-, and postoperative variables were assessed by standardized questionnaires. These data were used to estimate the average use of diagnostics, drug consumption, operation time, and hospital stay. In addition, costs for loss in income, "hotel services", diagnostic procedures, and for the operation itself were calculated in detail. The total costs for a standard laparoscopic cholecystectomy were 3,395 deutsche marks (DM). The costs for the operation itself represented 19%, "hotel services" and medical treatment except the operation such as nursing, visits, or diagnostic procedures represented 47%, and the loss of income another 33% of the total costs. Thus, most effective savings may be achieved by shortening the hospital stay and the time of inability to work. However, each additional 30 min of operating time costed 146 DM (4.88 DM/min) and an "ideal" operation performed within 40 mins and with a 3-day hospital stay would save 20% of the total and 31% of the hospital costs. An increase in the number of operations per year would not have a relevant impact on the cost. Disposable instruments would have increased the costs by 1,118 DM (33%). The costs for cleaning, packing, and disposal were only marginal. Reusable instruments were not related to any disadvantage either to the patients or to the staff.(ABSTRACT TRUNCATED AT 250 WORDS)


Corrigendum: The heart of silk road "Xinjiang", its genetic portray, and forensic parameters inferred from autosomal STRs.
[This corrects the article DOI: 10.3389/fgene.2021.760760.].


Conjugation of amino-bioactive glasses with 5-aminofluorescein as probe molecule for the development of pH sensitive stimuli-responsive biomaterials.
Bioceramics, such as silica-based glasses, are widely used in bone and teeth restoration. Nowadays, the association between nanotechnology and pharmacology is one of the most promising research fields in cancer therapy. The advanced processing methods and new chemical strategies allow the incorporation of drugs within them or on their functionalized surfaces. Bioceramics can act as local drug delivery systems to treat bone and teeth diseases. The present paper reports data related to the development of a pH-stimuli responsive bioactive glass. The glass conjugation with 5-aminofluorescein (5-AF), through a pH-sensitive organic spacer, allows to produce a pH-responsive bioactive biomaterial: when it is exposed to specific pH changes, it can favour the release of 5-AF directly at the target site. 5-AF has been chosen as a simple, low cost, non toxic model to simulate doxorubicin, an anticancer drug. As doxorubicin, 5-AF contains an amino group in its structure in order to form an amide bond with the carboxylic functionalities of the glass. Raman spectroscopy and thermal analysis confirm the glass conjugation of 5-AF by means of an amide bond; the amount of 5-AF loaded was very high (≈ 65 and 44 wt%). The release tests at two different pH (4.2 and 7.4) show that the amount of released 5-AF is higher at acid pH with respect to physiological one. This preliminary datum evidenced that a pH-sensitive drug delivery system has been developed. The low amount of 5-AF released (<1 wt% of the total 5-AF) is due to the very low solubility of 5-AF in aqueous medium. This disadvantage, may be overcome in a dynamic environment (physiological conditions), where it is possible to obtain a drug release system ensuring an effective therapeutic dose for long times and, at the same time, avoiding the drug toxicity.


Polyclonal origin and hair induction ability of dermal papillae in neonatal and adult mouse back skin.
Hair follicle development and growth are regulated by Wnt signalling and depend on interactions between epidermal cells and a population of fibroblasts at the base of the follicle, known as the dermal papilla (DP). DP cells have a distinct gene expression signature from non-DP dermal fibroblasts. However, their origins are largely unknown. By generating chimeric mice and performing skin reconstitution assays we show that, irrespective of whether DP form during development, are induced by epidermal Wnt activation in adult skin or assemble from disaggregated cells, they are polyclonal in origin. While fibroblast proliferation is necessary for hair follicle formation in skin reconstitution assays, mitotically inhibited cells readily contribute to DP. Although new hair follicles do not usually develop in adult skin, adult dermal fibroblasts are competent to contribute to DP during hair follicle neogenesis, irrespective of whether they originate from skin in the resting or growth phase of the hair cycle or skin with β-catenin-induced ectopic follicles. We propose that during skin reconstitution fibroblasts may be induced to become DP cells by interactions with hair follicle epidermal cells, rather than being derived from a distinct subpopulation of cells.


Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells.
Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or secreted cytokines (tumor necrosis factor [TNF]-alpha) to induce target cell death. Fas belongs to the TNF receptor family of molecules, containing a conserved intracytoplasmic "death domain" that indirectly activates the caspase enzymatic cascade and ultimately apoptotic mechanisms in numerous cell types. Two additional members of this family, DR4 and DR5, transduce apoptotic signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL) that, like FasL, belongs to the growing TNF family of molecules. Here, we report that TRAIL produced or expressed by different populations of primary human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During differentiation NK cells, sequentially and differentially, use distinct members of the TNF family or granule exocytosis to mediate target cell death. Phenotypically immature CD161(+)/CD56(-) NK cells mediate TRAIL-dependent but not FasL- or granule release-dependent cytotoxicity, whereas mature CD56(+) NK cells mediate the latter two.


A computational approach for investigating Coulomb interaction using Wigner-Poisson coupling.
Entangled quantum particles, in which operating on one particle instantaneously influences the state of the entangled particle, are attractive options for carrying quantum information at the nanoscale. However, fully-describing entanglement in traditional time-dependent quantum transport simulation approaches requires significant computational effort, bordering on being prohibitive. Considering electrons, one approach to analyzing their entanglement is through modeling the Coulomb interaction via the Wigner formalism. In this work, we reduce the computational complexity of the time evolution of two interacting electrons by resorting to reasonable approximations. In particular, we replace the Wigner potential of the electron-electron interaction by a local electrostatic field, which is introduced through the spectral decomposition of the potential. It is demonstrated that for some particular configurations of an electron-electron system, the introduced approximations are feasible. Purity, identified as the maximal coherence for a quantum state, is also analyzed and its corresponding analysis demonstrates that the entanglement due to the Coulomb interaction is well accounted for by the introduced local approximation.


Expression of human oviductin in an immortalized human oviductal cell line.
To determine whether OE-E6/E7, an immortalized human oviductal epithelial cell line, expresses oviductin messenger RNA (mRNA) and its translated protein. Transmission electron microscopy was employed to characterize the morphology of OE-E6/E7 cells followed by reverse-transcription polymerase chain reaction (PCR) analysis of oviductin mRNA and sequencing of the nested-PCR product. Confocal microscopy was used, using a polyclonal antibody against human oviductin and Con A as a marker for mannose residues, to reveal the colocalization of human oviduct-specific glycoprotein with the endoplasmic reticulum and Golgi compartments. University-based anatomy and cell biology department. Women undergoing laparoscopy for tubal ligation or hysterectomy due to uterine fibroma. An immortalized OE-E6/E7 cell line was previously established using human oviductal epithelial cells. Electron microscopy, RT-PCR, sequencing, immunohistochemistry and confocal microscopy were performed. The presence of human oviductin mRNA and protein in OE-E6/E7 cells. OE-E6/E7 cells retain morphological features characteristic of secretory cells and express human oviductin mRNA and its translated protein. OE-E6/E7 cells were characterized for the first time by electron microscopy and shown to exhibit histological features typical of secretory cells. Reverse-transcription PCR with sequencing and confocal microscopy showed, respectively, that human oviductin mRNA and protein are expressed in OE-E6/E7 cells. Our results suggest that OE-E6/E7 could be a useful tool for future studies of the function of human oviductin.


Bisphosphonate-related osteonecrosis of the jaw: diagnosis, prevention, and management.
Bisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.


Osteoconductive composite graft based on bacterial synthesized hydroxyapatite nanoparticles doped with different ions: From synthesis to in vivo studies.
To repair damaged bone tissues, osteoconductive bone graft substitutes are required for enhancement of the regenerative potential of osteoblast cells. Nanostructured hydroxyapatite is a bioactive ceramic used for bone tissue engineering purposes. In this study, carbonate hydroxyapatite (cHA) and zinc-magnesium substituted hydroxyapatite (Zn-Mg-HA) nanoparticles were synthesized via biomineralization method using Enterobacter aerogenes. The structural phase composition and the morphology of the samples were analyzed using appropriate powder characterization methods. Next, a composite graft was fabricated by using polyvinyl alcohol and both cHA and Zn-Mg-HA samples. In vivo osteogenic potential of the graft was then investigated in a rabbit tibial osteotomy model. Histological, radiological and morphological studies showed that the graft was mineralized by the newly formed bone tissue without signs of inflammation or infection after 4 weeks of implantation. These histomorphometric results suggest that the fabricated graft can function as a potent osteoconductive bone tissue substitute.


Hypoxia-induced Circular RNA hsa_circ_0006508 Promotes the Warburg Effect in Colorectal Cancer Cells
The hypoxia-induced Warburg effect promotes colorectal cancer malignancy with altered circular RNA (circRNA) expression. To investigate the association with the Warburg effect in colorectal cancer and whether has_circ_0006508 can be induced by hypoxia. In vitro cell lines and human-sample study. The biological functions of circ_0006508 and miR-1272 in the viability, colony formation, and glycolysis under hypoxic conditions were determined by loss-of-function and gain-of-function experiments. The chromatin immunoprecipitation assay was used to demonstrate the direct binding between circ_0006508 promoters and hypoxia-inducible factor 1α (HIF-1α). Transcription activity was subjected to the Luciferase reporter assay. The correlation of circ_0006508 and miR-1272 with overall survival was determined with the Kaplan-Meier analysis. Upregulated circ_0006508 and downregulated miR-1272 were observed in colorectal cancer samples, which was associated with the TNM stage and overall survival. Functional assays demonstrated that the hypoxia-induced upregulated circ_0006508 and downregulated miR-1272 promoted the viability and Warburg effect of colorectal cancer in vitro. Mechanistically, HIF-1α-induced circ_0006508 could directly sponge miR-1272, which played a suppressive role in glycolysis. Circ_0006508-mediated miR-1272 inhibition could promote the malignant behaviors of colorectal cancer with an upregulated Warburg effect.


The effect of varying alveolar carbon dioxide levels on free recall.
A recent study suggested that students who have increased minute ventilation receive poorer grades. The present study was interested in determining the role alveolar carbon dioxide (CO2) levels play with cognitive abilities. A free recall task was used to examine list learning under two conditions of alveolar CO2 level: normal and decreased. The results suggested that decreased alveolar CO2 level affect the participant's ability to rehearse and recall information. It was concluded that conditions that reduce alveolar CO2 levels, such as hyperventilation resulting from stress, nervousness, or inappropriate breathing habits, can lead to poorer learning. If these conditions produce a habitual breathing pattern, the academic performance of the individual may suffer.


Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist.
Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.


Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.
Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.


A biochemical basis for the radiosensitizing and cytotoxic effects of chlorpromazine hydrochloride in vitro and in vivo.
There have been many investigations on the radiosensitizing and cytotoxic effects of chlorpromazine, both in vitro and in vivo. We have extended the studies to include the chemotherapeutic effect of chlorpromazine on lymphosarcoma and on a mammary adenocarcinoma arising spontaneously in breeding female CBA mice. Chlorpromazine was ineffective in the former tumor but enhanced the longevity of tumor-bearing mice in the latter case. The drug was also observed to potentiate the hyperthermic killing of L5178Y cells and inhibit cellular oxygen utilization by cultured mammalian cells. The possible mechanisms involved are discussed.


PEGylated starch acetate nanoparticles and its potential use for oral insulin delivery.
A novel controlled release formulation has been developed with PEGylated starch acetate nanoparticles. Biodegradable polymers, such as starch, have been studied for various pharmaceutical applications because of their biocompatibility and biodegradability. Starch acetate is one of the hydrophobic biodegradable polymers currently being used or studied for controlled drug delivery. Polyethylene glycol was conjugated with starch acetate, to obtain an amphiphilic polymeric derivative. On its incubation with insulin solution at the critical micelle concentration, self-aggregated nanoparticles with mean particle size of 32 nm are formed. These self-aggregated nanoparticles with associated insulin have enhanced encapsulation efficiency. The mean particle size of these nanoparticles increased with the increase in the molecular weight of PEG. Present study indicated that PEGylated starch acetate nanoparticles are highly bioadhesive and can be utilized as a carrier system for controlled delivery of insulin or other proteins for various therapeutic applications.


Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells.
During persistent murine cytomegalovirus (MCMV) infection, the T cell response is maintained at extremely high intensity for the life of the host. These cells closely resemble human CMV-specific cells, which compose a major component of the peripheral T cell compartment in most people. Despite a phenotype that suggests extensive antigen-driven differentiation, MCMV-specific T cells remain functional and respond vigorously to viral challenge. We hypothesized that a low rate of antigen-driven proliferation would account for the maintenance of this population. Instead, we found that most of these cells divided only sporadically in chronically infected hosts and had a short half-life in circulation. The overall population was supported, at least in part, by memory T cells primed early in infection, as well as by recruitment of naive T cells at late times. Thus, these data show that memory inflation is maintained by a continuous replacement of short-lived, functional cells during chronic MCMV infection.


Characterization, scaling, and partial representation of neural junctions and coordinated firing patterns by dynamic similarity.
This paper presents a dynamic-similarity-based system for mathematically characterizing the functional connectivity and information flow of neural junctions. This approach allows for quantitative comparison of operations of neural junctions across systems, and an interpretation of their connectivity parameters in terms of the flow of multiunit firing patterns. The paper further uses this characterization to show how to rationally construct reduced operational models of neural junctions. Both uniformly proportional scaling and partial fragmentary representations are developed. The uniformly scaled models are better adapted to overall capacities and broader theoretical conceptualizations; the partial representations are better adapted to direct comparison with microelectrode experimentation. The characterization of information flow is based on coordinated multiunit patterns such as synfire chains or sequential configurations. The system can be applied to component parts of large composite networks including junctions with topographical patchiness and other irregularities. The characterization should be of use to anatomists, physiologists, modelers, and theorists. The theory predicts that the necessity for cooperative confluence of synaptic potentials in sending and receiving sequential configurations across topographically constrained projection fields requires the existence of functional 'pattern modules' within the topographical synaptology of the junction.


High analgesic and anti-inflammatory in vivo activities of six new hybrids NSAIAs tetrahydropyran derivatives.
We present in this article syntheses of six new hybrids compounds (4-9) that were efficiently prepared in one or two steps (70-84.6%) from our previous prototype (±)-cis-4-chloro-6-(naphthalen-1-yl)-tetrahydro-2H-pyran-2-yl)methanol (3) and the NSAIAs: acetyl salicylic acid, indomethacin, ibuprofen, ketoprofen, naproxen and diclofenac. The acetic acid-induced writhing method is able to determine that all investigated new hybrids showed stronger antinociceptive properties (2- to 10-fold less ED50 values) than their precursors. The highest antinociceptive effect was observed for compound 9 showing more than 10-fold less ED50 values than diclofenac and ninefold less ED50 value than compound 2. All compounds presented greater activity than the control group in the tail-flick test confirming the central antinociceptive effect. New hybrids did not alter the motor performance of mice by rota-rod performance and open-field tests. Investigated compounds 4-9 were not toxic after oral administration (LD50 >2000mg/kg).


Multiplex TaqMan® detection of pathogenic and multi-drug resistant Salmonella.
Overuse of antibiotics in the medical and animal industries is one of the major causes for the development of multi-drug-resistant (MDR) food pathogens that are often difficult to treat. In the past few years, higher incidences of outbreaks caused by MDR Salmonella have been increasingly documented. The objective of this study was to develop a rapid multiplex real-time polymerase chain reaction (PCR) assay for simultaneous detection of pathogenic and MDR Salmonella spp. A multiplex TaqMan®real-time PCR was designed by targeting the invasin virulence gene (invA), and four commonly found antibiotic resistance genes, viz. ampicillin, chloramphenicol, streptomycin and tetracycline. To avoid false negative results and to increase the reliability of the assay, an internal amplification control (IAC) was added which was detected using a locked nucleic acid (LNA) probe. In serially diluted (5 ng-50 fg) DNA samples, the assay was able to detect 100 genomic equivalents of Salmonella, while in a multiplex format, the sensitivity was 1000 genomic equivalents. The assay performed equally well on artificially contaminated samples of beef trim, ground beef of different fat contents (73:27, 80:20, 85:15 and 93:7), chicken rinse, ground chicken, ground turkey, egg, spinach and tomato. While the detection limit for un-enriched inoculated food samples was 10(4) CFU/g, this was improved to 10 CFU/g after a 12-h enrichment in buffered peptone water, with 100% reproducibility. The multiplex real-time assay developed in this study can be used as a valuable tool to detect MDR virulent Salmonella, thus enhancing the safety of food.


Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence.
Recent studies have implicated interferon signaling in the regulation of cellular senescence. However, the role of specific interferon-inducible proteins in cellular senescence remains to be defined. Here we report that IFI 16, an interferon-inducible transcriptional modulator from the p200-protein family, contributes to cellular senescence of prostate epithelial cells. Normal human prostate epithelial cells (PrEC) in culture expressed detectable levels of IFI 16, and the levels increased more than fourfold when cells approached cellular senescence. Consistent with a role of IFI 16 in cellular senescence, human prostate cancer cell lines either did not express IFI 16 or expressed a variant form, which was primarily detected in the cytoplasm of prostate cancer cells and not in the nucleus. Moreover, overexpression of functional IFI 16 in human prostate cancer cell lines inhibited colony formation. Additionally, ectopic expression of IFI 16 in clonal prostate cancer cell lines was associated with a senescence-like phenotype, production of senescence-associated beta-galactosidase (a biochemical marker for cellular senescence), and reduction of S-phase cells in culture. Importantly, upregulation of p21WAF1 and inhibition of E2F-stimulated transcription accompanied inhibition of cell growth by IFI 16 in prostate cancer cell lines. Collectively, our observations support the idea that increased levels of IFI 16 in PrECs contribute to senescence-associated irreversible cell growth arrest.


Repair of aortic-left atrial fistula following the transcatheter closure of an atrial septal defect.
We describe the surgical treatment of an aortic-left atrial fistula that appeared 6 months after the placement of an Amplatzer septal occluder for closure of a large secundum atrial septal defect. Successful repair of the fistula was accomplished by a combined transatrial-transaortic approach similar to that used to repair the rupture of a sinus of Valsalva aneurysm.


Implementation challenges and perception of care providers on Electronic Medical Records at St. Paul's and Ayder Hospitals, Ethiopia.
In resources constrained settings, effectively implemented Electronic Medical Record systems have numerous benefits over paper-based record keeping. This system was implemented in the 2009 Gregorian Calendar in the two Ethiopian territory hospitals, Ayder and St. Paul's. The pilot implementation and similar re-deployment efforts done in 2014 and 2017 Gregorian Calendar failed at St. Paul's. This study aimed to assess the current status, identify challenges, success factors and perception of health care providers to the system to inform on future roll-outs and scale-up plans. A cross sectional study design with quantitative and qualitative methods was employed. A survey was administered October to December 2019 using a structured questionnaire. A total of 240 health care providers participated in the study based on a stratified random sampling technique. An interview was conducted with a total of 10 persons that include IT experts and higher managements of the hospital. Descriptive statistics were employed to summarize the survey data using SPSS V.21. Qualitative data were thematically presented. St. Paul's hospital predominantly practiced the manual medical recording system. The majority of respondents (30.6%) declared that a lack of training and follow up, lack of management commitment, poor network infrastructure and hardware/software-related issues were challenges and contributed to EMR system failure at St. Paul's. Results from the qualitative data attested to the above results. The system is found well-functioning at Ayder, and the majority of respondents (38%) noted that lack of training and follow-up was the most piercing challenge. As per the qualitative findings, ICT infrastructure, availability of equipment, incentive mechanisms, and management commitment are mentioned as supportive for successful implementation. At both hospitals, 70 to 95% of participants hold favorable perceptions and are willing to use the system. Assessing the readiness of the hospital, selecting and acquiring standard and certified EMR systems, provision of adequate logistic requirements including equipment and supplies, and upgrading the hospital ICT infrastructure will allow sustainable deployment of an EMR system.


Partial breast irradiation versus whole breast radiotherapy for early-stage breast cancer: a decision analysis.
To compare the quality-adjusted life expectancy between women treated with partial breast irradiation (PBI) vs. whole breast radiotherapy (WBRT) for estrogen receptor-positive early-stage breast cancer. We developed a Markov model to describe health states in the 15 years after radiotherapy for estrogen receptor-positive early-stage breast cancer. Breast cancer recurrences were separated into local recurrences and elsewhere failures. Ipsilateral breast tumor recurrence (IBTR) risk was extracted from the Oxford overview, and rates and utilities were adapted from the literature. We studied two cohorts of women (aged 40 and 55 years), both of whom received adjuvant tamoxifen. Assuming a no evidence of disease (NED)-PBI utility of 0.93, quality-adjusted life expectancy after PBI (and WBRT) was 12.61 (12.57) and 12.10 (12.06) years for 40-year-old and 55-year-old women, respectively. The NED-PBI utility thresholds for preferring PBI over WBRT were 0.923 and 0.921 for 40-year-old and 55-year-old women, respectively, both slightly greater than the NED-WBRT utility. Outcomes were sensitive to the utility of NED-PBI, the PBI hazard ratio for local recurrence, the baseline IBTR risk, and the percentage of IBTRs that were local. Overall the degree of superiority of PBI over WBRT was greater for 55-year-old women than for 40-year-old women. For most utility values of the NED-PBI health state, PBI was the preferred treatment modality. This result was highly sensitive to patient preferences and was also dependent on patient age, PBI efficacy, IBTR risk, and the fraction of IBTRs that were local.


On effects of relaxed selection in familial disorders.
Theoretical predictions are made of the effect of improved treatments, with consequent increase in fertility of affected individuals, on the frequency of familial disorders. Multifactorial inheritance and some two-locus models are considered. (Changes for simple Mendelian disorders have been estimated previously by many authors.) It is estimated that, with two-locus or multifactorial models, an increase in frequency per generation of not more than a few per cent of the frequency of a disorder may be expected. The greatest increase will be in the first generation following introduction of the new treatment.


Macular and choroidal thickness after intracameral moxifloxacin for prevention of postcataract endophthalmitis.
To determine any changes in macular or choroidal thickness associated with the use of intracameral moxifloxacin as postcataract endophthalmitis prophylaxis. University of Campinas, Campinas, São Paulo, Brazil. Prospective, randomized, partially masked, single-site clinical trial. Phacoemulsification surgery patients in the experimental group (Group A) received a 0.03 mL intracameral injection of undiluted moxifloxacin from a sealed bottle immediately after phacoemulsification surgery (150 μg in 0.03 mL-Vigamox solution), whereas the control group (Group B) did not. Investigators evaluated in masked fashion macular and choroidal thickness using spectral-domain optical coherence tomography preoperatively and postoperatively. A total of 93 patients were included (48 in Group A and 45 in Group B). Baseline parameters were similar between the groups. Either of the 2 parameters assessed differed statistically between the groups or preoperatively vs postoperatively. On postoperative day 30, central macular thickness was 8.85 ± 14.78 μm in Group A and 10.26 ± 22.44 μm in Group B (P = .7232); choroidal thickness as measured by enhanced depth imaging (EDI) was 1.45 ± 16.13 μm in Group A and 3.74 ± 16.15 in Group B (P = .5017). On postoperative day 60, central macular thickness was 19.53 ± 39.28 μm in Group A and 17.14 ± 53.68 μm in Group B (P = .8363); EDI was 5.08 ± 21.96 μm in Group A and 5.24 ± 15.8 in Group B (P = .9752). The application of intracameral injection of 0.03 mL of undiluted 0.5% moxifloxacin during phacoemulsification surgery as endophthalmitis prophylaxis induced no changes in macular or choroidal thickness.


Distinct implications of body mass index in different subgroups of nonobese patients with heart failure with preserved ejection fraction: a latent class analysis of data from the TOPCAT trial.
Obesity is a well-defined risk factor for heart failure with preserved ejection fraction (HFpEF), but it is associated with a better prognosis in patients with diagnosed HFpEF. The paradoxically poor prognosis in nonobese patients with HFpEF may be driven by a subset of high-risk patients, which suggests that the nonobese HFpEF subpopulation is heterogeneous. Latent class analysis (LCA) was adopted to identify the potential subgroups of 623 nonobese patients enrolled in the TOPCAT trial. The baseline characteristics of the identified nonobese subgroups were compared with each other and with the obese patients. The risks of all-cause, cardiovascular, and noncardiovascular mortality, and an HF composite outcome were also compared. Two subgroups of nonobese patients with HFpEF (the physiological non-obesity and the pathological non-obesity) were identified. The obese patients were younger than both nonobese subgroups. The clinical profile of patients with pathological non-obesity was poorer than that of patients with physiological non-obesity. They had more comorbidities, more severe HF, poorer quality of life, and lower levels of physical activity. Patients with pathological non-obesity showed low serum hemoglobin and albumin levels. After 2 years of follow-up, more patients in the pathological group lost ≥ 10% of body weight compared with those in the physiological group (11.34% vs. 4.19%, P = 0.009). The prognostic implications of the two subgroups were opposite. Compared to patients with obesity, patients with physiological non-obesity had a 47% decrease in the risk of HF composite outcome (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.40-0.70, P<0.001) and a trend of decreased all-cause mortality risk (HR 0.75, 95% CI 0.55-1.01, P=0.06), while patients with pathological non-obesity had a 59% increase (HR 1.59, 95% CI 1.24-2.02, P<0.001) in all-cause mortality risk. Two subgroups of nonobese patients with HFpEF with distinct clinical profiles and prognostic implications were identified. The low BMI was likely physiological in one group but pathological in the other group. Using a data-driven approach, our study provided an alternative explanation for the "obesity paradox" that the poor prognosis of nonobese patients with HFpEF was driven by a pathological subgroup.


Hearing improvement in patients with Fabry disease treated with agalsidase alfa.
To describe the nature and prevalence of hearing loss in Fabry disease, and its response to enzyme replacement therapy (ERT) with agalsidase alfa. Fifteen male patients with Fabry disease were enrolled in a randomized, double-blind study and received placebo (n = 8) or ERT (n = 7) with agalsidase alfa for 6 months. This was followed by an open-label extension of 36 months thus far. Alongside this trial, an additional eight men and two women have so far received open-label ERT for between 6 and 30 months. Pure-tone audiometry, impedance audiometry and otoacoustic emission testing were performed at 0 (baseline), 6, 18, 30 and 42 months. Nine patients (36%) had bilateral and ten (40%) had unilateral high-frequency sensorineural hearing loss (SNHL). Three (12%) had unilateral middle ear effusions with conductive losses persisting beyond 6 months. Only five patients (20%) had normal hearing. The high-frequency SNHL deteriorated over the first 6 months in both placebo and active treatment groups by a median 6.3 dB (p < 0.0001, Wilcoxon matched-pairs). This hearing loss subsequently improved above baseline by 1.5 dB at 18 months (p = 0.07), by 5.0 dB at 30 months (p = 0.006) and by 4.0 dB at 42 months (p = 0.01). Significant hearing loss, usually high-frequency SNHL, is a common manifestation of Fabry disease in adults. Alpha-galactosidase A replacement therapy with agalsidase alfa appears to reverse the hearing deterioration in these patients. This improvement, however, is gradual, suggesting the need for long-term ERT.


Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing.
Solid dispersions containing various stabilizers and tacrolimus (TAC) prepared by an Ultra-rapid Freezing (URF) process were investigated to determine the effect on their ability to form supersaturated solutions in aqueous media and on enhancing transport across biological membranes. The stabilizers included poly(vinyl alcohol; PVA), poloxamer 407 (P407), and sodium dodecyl sulfate (SDS). In vivo absorption enhancement in rats was also investigated. Dissolution studies were conducted at supersaturated conditions in both acidic media for 24 h and at delayed release (enteric) conditions to simulate intestinal transit. The rank order of C/Ceq(max) in the dissolution studies at acidic conditions was URF-P407 > URF-SDS > Prograf (PRO) > URF-PVA:P407. For C/Ceq(max) under enteric conditions, the order was URF-SDS > PRO > URF-PVA:P407 > URF-P407, and for the extent of supersaturation (AUC) in acidic and pH shift conditions it was URF-SDS>PRO>URF-PVA:P407>URF-P407. The pharmacokinetic data suggests URF-P407 had the greatest absorption having higher C (max) with a 1.5-fold increase in AUC compared to PRO. All URF compositions had a shorter T (max) compared to PRO. The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.


The use of metronidazole in women undergoing obstetric anal sphincter injuries: a systematic review of the literature.
Antibiotic treatment during surgical repair of obstetric anal sphincter injuries (OASIS) had been a matter of debate. We aimed to review the available literature regarding the efficacy of metronidazole administration in women undergoing perineal repair following obstetric OASIS. To identify potentially eligible studies, we searched PubMed, Scopus, Embase and the Cochrane Library from inception to January 13th, 2019.Reference lists of identified studies were searched. No language restrictions were applied. We used a combination of keywords and text words represented by "Metronidazole", "obstetrics", "obstetric anal sphincter injury", "OASIS", "third degree tear", "fourth degree tear", "third degree laceration", "fourth degree laceration", "antibiotic therapy", "perineal damage" and "perineal trauma". Two reviewers independently screened the titles and abstracts of records retrieved from the database searches. Both reviewers recommended studies for the full-text review. Thescreen of full-text articles recommended by at least one reviewer was done independently by the same two reviewers and assessedfor inclusion in the systematic review. Disagreements between reviewers were resolved by consensus. The electronic database search yielded a total of 54,356 results (Fig. 1). After duplicate exclusion 28,154 references remained. Of them, 26 were relevant to the review based on title and abstract screening. None of these articles dealt with the use of metronidazole for the prevention of infections complicating anal sphincter repair in women with OASIS. A Cochrane review addressing antibiotic prophylaxis for patients following OASIS, compared prophylactic antibiotics against placebo or no antibiotics, included only one randomized controlled trial of 147 participants. This study showed that prophylactic antibiotics (not metronidazole) may be helpful to prevent perineal wound complications following OASIS. Fig. 1 Study seection process CONCLUSION: Anaerobic infections potentially complicate wound repair after OASIS. Although scientific societies recommend the use of antibiotics for the prevention of infectious morbidity after OASIS, no study has specifically assessed the role of metronidazole.


Phylogeographic relationships among Asian eggplants and new perspectives on eggplant domestication.
The domestication history of eggplant (Solanum melongena L.) has long been debated, with studies unable to narrow down where domestication occurred within a broad region of tropical Asia. The most commonly hypothesized region is India, however China has an equally old written record of eggplant use dating ca. 2000 years before present. Both regions have a high diversity of landraces and populations of putatively wild eggplant: Solanum incanum L. in India and Solanum undatum Lam. in SE Asia. An additional complication is that there is taxonomic confusion regarding the two candidate progenitors. Here, we synthesize historic, morphologic, and molecular data (nrITS sequence and AFLP) to interpret the phylogeographic relationships among candidate progenitors and Asian eggplant landraces in order to test theories of domestication. A minimum of two domestication events is supported: one in India and one in southern China/SE Asia. Results also support separate domestication of S. melongena subsp. ovigerum, a group of morphologically distinct eggplants found in SE Asia, and suggest Asian S. incanum and S. undatum may not be genetically distinct. Routes of the spread of eggplant cultivation throughout Asia are proposed, and evolutionary relationships among allied species are discussed.


[Complications of cocaine transport in the gastrointestinal tract].
Smuggling of cocaine in the intestinal tract is becoming more and more common. The risks entailed are discussed on the basis of a review of the literature and a description of a complicated case of mechanical ileus seen by the authors.


Ghrelin suppression and fat loss after left gastric artery embolization in canine model.
To evaluate the effects of left gastric artery embolization (LGAE) on plasma ghrelin levels, abdominal fat, and body weight in beagles. The institutional animal care and use committee approved this study. Fifteen healthy adult beagles (12 male and three female animals) were randomly divided into three experimental groups: LGAE was proceeded with mixed emulsion of bleomycin A(5) hydrochloride and lipiodol (group A), and polyvinyl alcohol particles (group B). Transcatheter saline injections in the left gastric artery were performed as a control. Weight and fasting plasma ghrelin levels were obtained at baseline and at weekly intervals for 8 weeks after the procedure in all animals. All animals were scanned and measured by multidetector computed tomography at baseline and at week 8 for evaluation of abdominal fat. In LGAE-treated animals, plasma ghrelin and body weight significantly decreased compared to control animals (group A: P = 0.007 and P = 0.000; group B: P = 0.004 and P = 0.000, respectively). Subcutaneous fat size was also significantly reduced (P = 0.011 and P = 0.027 for groups A and B, respectively). The decreasing percentage in ghrelin levels at week 6 (peak of recovery) of LGAE-treated animals were negatively correlated with the size of area supplied by left gastric artery (r = -0.693, P = 0.026). LGAE could suppress the plasma concentration of ghrelin, which results in subcutaneous fat size reduction and weight loss. Compensatory ghrelin production might occur in the remnant gastric fundus after LGAE.


The Effect of Poly(Vinyl Chloride) Powder Addition on the Thermomechanical Properties of Epoxy Composites Reinforced with Basalt Fiber.
The aim of the article was to determine the effect of the poly(vinyl chloride) additive (PVC) on the thermomechanical and fire properties of epoxy composites reinforced with basalt fabric. Ten-layered composites with 2.5, 5 and 10 wt.% of PVC powder were fabricated using hand lay-up. The following features were evaluated for composites: structure (by scanning electron microscopy, SEM), thermomechanical properties (by dynamical thermomechanical analysis, DMTA), mechanical properties (in bending, tensile and interlaminar shear strength tests), hardness (using the Barcol method), thermal stability (by thermogravimetry, TGA) and fire behavior (using a cone calorimeter). It was found that the introduction of micron PVC powder into the epoxy matrix improved the thermomechanical properties of composites, such as storage module, and mechanical properties, such as flexural strength and modulus, as well as hardness.


The full stomach test as a novel diagnostic technique for identifying patients at risk of Brugada syndrome.
Autonomic modulation, particularly high vagal tone, plays an important role in the occurrence of ventricular tachyarrhythmias in the Brugada syndrome. Food intake modulates vagal activity. We assessed the usefulness of a novel diagnostic technique, the "full stomach test," for identifying a high-risk group in patients with a Brugada-type electrocardiogram (ECG). In 35 patients with a Brugada-type ECG, we assessed 12-lead ECGs before and after a large meal, a pilsicainide pharmacological test, spontaneous ST-segment change, late potentials by signal-averaged ECG, microvolt T-wave alternans, and four other ECG parameters. These patients were divided into two groups (i.e., high-risk group [n = 17] and indeterminate risk group [n = 18]). The full stomach test was defined as positive when augmentation of characteristic ECG abnormalities was observed after meals. Thirteen patients had a prior history of life-threatening events such as aborted sudden death and syncope, with a total of 30 episodes. These episodes had a circadian pattern, at night and after meals. The full stomach test was positive in 17 of the study patients (49%). A positive test outcome was characterized by a higher incidence of a history of life-threatening events than a negative test outcome (P = 0.015, odds ratio = 7.1). In comparison between the two groups, the incidence (82%) of positive outcomes in the high-risk group was significantly higher than that (17%) in the indeterminate risk group (P = 0.0002). Characteristic ECG changes diagnostic of Brugada syndrome are augmented by a large meal. These data are associated with a history of life-threatening events in Brugada syndrome.


Frequent functional activation of RAS signalling not explained by RAS/RAF mutations in relapsed/refractory multiple myeloma.
RAS mutations are frequent in relapsed/refractory multiple myeloma (RRMM) but functional study in primary samples is scanty. Herein, in primary myeloma plasma cells of 17 suspected RRMM, functional activation of RAS signalling was studied by Western blot of phosphorylated ERK1/2 (phospho-ERK1/2). Moreover, activating mutations in KRAS, NRAS, BRAF, and ALK were studied by PCR and bidirectional direct sequencing. Furthermore, methylation of negative RAS signalling regulator genes, RASSF1A and RASD1, were analyzed by methylation-specific PCR. As evidenced by phospho-ERK1/2 over-expression, functional RAS activation was detected in 12 (75.0%) RRMM. Of patients with functional RAS activation, sequencing data showed only seven (58.3%) patients with one each had NRAS Q61H, NRAS Q61K, KRAS G12D, KRAS G12V, KRAS G13D, KRAS Q61P, or BRAF V600E mutation, whereas five (41.7%) patients had no RAS/RAF mutation. Conversely, patients without functional RAS activation had no RAS/RAF mutation. Moreover, none of the patients with functional RAS activation had ALK mutations, or methylation of RASSF1A and RASD1. Collectively, functional activation of RAS signalling was present in majority of RRMM but only about half (58.3%) accountable by RAS/RAF mutations. If verified in larger studies, clinical investigations of MEK inhibitors are warranted regardless of RAS/RAF mutations.


Characterization of rat skeletal muscle sarcolemmal insulin receptors and a sarcolemmal insulin binding inhibitor.
When insulin receptors of rat skeletal muscle sarcolemmal vesicles were solubilized with Triton X-100, the specific binding of 125I-labeled insulin increased by more than 10-fold over that seen in the intact vesicles. Partial purification of the skeletal muscle insulin receptors on wheat germ agglutinin affinity columns increased the total insulin binding activity by 7-fold and reduced the Kd for insulin binding from 1.92 to 0.20 nM, suggesting that an inhibitor of insulin binding was removed by this purification step. This was confirmed when the unbound fractions of the affinity column were dialyzed and reconstituted with the insulin receptors. The inhibitory activity in the sarcolemmal extract could not be accounted for by the presence of Triton X-100. The skeletal muscle inhibitor was more potent in inhibiting insulin binding to skeletal muscle insulin receptors than to liver or adipose receptors. The inhibitor was very effective in inhibiting insulin binding to wheat germ agglutinin-purified IM-9 receptors, but had negligible effects on insulin binding to intact IM-9 cells. The properties of the alpha and beta subunits of the skeletal muscle insulin receptors appear to be the same as those of insulin receptors of other tissues: cross-linking of 125I-labeled insulin to the receptor revealed a band of 130,000 daltons, and insulin stimulated the phosphorylation of bands of 90,000 and 95,000 daltons in the receptor preparation. The skeletal muscle insulin binding inhibitor elutes from molecular sieves in a major 160,000-dalton peak and minor 75,000-dalton peak. The binding inhibitor is not inactivated by heat, by mercaptoethanol, or by trypsin, pepsin, or proteinase K. Collectively, these data suggest that the inhibitor may be a small molecule that aggregates with itself, with larger proteins, or with detergent micelles.


The ZPR1 genotype predicts myocardial infarction in patients with familial hypercholesterolemia.
The rs964184 variant in the ZPR1 gene has been associated with blood lipids and cardiovascular disease risk in the general population through genome-wide association study, but its effect in patients with familial hypercholesterolemia (FH) has never been studied. The objectives of the present study are to investigate the effect of the rs964184 SNP on blood lipids and on the risk of incident myocardial infarction (MI) in patients with FH. This study included 725 patients with genetically confirmed FH. The MI events that occurred throughout the lifespan until the last medical visit were included. The median observation period was 50 years. An exome chip genotyping method (Illumina) was used to impute the rs964184 genotype. Among the 725 patients, 190 individuals carried one risk allele G (CG genotype), whereas 15 patients were carriers of the GG genotype. A significant difference in circulating triglycerides was observed between the 3 groups (1.33 [1.03-1.73] vs 1.46 [1.09-2.11] vs 1.56 [1.07-2.42] mmol/L, for the CC, CG, and GG carriers, respectively, P = .004 for the analysis of variance). The ZPR1 SNP rs964184 was significantly associated with MI even after correction for classical cardiovascular risk factors (hazard ratio 5.68, 95% confidence interval 2.40-13.45, P = .00008). The cardiovascular risk in patients with FH is highly heterogeneous, and this study suggests that the rs964184 variant of the ZPR1 gene represents one of the important modulating factors.


Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma.
Radical pleurectomy (RP) for mesothelioma is often considered either technically unfeasible or an operation limited to patients who would not tolerate a pneumonectomy. The purpose of this study was to review our experience using RP and intraoperative photodynamic therapy (PDT) for mesothelioma. Thirty-eight patients (42-81 years) underwent RP-PDT. Thirty five of 38 (92%) patients also received systemic therapy. Standard statistical techniques were used for analysis. Thirty seven of 38 (97%) patients had stage III/IV cancer (according to the American Joint Committee on Cancer [AJCC manual 7th Edition, 2010]) and 7/38 (18%) patients had nonepithelial subtypes. Macroscopic complete resection was achieved in 37/38 (97%) patients. There was 1 postoperative mortality (stroke). At a median follow-up of 34.4 months, the median survival was 31.7 months for all 38 patients, 41.2 months for the 31/38 (82%) patients with epithelial subtypes, and 6.8 months for the 7/38 (18%) patients with nonepithelial subtypes. Median progression-free survival (PFS) was 9.6, 15.1, and 4.8 months, respectively. The median survival and PFS for the 20/31 (64%) patients with N2 epithelial disease were 31.7 and 15.1 months, respectively. It was possible to achieve a macroscopic complete resection using lung-sparing surgery in 97% of these patients with stage III/IV disease. The survival we observed with this approach was unusually long for the patients with the epithelial subtype but, interestingly, the PFS was not. The reason for this prolonged survival despite recurrence is not clear but is potentially related to preservation of the lung or some PDT-induced effect, or both. We conclude that the results of this lung-sparing approach are safe, encouraging, and warrant further investigation.


Primary pulmonary neoplasia in the dog and cat.
This article covers the pertinent clinical, physical, and radiographic findings in dogs and cats with primary pulmonary neoplasia. Diagnostic and treatment recommendations are made. Although primary pulmonary neoplasia is rare in both the dog and cat, it appears to be diagnosed with increasing frequency. Early detection and surgical treatment of carefully selected cases can prolong a good quality of life.


Together we can make a difference: the case for transnational action for improved health in prisons.
In spite of international differences in the treatment of incarcerated persons, as a group, they are vulnerable to poor health status and lack of access to quality health care. The health care of prisoners is affected by knowledge and commitment to ideas of human rights and social justice, as well as economic conditions. Prisoners are at increased risk of both acute and chronic diseases, and may constitute a threat to the health of other prisoners, their attendants or outside communities upon release. Mental illness and related problems of substance abuse are prevalent in prison populations, with many US prisons serving as modern asylums. Public health workers and organizations can stimulate and implement action to improve health in prisons. The World Federation of Public Health Associations can play a leadership role in co-ordinating and facilitating collaborative international action and research to enhance the health of prisoners and their communities worldwide.


Expression of recombinant Clostridium difficile toxin A using the Bacillus megaterium system.
Pathogenic Clostridium difficile produces two major protein toxins, toxin A and toxin B. We used the Bacillus megaterium expression system for expression of recombinant toxin A. The construct for the toxin A gene was obtained by the following cloning strategy: the gene for toxin A was generated in three parts, each of them ligated into a cloning vector. The three parts were sequentially fused to the complete gene. The holotoxin gene was ligated into the expression vector pWH1520. This vector was modified to generate a toxin with a C-terminally located His-tag. Gene expression in the B. megaterium system resulted in an approximate 300 kDa protein, which was identified by specific antibody as toxin A. Recombinant, His-tagged toxin A was purified by Ni(2+) as well as thyroglobulin affinity chromatography. Characterization of the recombinant toxin A showed identical cytotoxicity and in vitro-glucosyltransferase activity as the native toxin A from C. difficile.


Exploring the association between birthweight and breast cancer using summary statistics from a perspective of genetic correlation, mediation, and causality.
Previous studies demonstrated a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations also emerged, and the nature of such relationship remains unknown. Using summary statistics of birthweight and breast cancer, we assessed the fetal/maternal-specific genetic correlation between them via LDSC and prioritized fetal/maternal-specific pleiotropic genes through MAIUP. Relying on summary statistics we conducted Mendelian randomization (MR) to evaluate the fetal/maternal-specific origin of causal relationship between birthweight, age of menarche, age at menopause and breast cancer. With summary statistics we identified a positive genetic correlation between fetal-specific birthweight and breast cancer (rg = 0.123 and P = 0.013) as well as a negative but insignificant correlation between maternal-specific birthweight and breast cancer (rg = - 0.068, P = 0.206); and detected 84 pleiotropic genes shared by fetal-specific birthweight and breast cancer, 49 shared by maternal-specific birthweight and breast cancer. We also revealed fetal-specific birthweight indirectly influenced breast cancer risk in adulthood via the path of age of menarche or age at menopause in terms of MR-based mediation analysis. This study reveals that shared genetic foundation and causal mediation commonly drive the connection between the two traits, and that fetal/maternal-specific birthweight plays substantially distinct roles in such relationship. However, our work offers little supportive evidence for the fetal origins hypothesis of breast cancer originating in utero.


Potential impact of a 32-channel receiving head coil technology on the results of a functional MRI paradigm.
The authors investigated the potential of a 32-channel (32ch) receiving head coil for functional magnetic resonance imaging (fMRI) compared to a standard eight-channel (8ch) coil using a motor task. Brain activation was analyzed in 14 healthy right-handed subjects performing finger tapping with the right index finger (block design) during two experimental sessions, one with the 8ch and one with the 32ch coil (applied in a pseudorandomized order). Additionally, a phantom study was performed to compare signal-to-noise ratios (SNRs) of both coils. During both fMRI sessions, analysis of motor conditions resulted in an activation of the left "hand knob" (precentral gyrus). Application of the 32ch coil obtained additional activation clusters in the right cerebellum, left superior frontal gyrus (SMA), left supramarginal gyrus, and left postcentral gyrus. The phantom study revealed a significantly higher SNR for the 32ch coil compared to the 8ch coil in superficial cortical areas located near the surface of the brain. The 32ch technology has a potential impact on fMRI studies, especially in paradigms that result in activation of cortical areas located near the surface of the brain.


In vivo treatment of rat arterial adventitia with interleukin‑1β induces intimal proliferation via the JAK2/STAT3 signaling pathway.
Previous studies have indicated that adventitial inflammation is involved in the development of atherosclerosis. The aim of this study was to investigate the effect of arterial adventitia inflammation induced by interleukin (IL)‑1β on intimal proliferation and the mechanisms involved in this process. The left common carotid artery adventitia of male rats in the experimental and control groups (25 rats/group) was wrapped with agar containing or without a sustained‑release suspension of 2.5 µg IL‑1β, respectively. Five animals in each group were randomly selected for sacrifice at 2 h, 8 h, 24 h, 48 h, and 1 week post‑treatment. Hematoxylin and eosin staining was performed for to analyze the morphology of the adventitia. The expression of janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, phosphorylated (p‑)JAK2 and p‑STAT3 were detected by western blot analysis or immunohistochemistry staining. A model of adventitial inflammation was successfully created by wrapping IL‑1β around the rat carotid artery. IL‑1β treatment induced vascular smooth muscle cell proliferation and migration as well as intimal proliferation. In addition, the expression of p‑JAK2 and p‑STAT3 increased after IL‑1β treatment. Furthermore, an inhibitor of JAK2/STAT3 pathway, AG490, suppressed IL‑1β‑induced intimal proliferation and phosphorylation of JAK2 and STAT3. Thus, the JAK2/STAT3 signaling pathway is involved in intimal proliferation caused by vascular adventitial inflammation. Inhibiting the JAK2/STAT3 signaling pathway may be a novel method for the clinical treatment of artery atherosclerosis.


MELAS mitochondrial DNA mutation A3243G reduces glutamate transport in cybrids cell lines.
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is commonly associated with the A3243G mitochondrial DNA (mtDNA) mutation encoding the transfer RNA of leucine (UUR) (tRNA (Leu(UUR))). The pathogenetic mechanisms of this mutation are not completely understood. Neuronal functions are particularly vulnerable to alterations in oxidative phosphorylation, which may affect the function of the neurotransmitter glutamate, leading to excitotoxicity. In order to investigate the possible effects of A3243G upon glutamate homeostasis, we assessed glutamate uptake in osteosarcoma-derived cytoplasmic hybrids (cybrids) expressing high levels of this mutation. High-affinity Na(+)-dependent glutamate uptake was assessed as radioactive [(3)H]-glutamate influx mediated by specific excitatory amino acid transporters (EAATs). The maximal rate (V(max)) of Na(+)-dependent glutamate uptake was significantly reduced in all the mutant clones. Although the defect did not relate to either the mutant load or magnitude of oxidative phosphorylation defect, we found an inverse relationship between A3243G mutation load and mitochondrial ATP synthesis, without any evidence of increased cellular or mitochondrial free radical production in these A3243G clones. These data suggest that a defect of glutamate transport in MELAS neurons may be due to decreased energy production and might be involved in mediating the pathogenic effects of the A3243G mtDNA mutation.


Factors facilitating the development of low-carbon cities: evidence from China's pilot cities.
As the largest developing country, China has recognized the importance of low carbon cities. To date, three batches of low-carbon pilot provinces and cities were presented by the Chinese government from 2010 to 2017. Therefore, the local governments in the pilot group should take effective measures to promote the development of low-carbon cities. However, because of the lack of experience in implementing special policies for low-carbon cities, many local governments have encountered difficulties in promoting the development of low-carbon cities. This study critically analysed various policies promulgated during 2010-2021 by the Chinese local governments. The most relevant programming policies of pilot cities were selected. A multidimensional framework is developed to better understand the policies in facilitating low-carbon city development in China. The results showed that there are 16 factors at both the macro level and the micro level that affect the development of Chinese low-carbon pilot cities. The successful promotion of China's low-carbon cities requires combined efforts from all related stakeholders. In addition, the development of pilot cities is actively promoted by the Chinese national government and linked to other strategic initiatives, such as "peak carbon" by 2030 and "carbon neutral" by 2060. The findings help to better understand the landscape of policy measures of low-carbon city development in China and provide useful references for policy making in other countries.


Switching from tenofovir disoproxil fumarate to tenofovir alafenamide or dual therapy-based regimens in HIV-infected individuals with viral load ≤50 copies/mL: does estimated glomerular filtration rate matter?
Our aim was to evaluate the association between recent eGFR values and risk of switching from TDF to TAF or dual therapy (DT) in real life. HIV-positive patients achieving HIV-RNA ≤50 copies/mL for the first time after starting a TDF-based regimen were included. Kaplan-Meier (KM) curves and Cox regression models were used to estimate the time from TDF to switch to TAF or DT. 1486 participants were included: median (IQR) age 36 (30-42) years; baseline CKD-EPI eGFR 99.92 (86.47-111.4) mL/min/1.73m2. We observed a consistently higher proportion of people with HIV-RNA ≤50 copies/mL who switched from TDF to TAF rather than to DT. By competing risk analysis, at 2 years from baseline, the probability of switching was 3.5% (95% CI 2.6-4.7%) to DT and 46.7% (42.8-48.5%) to TAF. A significantly higher probability of switching to TAF was found for patients receiving INSTI at baseline versus NNRTIs and PI/b [KM, 65.6% (61.7-69.4%) vs. 4.0% (1.8-6.1%) and 59.9% (52.7-67.2%), respectively; P < 0.0001]. eGFR <60 mL/min/1.73m2 both as time-fixed covariate at baseline or as current value was associated with a higher risk of switching to DT [aHR 6.68 (2.69-16.60) and 8.18 (3.54-18.90); P < 0.001] but not to TAF-based cART [aHR 0.94 (0.39-2.31), P = 0.897; and 1.19 (0.60-2.38), P = 0.617]. Counter to our original hypothesis, current eGFR is used by clinicians to guide switches to DT but does not appear to be a key determinant for switching to TAF.


The metalloprotease ADAM10 generates soluble interleukin-2 receptor alpha (sCD25) in vivo.
The cytokine interleukin-2 (IL-2) plays a critical role in controlling the immune homeostasis by regulating the proliferation and differentiation of immune cells, especially T cells. IL-2 signaling is mediated via the IL-2 receptor (IL-2R) complex, which consists of the IL-2Rα (CD25), the IL-2Rβ, and the IL-2Rγ. While the latter are required for signal transduction, IL-2Rα controls the ligand-binding affinity of the receptor complex. A soluble form of the IL-2Rα (sIL-2Rα) is found constitutively in human serum, though its levels are increased under various pathophysiological conditions. The sIL-2Rα originates partly from activated T cells through proteolytic cleavage, but neither the responsible proteases nor stimuli that lead to IL-2Rα cleavage are known. Here, we show that the metalloproteases ADAM10 and ADAM17 can cleave the IL-2Rα and generate a soluble ectodomain, which functions as a decoy receptor that inhibits IL-2 signaling in T cells. We demonstrate that ADAM10 is mainly responsible for constitutive shedding of the IL-2Rα, while ADAM17 is involved in IL-2Rα cleavage upon T cell activation. In vivo, we found that mice with a CD4-specific deletion of ADAM10, but not ADAM17, show reduced steady-state sIL-2Rα serum levels. We propose that the identification of proteases involved in sIL-2Rα generation will allow for manipulation of IL-2Rα cleavage, especially as constitutive and induced cleavage of IL-2Rα are executed by different proteases, and thus offer a novel opportunity to alter IL-2 function.


Electron-microscopic study of a Mycoplasmatales virus, strain MV-Lg-pS2-L 172.
Morphology and adsorption of a globular virus, lysing Acholeplasma laidlawii were studied in ultrathin sections of plaques in a lawn of the host strain. The virus was globular, about 50 to 90 nm in diameter, with a clearly defined membrane, 6.5 to 8 nm thick. A protuberance about 25 to 35 nm long and 12 to 20 nm thick was observed on numerous virus particles. The evenly granulated, electron-optically dense content of the cells became clearer in cells affected by the viruses. Fibrillar structures of different thickness and small dense areas appeared in cells assumed to be in the preliminary stages of lysis. The interactions in the virus-host system and possible development stages of the virsu are discussed.


Emognition dataset: emotion recognition with self-reports, facial expressions, and physiology using wearables.
The Emognition dataset is dedicated to testing methods for emotion recognition (ER) from physiological responses and facial expressions. We collected data from 43 participants who watched short film clips eliciting nine discrete emotions: amusement, awe, enthusiasm, liking, surprise, anger, disgust, fear, and sadness. Three wearables were used to record physiological data: EEG, BVP (2x), HR, EDA, SKT, ACC (3x), and GYRO (2x); in parallel with the upper-body videos. After each film clip, participants completed two types of self-reports: (1) related to nine discrete emotions and (2) three affective dimensions: valence, arousal, and motivation. The obtained data facilitates various ER approaches, e.g., multimodal ER, EEG- vs. cardiovascular-based ER, discrete to dimensional representation transitions. The technical validation indicated that watching film clips elicited the targeted emotions. It also supported signals' high quality.


Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses.
Antiviral therapy of primary and recurrent infections with human cytomegalovirus is reserved for severe manifestations and faces several limitations. Presently candidates for novel drugs with lower adverse side effects and a minimized frequency of resistance formation are under investigation. Here we demonstrate that artesunate, an antimalaria drug with highly valuable pharmacological properties, possesses antiviral activity. A concentration-dependent inhibition of the replication of human cytomegaloviruses with wild-type phenotype was demonstrated in several cell lines. Inhibition was quantified using recombinant green fluorescent protein expressing virus variants. The IC50 values were in the same range for ganciclovir-sensitive and ganciclovir-resistant human cytomegalovirus, as calculated with 5.8+/-0.4 microM and 6.9+/-0.2 microM, respectively. This indicated a strong antiviral potential and a lack of cross-resistance. The optimal antiviral concentrations of artesunate were separable from those inducing cytotoxicity. In addition, the replication of viruses from three genera was seen to be artesunate-sensitive to varying degrees. This suggests a mechanism linked to cellular activation pathways. Both the protein levels and the DNA binding activity of the two virus-induced cellular transcription factors Sp1 and NF-kappaB were found to be markedly reduced in the presence of artesunate. We also analyzed the cellular signaling kinase phosphoinositide 3-kinase, required for the activation of factors such as Sp1 and NF-kappaB in infected fibroblasts. The phosphorylation of two downstream effectors of phosphoinositide 3-kinase, Akt and p70S6K, was markedly inhibited in the presence of artesunate. Thus, artesunate possesses attractive antiviral characteristics which are suggestively based on the interference with essential steps in the host cell kinase cascades.


The RING for gypsy moth control: Topical application of fragment of its nuclear polyhedrosis virus anti-apoptosis gene as insecticide.
Numerous studies suggest a cellular origin for the Lymantria dispar multicapsid nuclear polyhedrosis virus (LdMNPV) anti-apoptosis genes IAPs, thus opening a possibility to use the fragments of these genes for modulation of host metabolism. We report here the strong insecticidal and metabolic effect of single-stranded antisense DNA fragment from RING (really interesting new gene) domain of gypsy moth LdMNPV IAP-3 gene: specifically, on reduction of biomass (by 35%) and survival of L. dispar caterpillars. The treatment with this DNA fragment leads to a significantly higher mortality rates of female insects (1.7 fold) accompanied with the signs of apoptosis. Additionally, we show increased expression of host IAP-1, caspase-4 and gelsolin genes in eggs laid by survived females treated with RING DNA fragment accompanied with calcium and magnesium imbalance, indicating that the strong stress reactions and metabolic effects are not confined to treated insects but likely led to apoptosis in eggs too. The proposed new approach for insect pest management, which can be considered as advancement of "microbial pesticides", is based on the application of the specific virus DNA, exploiting the knowledge about virus-pest interactions and putting it to the benefit of mankind.


The Mechanism and Function of Group II Chaperonins.
Protein folding in the cell requires the assistance of enzymes collectively called chaperones. Among these, the chaperonins are 1-MDa ring-shaped oligomeric complexes that bind unfolded polypeptides and promote their folding within an isolated chamber in an ATP-dependent manner. Group II chaperonins, found in archaea and eukaryotes, contain a built-in lid that opens and closes over the central chamber. In eukaryotes, the chaperonin TRiC/CCT is hetero-oligomeric, consisting of two stacked rings of eight paralogous subunits each. TRiC facilitates folding of approximately 10% of the eukaryotic proteome, including many cytoskeletal components and cell cycle regulators. Folding of many cellular substrates of TRiC cannot be assisted by any other chaperone. A complete structural and mechanistic understanding of this highly conserved and essential chaperonin remains elusive. However, recent work is beginning to shed light on key aspects of chaperonin function and how their unique properties underlie their contribution to maintaining cellular proteostasis.


Collective Total Syntheses of Benzo[c]phenanthridine Alkaloids via a Sequential Transition Metal-Catalyzed Pot-Economic Approach.
Collective total syntheses of 10 benzo[c]phenanthridines were achieved on the basis of the construction of rings C and B through sequential transition metal-catalyzed reactions and flexible condition-controlled Mannich reaction via three pots in 25-34% yields, which provided an efficient route to benzo[c]phenanthridines via a pot-economic approach.