Isolation, partial characterization, and localization of a rat renal tubular glycoprotein antigen. Antibody-induced birth defects.
A glycoprotein with an apparent 340,000 mol wt (gp 340K) was isolated from rat kidney saline-soluble extract by ammonium sulfate precipitation, DE 52 ion-exchange cellulose chromatography, concanavalin A affinity column, Sephacryl S-300 gel filtration, and discontinuous polyacrylamide gel electrophoresis (PAGE). The relative purity of gp 340K was examined by double immunodiffusion analysis, disc PAGE, and immunoelectrophoresis. Injection of rabbit gp 340K antiserum into pregnant rats during the organogenetic period induced abnormal embryonic development, fetal growth retardation, and embryonic death. Antiserum against the immunocomplexes isolated by immobilized protein A also produced the same embryotoxic effects. The biologic effects of the antisera appeared to be dose dependent. Defects such as anophthalmia, hydrocephaly, exencephaly, cleft palate, cleft lip, and some cardiovascular anomalies were observed. The most frequently observed anomaly was anophthalmia. Immunofluorescent localization studies indicated that gp 340K antibodies localized in vivo in the visceral yolk-sac endodermal cells and the embryonic endoderm. In vitro immunofluorescent localization studies revealed that gp 340K was a component of the renal tubular cells that cross-reacted with antigen in the visceral yolk-sac endodermal cells and embryonic endoderm. The underlying mechanism whereby gp 340K antibodies induce birth defects is not known. Three hypotheses were discussed.


3D printed HUVECs/MSCs cocultures impact cellular interactions and angiogenesis depending on cell-cell distance.
Vascularization is a crucial process during the growth and development of bone 1, yet it remains one of the main challenges in the reconstruction of large bone defects. The use of in vitro coculture of human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs) has been one of the most explored options. Both cell types secrete specific growth factors that are mutually beneficial, and studies suggested that cell-cell communication and paracrine secretion could be affected by a number of factors. However, little is known about the effect of cell patterning and the distance between cell populations on their crosstalk. In the present study, we showed that the separation and distance between ECs and MSCs populations affects angiogenesis by modulating cell-cell communication. HUVECs grown farther apart from MSCs (˃400 μm) presented characteristics of an early stage of angiogenesis (migration/proliferation). Results showed an increase in the up-regulation of VEGF, FGF-2, and ITGA3 (integrins) but a smaller fold change in the expression of VE-Cadherin and Ang-1. HUVECs were also still highly proliferative. On the contrary, HUVECs incubated closer (≤200 μm) to MSCs, showed signs of stabilization, mainly an increase in Ang-1 and VE-cadherin expression, as well as tighter monolayers. Conditioned media collected from HUVECs and MSCs grown ≤200 μm apart preferentially promoted tube formation, a later stage of angiogenesis, due in part to a significant increase in Ang-1 paracrine secretion. In addition, in groups in which fibers were printed farther apart (400 μm), cells produced EVs with a significantly increase cargo. Finally, in vivo experiment results showed an increase in blood vessels density and new bone thickness after 12 weeks of implantation in rat cranial defect, further suggesting the higher efficiency of indirect ECs/MSCs contact in prompting the release of paracrine signals that stimulate the angiogenesis of local tissues, and enhanced subsequent bone regeneration.


Efficacy of glucose-based oral rehydration therapy.
This article reviews and synthesizes evidence in the published literature on the safety and efficacy of oral rehydration therapy (ORT) among young children with pediatric gastroenteritis in developed nations. We searched the literature for randomized, controlled trials comparing the safety and efficacy of ORT with intravenous (IV) rehydration treatment and/or oral rehydration solutions (ORSs) of different sodium content. We combined the failure rates of each set of studies in statistical meta-analyses and conducted tests of homogeneity of treatment effect over all the studies and for subgroups of children defined by the trial type, the sodium content of the ORS, and the setting of care. We also conducted a multivariate logistic regression on the probability of failure to determine the relative importance of these factors, controlling for other characteristics of the trials. Other outcomes were also tabulated and discussed. These include the relative incidence of hypernatremia and hyponatremia induced by treatment; weight gain; the volume, frequency, and duration of diarrhea; for inpatient trials, the length of stay; and for outpatient trials, rates of hospitalization. The evidence suggests that among pediatric patients with gastroenteritis in developed countries, failure of ORT, defined as the need to rehydrate children intravenously, is infrequent. We found a combined overall ORT failure rate of 3.6%. We found no statistically significant difference in failure rates by trial type or the sodium content of the ORS. However, we did find some supporting evidence for a lower failure rate among children treated in outpatient settings. In addition, compared with patients rehydrated intravenously, pediatric patients treated with ORT were not found to be at higher risk of iatrogenic hypernatremia or hyponatremia. The evidence from the literature fails to show a consistent trend in favor of either high- or low-sodium solutions for rehydration of pediatric patients. There seems to be a great potential for improving the medical treatment of children with acute gastroenteritis by the greater use of ORT.


An improved de novo genome assembly of the common marmoset genome yields improved contiguity and increased mapping rates of sequence data.
The common marmoset (Callithrix jacchus) is one of the most studied primate model organisms. However, the marmoset genomes available in the public databases are highly fragmented and filled with sequence gaps, hindering research advances related to marmoset genomics and transcriptomics. Here we utilize single-molecule, long-read sequence data to improve and update the existing genome assembly and report a near-complete genome of the common marmoset. The assembly is of 2.79 Gb size, with a contig N50 length of 6.37 Mb and a chromosomal scaffold N50 length of 143.91 Mb, representing the most contiguous and high-quality marmoset genome up to date. Approximately 90% of the assembled genome was represented in contigs longer than 1 Mb, with approximately 104-fold improvement in contiguity over the previously published marmoset genome. More than 98% of the gaps from the previously published genomes were filled successfully, which improved the mapping rates of genomic and transcriptomic data on to the assembled genome. Altogether the updated, high-quality common marmoset genome assembly provide improvements at various levels over the previous versions of the marmoset genome assemblies. This will allow researchers working on primate genomics to apply the genome more efficiently for their genomic and transcriptomic sequence data.


ALPPS procedure with the use of pneumoperitoneum.
A new method for liver hypertrophy was recently introduced, the so-called associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure. We present a video of an ALPPS procedure with the use of pneumoperitoneum. A 29-year-old woman with colon cancer and synchronous liver metastasis underwent a two-stage liver resection by the ALPPS technique because of an extremely small future liver remnant. The first operation began with 30 min pneumoperitoneum. Anatomical resection of segment 2 was performed, followed by multiple enucleations on the left liver. The right portal vein was ligated and the liver partitioned. The abdominal cavity was partially closed, and a 10 mm trocar was left to create a pneumoperitoneum for additional 30 min. The patient had an adequate future liver remnant volume after 7 days, but she was not clinically fit for the second stage of therapy, so it was postponed. She was discharged on day 7 after surgery. The second stage took place 3 weeks later and consisted of an en-bloc right trisectionectomy extended to segment 1. The patient recovered and was discharged 9 days after second-stage surgery. Postoperative CT scan revealed an enlarged remnant liver. The ALPPS procedure is a new revolutionary technique that permits R0 resection even in patients with massive liver metastasis. The use of pneumoperitoneum during the first stage is an easy tool that may prevent hard adhesions, allowing an easier second stage. This video may help oncological surgeons to perform and standardize this challenging procedure.


Indirect Bonding Revisited.
In recent years, the popularity of indirect bonding increased due to advantages such as reduction of chair time and enhancement of patient comfort. Although the indirect bonding technique has improved over the years, the literature has shown different techniques of bracket placement; furthermore, new materials were specially developed for this technique. The aim of this article is to provide a review of the literature, advantages, disadvantages, and laboratory and clinical stages of the indirect bonding technique.


Metagenomics as a Tool To Monitor Reclaimed-Water Quality.
Many biological contaminants are disseminated through water, and their occurrence has potential detrimental impacts on public and environmental health. Conventional monitoring tools rely on cultivation and are not robust in addressing modern water quality concerns. This review proposes metagenomics as a means to provide a rapid, nontargeted assessment of biological contaminants in water. When further coupled with appropriate methods (e.g., quantitative PCR and flow cytometry) and bioinformatic tools, metagenomics can provide information concerning both the abundance and diversity of biological contaminants in reclaimed waters. Further correlation between the metagenomic-derived data of selected contaminants and the measurable parameters of water quality can also aid in devising strategies to alleviate undesirable water quality. Here, we review metagenomic approaches (i.e., both sequencing platforms and bioinformatic tools) and studies that demonstrated their use for reclaimed-water quality monitoring. We also provide recommendations on areas of improvement that will allow metagenomics to significantly impact how the water industry performs reclaimed-water quality monitoring in the future.


Visual Interaction with Deep Learning Models through Collaborative Semantic Inference.
Automation of tasks can have critical consequences when humans lose agency over decision processes. Deep learning models are particularly susceptible since current black-box approaches lack explainable reasoning. We argue that both the visual interface and model structure of deep learning systems need to take into account interaction design. We propose a framework of collaborative semantic inference (CSI) for the co-design of interactions and models to enable visual collaboration between humans and algorithms. The approach exposes the intermediate reasoning process of models which allows semantic interactions with the visual metaphors of a problem, which means that a user can both understand and control parts of the model reasoning process. We demonstrate the feasibility of CSI with a co-designed case study of a document summarization system.


A task-based assessment of parental occupational exposure to pesticides and childhood acute lymphoblastic leukemia.
Associations between parental occupational pesticide exposure and childhood acute lymphoblastic leukemia (ALL) vary across studies, likely due to different exposure assessment methodologies. We assessed parental occupational pesticide exposure from the year before pregnancy to the child's third year of life for 669 children diagnosed with ALL and 1021 controls. We conducted expert rating using task-based job modules (JM) to estimate exposure to pesticides among farmer workers, gardeners, agricultural packers, and pesticide applicators. We compared this method to (1) partial JM using job titles and a brief description, but without completing the task-based questionnaire, and (2) job exposure matrix (JEM) linking job titles to the International Standard Classifications of Occupation Codes. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for ALL cancer risk and pesticide exposure adjusting for child's sex, age, race/ethnicity and household income. Compared to complete JMs, partial JMs and JEM led to 3.1% and 9.4% of parents with pesticide exposure misclassified, respectively. Misclassification was similar in cases and controls. Using complete JMs, we observed an increased risk of ALL for paternal occupational exposure to any pesticides (OR=1.7; 95% CI=1.2, 2.5), with higher risks reported for pesticides to treat nut crops (OR=4.5; 95% CI=0.9, 23.0), and for children diagnosed before five years of age (OR=2.3; 95% CI: 1.3, 4.1). Exposure misclassification from JEM attenuated these associations by about 57%. Maternal occupational pesticide exposure before and after birth was not associated with ALL. The risk of ALL was elevated in young children with paternal occupational pesticide exposure during the perinatal period, using more detailed occupational information for exposure classification.


An unusual case of foreign body in the anterior abdominal wall.
Accidental or intentional ingestion of sharp metallic foreign bodies is a common clinical occurrence. Predisposing factors include excessive alcohol intake, mental impairment and psychiatric illnesses. Usually, the detection of a migratory foreign body is incidental when patients present with unrelated symptoms. A 50-year-old woman attended the surgical outpatient clinic with a foreign body in the anterior abdominal wall. A foreign body was easily palpable on the right upper quadrant of abdomen. Patient was admitted electively and taken to theatre for removal of foreign body under general anaesthesia. Patient made an uneventful recovery and was discharged with no further follow-up. Foreign body; Abdomen; Ingestion; Perforation.


Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.


Field-flow fractionation: analysis of macromolecular, colloidal, and particulate materials.
Field-flow fractionation (FFF) is a family of flexible elution techniques capable of simultaneous separation and measurement. Its sample domain extends across a broad macromolecular-colloidal-particulate continuum from about 1 nanometer to more than 100 micrometers and incorporates both simple and complex macromaterials of biological, biomedical, industrial, and environmental relevance. Complex materials are separated into components to simplify measurement. Component properties measurable by FFF include mass, size, density, charge, diffusivity, and thickness of adsorbed layers. When characterization by these properties is inadequate, other measurement tools can be readily coupled to FFF, either off-line or on-line, by virtue of its flow-elution operation. This article describes the principles and major subtechniques of the FFF family along with application of its measurement and separative capabilities.


A qualitative study of patients' perceptions of the value of molecular diagnosis for familial hypercholesterolemia (FH).
For many years, familial hypercholesterolemia (FH), an inherited disorder, has been diagnosed using phenotypic features plus family history of early onset cardiovascular disease (CVD), and has been successfully treated using statin therapy. DNA testing is now available and this has been incorporated into familial cascade screening programmes in many parts of Europe. Little is known about patients' perceptions of the value of undergoing molecular diagnosis for FH. In-depth interviews were carried out with patients (n = 38) being treated for FH who were the first in their family to undergo DNA testing for FH. Data were analysed thematically. While interviewees regarded DNA testing as an unexceptional event, it was seen as a positive innovation because it confirmed that their family carried a particular disorder, offered an aetiological explanation for their hypercholesterolemia and provided information about their own and family members' future risks. From the patient perspective, the main benefit of molecular diagnosis lies in its ability to provide information which allows (younger) family members to access genetic screening and, thus, timely treatment. The implications for future developments in genetic services and the need to investigate further the provision of molecular testing in mainstream specialties are briefly discussed.


TβRIII independently binds type I and type II TGF-β receptors to inhibit TGF-β signaling.
Transforming growth factor-β (TGF-β) receptor oligomerization has important roles in signaling. Complex formation among type I and type II (TβRI and TβRII) TGF-β receptors is well characterized and is essential for signal transduction. However, studies on their interactions with the type III TGF-β coreceptor (TβRIII) in live cells and their effects on TGF-β signaling are lacking. Here we investigated the homomeric and heteromeric interactions of TβRIII with TβRI and TβRII in live cells by combining IgG-mediated patching/immobilization of a given TGF-β receptor with fluorescence recovery after photobleaching studies on the lateral diffusion of a coexpressed receptor. Our studies demonstrate that TβRIII homo-oligomerization is indirect and depends on its cytoplasmic domain interactions with scaffold proteins (mainly GIPC). We show that TβRII and TβRI bind independently to TβRIII, whereas TβRIII augments TβRI/TβRII association, suggesting that TβRI and TβRII bind to TβRIII simultaneously but not as a complex. TβRIII expression inhibited TGF-β-mediated Smad2/3 signaling in MDA-MB-231 cell lines, an effect that depended on the TβRIII cytoplasmic domain and did not require TβRIII ectodomain shedding. We propose that independent binding of TβRI and TβRII to TβRIII competes with TβRI/TβRII signaling complex formation, thus inhibiting TGF-β-mediated Smad signaling.


Quality assurance for screening mammography data collection systems in 22 countries.
To document the mammography data that are gathered by the organized screening programs participating in the International Breast Cancer Screening Network (IBSN), the nature of their procedures for data quality assurance, and the measures used to assess program performance and impact. A detailed questionnaire covering multiple aspects of quality assurance in screening mammography was mailed to IBSN representatives in 23 countries. Countries collect a wealth of screening mammography data, much of it computerized. Most countries have designated staff for data quality assurance. All provide staff training, and most have documentation requirements for data collection. Nearly all have one or more procedures to maintain data confidentiality. Countries are heterogeneous in collecting and assessing data to monitor screening program performance and impact. Demonstrating that population-based screening mammography reduces breast cancer mortality requires collection of high-quality data on key aspects of the multi-step screening process. Assuring the quality of data collection systems for screening mammography programs is an important and evolving area for IBSN countries.


Transcriptome Analysis on Monocytes from Patients with Neovascular Age-Related Macular Degeneration.
Mononuclear phagocytes (MPs), including monocytes/macrophages, play complex roles in age-related macular degeneration (AMD) pathogenesis. We reported altered gene-expression signature in peripheral blood mononuclear cells from AMD patients, and a chemokine receptor signature on AMD monocytes. To obtain comprehensive understanding of MP involvement, particularly in peripheral circulation in AMD, we performed global gene expression analysis in monocytes. We separated monocytes from treatment-naïve neovascular AMD (nvAMD) patients (n = 14) and age-matched controls (n = 15), and performed microarray and bioinformatics analysis. Quantitative real-time PCR was performed on other sets of nvAMD (n = 25), atrophic AMD (n = 21), and controls (n = 28) for validation. This validated microarray genes (like TMEM176A/B and FOSB) tested, including differences between nvAMD and atrophic AMD. We identified 2,165 differentially-expressed genes (P < 0.05), including 79 genes with log2 fold change ≥1.5 between nvAMD and controls. Functional annotation using DAVID and TANGO demonstrated immune response alterations in AMD monocytes (FDR-P <0.05), validated by randomized data comparison (P < 0.0001). GSEA, ISMARA, and MEME analysis found immune enrichment and specific involved microRNAs. Enrichment of differentially-expressed genes in monocytes was found in retina via SAGE data-mining. These genes were enriched in non-classical vs. classical monocyte subsets (P < 0.05). Therefore, global gene expression analysis in AMD monocytes reveals an altered immune-related signature, further implicating systemic MP activation in AMD.


Diagnostic test for mucopolysaccharidosis. I. Direct method for quantifying excessive urinary glycosaminoglycan excretion.
This direct method for quantifying excessive urinary glycosaminoglycan excretion exploits the specific binding of 1,9-dimethylmethylene blue (DMB). The procedure obviates cumbersome and labor-intensive procedures for separating glycosaminoglycans from other constituents of urine. Pediatric pharmaceutical formulations (except heparin), in concentrations expected in urine, do not interfere with spectrophotometry, nor does protein. Results can be expressed in terms of urinary creatinine; thus the test is applicable to very small urine specimens (0.1 mL), such as those obtainable from neonates. In a pilot study, results of the direct DMB test for 48 urine specimens agreed with the clinical diagnosis, and quantitative measurements correlated moderately (r = 0.76) with results of a commonly used procedure (carbazole-borate reactivity after precipitation with cetylpyridinium chloride). The present method was also used to assess metabolic correction in a patient with Hurler's syndrome after treatment by bone-marrow transplantation. This quantitative method surmounts the major technical problems of developing mass screening programs for infants, thus offering the potential for earlier diagnosis and treatment of mucopolysaccharidosis diseases.


Blister-Actuated LIFT Printing for Multiparametric Functionalization of Paper-Like Biosensors.
Laser induced forward transfer (LIFT) is a flexible digital printing process for maskless, selective pattern transfer, which uses single laser pulses focused through a transparent carrier substrate onto a donor layer to eject a tiny volume of the donor material towards a receiver substrate. Here, we present an advanced method for the high-resolution micro printing of bio-active detection chemicals diluted in a viscous buffer solution by transferring droplets with precisely controllable volumes using blister-actuated LIFT (BA-LIFT). This variant of the LIFT process makes use of an intermediate polyimide layer partially ablated by the laser pulses. The expanding gaseous ablation products lead to blisters in the polyimide and ejection of droplets from the subjacent viscous solution layer. A relative movement of donor and receiver substrates for the transfer of partially overlapping pixels is realized with a custom-made positioning system. Using a specially developed donor ink containing bio-active components presented method allows to transfer droplets with well controllable volumes between 20 fL and 6 pL, which is far more precise than other methods like inkjet or contact printing. The usefulness of the process is demonstrated by locally functionalizing laser-structured nitrocellulose paper-like membranes to form a multiparametric lateral flow test. The recognition zones localized within parallel micro channels exhibit a well-defined and homogeneous color change free of coffee-ring patterns, which is of utmost importance for reliable optical readout in miniature multiparametric test systems.


Evaluation of the effect of insulin sensitivity-enhancing lifestyle- and dietary-related adjuncts on antidepressant treatment response: protocol for a systematic review and meta-analysis.
Depression is the leading cause of disability worldwide and is known to be associated with insulin resistance (IR). Insulin resistance worsens the symptoms of depression and reduces the effectiveness of antidepressant medications in some depressed patients. Many studies have assessed the effect of adjunctive exercise, vitamin D supplementation, zinc supplementation, magnesium, probiotics, unsaturated fatty acids, and hygienic-dietary recommendations (sleep hygiene, healthy diet, physical activity, and sunlight exposure, combined or singly used), individually, on antidepressant treatment response. However, despite the reported insulin sensitivity-enhancing potential of these adjuncts, no systematic review has collectively analysed their antidepressant effect with regards to insulin sensitivity. In this systematic review, we will analyse the effect of the above-stated adjuncts on antidepressant treatment response (primary outcome) in comparison with treatment as usual with or without adjunctive placebo after identifying the relevant trials from a systematic literature search. Randomised controlled trials involving clinically depressed patients with diagnosis of major depressive, dysthymic or bipolar disorder will be considered. Changes in insulin sensitivity parameters, following treatment, will also be analysed as the secondary outcome. Effect estimates of the included trials will be combined using random-effects meta-analysis, while addressing risk of bias issues. Any significant heterogeneity between studies will be explored using sensitivity and subgroup analyses. The findings of this review will contribute to the evidence base regarding the utility of non-pharmacological insulin-sensitising treatments in enhancing conventional antidepressant treatment response.


Transductive Learning for Multi-Label Protein Subchloroplast Localization Prediction.
Predicting the localization of chloroplast proteins at the sub-subcellular level is an essential yet challenging step to elucidate their functions. Most of the existing subchloroplast localization predictors are limited to predicting single-location proteins and ignore the multi-location chloroplast proteins. While recent studies have led to some multi-location chloroplast predictors, they usually perform poorly. This paper proposes an ensemble transductive learning method to tackle this multi-label classification problem. Specifically, given a protein in a dataset, its composition-based sequence information and profile-based evolutionary information are respectively extracted. These two kinds of features are respectively compared with those of other proteins in the dataset. The comparisons lead to two similarity vectors which are weighted-combined to constitute an ensemble feature vector. A transductive learning model based on the least squares and nearest neighbor algorithms is proposed to process the ensemble features. We refer to the resulting predictor to as EnTrans-Chlo. Experimental results on a stringent benchmark dataset and a novel dataset demonstrate that EnTrans-Chlo significantly outperforms state-of-the-art predictors and particularly gains more than 4% (absolute) improvement on the overall actual accuracy. For readers' convenience, EnTrans-Chlo is freely available online at http://bioinfo.eie.polyu.edu.hk/EnTransChloServer/.


Effect of hydraulic retention time and seed material on phosphorus recovery and crystal size from urine in an air-agitated reactor.
Phosphorus (P) recovery from urine is affected by various parameters. This study evaluates the effects of hydraulic retention time (HRT) and seed material on P recovery and crystal size in an air-agitated reactor. Results show that ortho-phosphate removal and struvite recovery efficiencies were 96.3% and 89.5%, and 97.1% and 93.0%, after five runs of HRTs of 1 and 2 h, respectively. Low loss of crystals from effluent urine solutions indicates high struvite recovery efficiency and is correlated with the structure and design of the reactor. The average particle size decreased from 40.0 to 31.7 μm as the HRT increased from 1 to 2 h. The two types of seed materials (zeolite and molecular sieve) did not affect the ortho-phosphate removal efficiency but affected the struvite crystal size. In particular, multi-stage addition of zeolites increased the average crystal size from 33.7 to 57.0 μm.


Towards a new combination therapy for tuberculosis with next generation benzothiazinones.
The benzothiazinone lead compound, BTZ043, kills Mycobacterium tuberculosis by inhibiting the essential flavo-enzyme DprE1, decaprenylphosphoryl-beta-D-ribose 2-epimerase. Here, we synthesized a new series of piperazine-containing benzothiazinones (PBTZ) and show that, like BTZ043, the preclinical candidate PBTZ169 binds covalently to DprE1. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Compared to BTZ043, PBTZ169 has improved potency, safety and efficacy in zebrafish and mouse models of tuberculosis (TB). When combined with other TB drugs, PBTZ169 showed additive activity against M. tuberculosis in vitro except with bedaquiline (BDQ) where synergy was observed. A new regimen comprising PBTZ169, BDQ and pyrazinamide was found to be more efficacious than the standard three drug treatment in a murine model of chronic disease. PBTZ169 is thus an attractive drug candidate to treat TB in humans.


Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight.
Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate while playing a role in anxiety behaviors and physiological responses to stress. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of glutamatergic GGC peptide-secreting hindbrain neurons in regulating metabolic homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation of GCG-producing neurons reduces metabolic rate and food intake in fed and fasted states and suppresses glucose production without an effect on glucose uptake. Stimulation of GCG neurons had no effect on corticosterone secretion, body weight, or conditioned taste aversion. In the diet-induced obese state, the effects of GCG neuronal stimulation on gluconeogenesis were lost, while the food intake-lowering effects remained, resulting in reductions in body weight and adiposity. Our work suggests that GCG peptide-expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion. We conclude that GCG neurons likely stimulate separate populations of downstream cells to produce a change in food intake and glucose homeostasis and that these effects depend on the metabolic state of the animal.


Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia.
Statin therapy is the gold standard for hypercholesterolemia. However, a significant number of patients cannot achieve their target low-density lipoprotein (LDL) levels despite a maximal dose of statin therapy, and some cannot tolerate statins at all. Approval of proprotein convertase subtilisin/kexin type 9 inhibitors has been revolutionary for those patients. However, the need for frequent injections limits patient compliance with their use. Recently, a twice-yearly injection of inclisiran, a small interfering RNA, has been shown to inhibit hepatic synthesis of proprotein convertase subtilisin/kexin type 9. However, patient randomized clinical trial has been underpowered for clinical end points, necessitating a meta-analysis of those trials. The weighted mean difference was used to describe continuous variables, and pooled risk ratios, calculated using a random effects model, were used to describe discrete variables. Data from 3 randomized clinical trials comprising 3,660 patients showed that inclisiran decreased LDL cholesterol levels by 51% (95% Confidence Interval, 48 to 53%; p < 0.001) compared with placebo. It was associated with a 24% lower major adverse cardiovascular events rate (risk ratios = 0.76; 95% Confidence Interval, 0.61 to 0.92). It also significantly decreased total cholesterol by 37%, apolipoprotein B by 41%, and non high-density lipoprotein (HDL) cholesterol by 45% (all p < 0.001). No differences were found in adverse events, abnormalities in liver function tests, or creatine kinase levels between the treatment strategies. However, a mild injection site reaction occurred more frequently in the inclisiran group. In conclusions, in patients with hypercholesterolemia, inclisiran decreased LDL level by 51% without significant adverse effects. Additionally, it was associated with a lower major adverse cardiovascular event rate.


Dry Needling Adds No Benefit to the Treatment of Neck Pain: A Sham-Controlled Randomized Clinical Trial With 1-Year Follow-up.
To examine the short- and long-term effectiveness of dry needling on disability, pain, and patient-perceived improvements in patients with mechanical neck pain when added to a multimodal treatment program that includes manual therapy and exercise. Randomized controlled trial. Seventy-seven adults (mean ± SD age, 46.68 ± 14.18 years; 79% female) who were referred to physical therapy with acute, subacute, or chronic mechanical neck pain were randomly allocated to receive 7 multimodal treatment sessions over 4 weeks of (1) dry needling, manual therapy, and exercise (needling group); or (2) sham dry needling, manual therapy, and exercise (sham needling group). The primary outcome of disability (Neck Disability Index score) and secondary outcomes of pain (current and 24-hour average) and patient-perceived improvement were assessed at baseline and follow-ups of 4 weeks, 6 months, and 1 year by blinded assessors. Between-group differences were analyzed with a 2-way, repeated-measures analysis of variance. Global rating of change was analyzed with a Mann-Whitney U test. There were no group-by-time interactions for disability (Neck Disability Index: F2.37,177.47 = 0.42, P = .69), current pain (visual analog scale: F2.84,213.16 = 1.04, P = .37), or average pain over 24 hours (F2.64,198.02 = 0.01, P = .10). There were no between-group differences for global rating of change at any time point (P≥.65). Both groups improved over time for all variables (Neck Disability Index: F2.37,177.47 = 124.70, P<.001; current pain: F2.84,213.16 = 64.28, P<.001; and average pain over 24 hours: F2.64,198.02 = 76.69, P<.001). There were no differences in outcomes between trigger point dry needling and sham dry needling when added to a multimodal treatment program for neck pain. Dry needling should not be part of a first-line approach to managing neck pain. J Orthop Sports Phys Ther 2021;51(1):37-45. doi:10.2519/jospt.2021.9864.


Experience with the design and start up of two full-scale UASB plants in Brazil: enhancements and drawbacks.
This paper discusses the main drawbacks and enhancements experienced with the design and start up of two full-scale UASB plants in Brazil. The topics addressed are related to blockage of inlet pipes, scum accumulation, seed sludge for the start-up, corrosion and gas leakage, odour generation and sludge management. The paper describes the main improvements achieved.


Relationship of acivicin-induced monocytoid differentiation of human myeloid leukemia cells to acivicin-induced modulation of growth factor, cytokine, and protooncogene mRNA expression.
We have previously noted that the glutamine antagonist acivicin (alpha S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces monocytoid differentiation of freshly isolated human myeloid leukemia cells and HL-60 cells. This study was designed to determine the effects of acivicin on the levels of HL-60 cell mRNA transcripts of several cytokines, growth factors, and protooncogenes implicated in the control of hematopoietic cell proliferation and differentiation. Control HL-60 cells did not express mRNA for granulocyte-colony-stimulating factor, granulocyte-macrophage-colony-stimulating factor, interleukin 3, or interleukin 6, and acivicin or phorbol myristate acetate did not induce their expression. Phorbol myristate acetate reduced expression of c-myc, c-myb, and heat shock protein 70 and enhanced those of macrophage-colony-stimulating factor and c-fms. Acivicin caused a decreased expression of c-myc, and an increased expression of mRNA for interleukin 1 beta and tumor necrosis factor alpha (TNF-alpha). The drug also caused an initial increase in c-myb, followed by a subsequent decrease below baseline levels. Supernatants and lysates of acivicin-treated HL-60 cells contained increased levels of interleukin 1 beta. Both TNF-alpha and interleukin 1 beta have been shown previously to influence hematopoietic cell differentiation. In our experiments, exogenous interleukin 1 added to HL-60 cells did not induce differentiation, but the combination of interleukin 1 and TNF synergistically enhanced the process. Pretreatment of the cells with TNF enhanced their responsiveness to subsequent treatment with interleukin 1. Our results demonstrate that the glutamine antagonist acivicin modulates HL-60 cell expression of TNF-alpha, interleukin 1 beta, c-myc, and c-myb and suggest that interleukin 1 beta and TNF-alpha might (in an autocrine manner) cause the differentiation.


The Cochrane Collaboration.
The Cochrane Collaboration is an international organisation that aims to help people make well-informed decisions about health care by preparing, maintaining and ensuring the accessibility of systematic reviews of the benefits and risks of health care interventions. We describe the structure and activities of the Cochrane Collaboration, especially focusing on the carrying out of systematic reviews of randomised trials. We describe the place of surgery and surgeons within the Cochrane Collaboration.


In vitro integration of retrotransposon Ty1: a direct physical assay.
Retrotransposon Ty1 of Saccharomyces cerevisiae inserts a double-stranded Ty1 cDNA into the yeast genome by a reaction analogous to the integration mechanism used by retroviruses. A quantitative in vitro integration assay that directly detects integrative recombination products was developed for Ty1. Blunt-ended artificial radioactive substrates bearing Ty1 termini integrate into circular or linear target DNAs. The reaction is specific for native integrase isolated in the form of virus-like particles; virus-like particles prepared from integrase mutants were completely inactive in this assay. The products are radioactive, allowing direct detection after gel electrophoresis by autoradiography. Using this simple and amenable system, we characterized the biochemical requirements of the system and the structures of the major integration products. Two classes of products were detected: those that were the result of bona fide complete integration events (concerted reactions) and single-end joinings of substrate to target (half-reactions). Additionally, we used a genetic selection scheme to identify and characterize target sites of complete integration events into a circular target plasmid; a 5-bp target site duplication flanking the inserted DNA resembling the duplication characteristic of in vivo integration was observed.


Molecular epidemiology of HIV-1 subtype A in former Soviet Union countries.
While in other parts of the world it is on decline, incidence of HIV infection continues to rise in the former Soviet Union (FSU) countries. The present study was conducted to investigate the patterns and modes of HIV transmission in FSU countries. We performed phylogenetic analysis of publicly available 2705 HIV-1 subtype A pol sequences from thirteen FSU countries: Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Russia, Ukraine and Uzbekistan. Our analysis showed that the clusters from FSU countries were intermixed, indicating a possible role of transmigration in HIV transmission. Injection drug use was found to be the most frequent mode of transmission, while the clusters from PWID and heterosexual transmission were intermixed, indicating bridging of HIV infection across populations. To control the expanding HIV epidemic in this region, harm reduction strategies should be focused on three modes of transmission, namely, cross-border migration, injection drug use and heterosexual.


2,6-Diisopropylphenol protects osteoblasts from oxidative stress-induced apoptosis through suppression of caspase-3 activation.
2,6-Diisopropylphenol is an intravenous anesthetic agent used for induction and maintenance of anesthesia. Since it is similar to alpha-tocopherol, 2,6-diisopropylphenol may have antioxidant effects. Osteoblasts play important roles in bone remodeling. In this study, we attempted to evaluate the protective effects of 2,6-diisopropylphenol on oxidative stress-induced osteoblast insults and their possible mechanisms, using neonatal rat calvarial osteoblasts as the experimental model. Clinically relevant concentrations of 2,6-diisopropylphenol (3 and 30 microM) had no effect on osteoblast viability. However, 2,6-diisopropylphenol at 300 microM time-dependently caused osteoblast death. Exposure to sodium nitroprusside (SNP), a nitric oxide donor, increased amounts of nitrite in osteoblasts. 2,6-Diisopropylphenol did not scavenge basal or SNP-releasing nitric oxide. Hydrogen peroxide (HP) enhanced levels of intracellular reactive oxygen species in osteoblasts. 2,6-Diisopropylphenol significantly reduced HP-induced oxidative stress. Exposure of osteoblasts to SNP and HP decreased cell viability time-dependently. 2,6-Diisopropylphenol protected osteoblasts from SNP- and HP-induced cell damage. Analysis by a flow cytometric method revealed that SNP and HP induced osteoblast apoptosis. 2,6-Diisopropylphenol significantly blocked SNP- and HP-induced osteoblast apoptosis. Administration of SNP and HP increased caspase-3 activities. However, 2,6-diisopropylphenol significantly decreased SNP- and HP-enhanced caspase-3 activities. This study shows that a therapeutic concentration of 2,6-diisopropylphenol can protect osteoblasts from SNP- and HP-induced cell insults, possibly via suppression of caspase-3 activities.


Quality of life in patients with gastroschisis is comparable with the general population: A questionnaire survey.
To evaluate long-term quality of life and somatic growth of patients with gastroschisis and compare them with the general population. We performed a questionnaire survey of the quality of life of our patients treated between 2004-2012. A questionnaire was sent to our 56 patients with gastroschisis, 38 mothers of patients (68%) responded to the questionnaire. 33 of 38 mothers claim that the quality of life of their child is very good, 4 of them responded that it is good. 1 mother confessed that the quality of life was very poor. Anthropometric data show comparable results with the standard population except for patients of 1 year of age who still have lower weight (P<0.001) and body height in the 5th percentile and patients of 3 years of age who are also significantly thinner. 13% of patients in our study group have gastrointestinal problems. 9 patients (24%) attend follow-up at the neurological center (Attention Deficit Hyperactivity Disorder n=6, mental retardation n=1, dysarthria n=2), however, overall intellectual abilities are within normal range. 7 patients underwent surgery for umbilical (n=3) or inguinal hernia (n=4), 2 patients were operated on for undescended testicles, 3 patients were operated on for an adhesive ileus. 92% of mothers are very satisfied with the cosmetic result of the scar. The study has shown that the majority of patients after operation of gastroschisis have a very good quality of life without limitation in comparison with the general population. The presented anthropometric data confirm that the development of patients with gastroschisis is favourable.


Substance use among Dutch homeless people, a follow-up study: prevalence, pattern and housing status.
Previous studies have shown that substance use among homeless people is a prevalent problem that is associated with longer durations of homelessness. Most studies of substance use among the homeless were carried out outside Europe and have limited generalizability to European countries. This study therefore aimed to address the prevalence of substance use among homeless people in the Netherlands, the pattern of their use and the relationship with housing status at follow-up. This study included 344 participants (67.1% of the initial cohort) who were followed from baseline to 18 months after the baseline interview. Multinomial logistic regression analyses examined the relationship between substance use and housing status. The most reported substances which were used among these homeless people were cannabis (43.9%) and alcohol (≥5 units on one occasion) (30.7%). Other substances were used by around 5% or less of the participants. Twenty-seven percent were classified as substance misuser and 20.9% as substance dependent. The odds to be marginally housed (4.14) or institutionalized (2.12) at follow-up compared to being housed of participants who were substance users were significantly higher than those of participants who did not use substances. The odds to be homeless were more than twice as high (2.80) for participants who were substance dependent compared with those who were not. Homeless people who use substances have a more disadvantageous housing situation at follow-up than homeless people who do not use substances. Attention is needed to prevent and reduce long-term homelessness among substance-using homeless people.


Direct and continuous strain control of catalysts with tunable battery electrode materials.
We report a method for using battery electrode materials to directly and continuously control the lattice strain of platinum (Pt) catalyst and thus tune its catalytic activity for the oxygen reduction reaction (ORR). Whereas the common approach of using metal overlayers introduces ligand effects in addition to strain, by electrochemically switching between the charging and discharging status of battery electrodes the change in volume can be precisely controlled to induce either compressive or tensile strain on supported catalysts. Lattice compression and tension induced by the lithium cobalt oxide substrate of ~5% were directly observed in individual Pt nanoparticles with aberration-corrected transmission electron microscopy. We observed 90% enhancement or 40% suppression in Pt ORR activity under compression or tension, respectively, which is consistent with theoretical predictions.


Electronic structure of solids with competing periodic potentials.
When electrons are subject to a potential with two incommensurate periods, translational invariance is lost, and no periodic band structure is expected. However, model calculations based on nearly free one-dimensional electrons and experimental results from high-resolution photoemission spectroscopy on a quasi-one-dimensional material do show dispersing band states with signatures of both periodicities. Apparent band structures are generated by the nonuniform distribution of electronic spectral weight over the complex eigenvalue spectrum.


Immunocytochemical demonstration of tissue-type plasminogen activator in endocrine cells of the rat pituitary gland.
We immunocytochemically stained rat pituitary glands using antibodies against plasminogen activators of the tissue type (t-PA) and the urokinase type (u-PA). A large population of endocrine cells in the anterior lobe of the gland displayed intense cytoplasmic immunoreactivity with anti-t-PA. In some areas of the intermediate lobe we found a weak staining, and we observed weakly staining granular structures in the posterior lobe. Controls included absorption of the antibodies with highly purified t-PA. In addition, SDS PAGE followed by immunoblotting of pituitary gland extracts revealed only one band with an electrophoretic mobility similar to that of t-PA when stained with anti-t-PA IgG. No u-PA immunoreactivity was detected in the rat pituitary gland. Sequential staining experiments using antibodies against growth hormone and t-PA demonstrated that the t-PA-immunoreactive cells constitute a large subpopulation of the growth hormone-containing cells. These findings represent the first direct evidence for the presence of t-PA in cell types other than endothelial cells in the intact normal organism. In this article we discuss the implications of the results for a possible role of t-PA in the posttranslational processing of prohormones.


Structure of the Catalytic Domain of the Class I Polyhydroxybutyrate Synthase from Cupriavidus necator.
Polyhydroxybutyrate synthase (PhaC) catalyzes the polymerization of 3-(R)-hydroxybutyryl-coenzyme A as a means of carbon storage in many bacteria. The resulting polymers can be used to make biodegradable materials with properties similar to those of thermoplastics and are an environmentally friendly alternative to traditional petroleum-based plastics. A full biochemical and mechanistic understanding of this process has been hindered in part by a lack of structural information on PhaC. Here we present the first structure of the catalytic domain (residues 201-589) of the class I PhaC from Cupriavidus necator (formerly Ralstonia eutropha) to 1.80 Å resolution. We observe a symmetrical dimeric architecture in which the active site of each monomer is separated from the other by ∼33 Å across an extensive dimer interface, suggesting a mechanism in which polyhydroxybutyrate biosynthesis occurs at a single active site. The structure additionally highlights key side chain interactions within the active site that play likely roles in facilitating catalysis, leading to the proposal of a modified mechanistic scheme involving two distinct roles for the active site histidine. We also identify putative substrate entrance and product egress routes within the enzyme, which are discussed in the context of previously reported biochemical observations. Our structure lays a foundation for further biochemical and structural characterization of PhaC, which could assist in engineering efforts for the production of eco-friendly materials.


Evaluation of Pulp Chamber Dimensions of Primary Molars From Bitewing Radiographs.
The purpose of this study was to measure key anatomic landmarks related to pulp chamber morphology in primary maxillary and mandibular first and second molars. Bitewing radiographs of 42 subjects were taken under standardized conditions using a millimeter X-ray grid. One hundred fifty-three primary molars (44 maxillary first molars, 49 maxillary second molars, 30 mandibular first molars, and 30 mandibular second molars) were analyzed for the required anatomic landmarks using Image J Analysis Software. The data were analyzed in terms of mean, standard deviation, and coefficient of variance for each measurement. Mean measurements were compared using one-way analysis of variance followed by Tukey's post-hoc HSD test. The distance between cusp tip to pulp chamber ceiling was approximately four mm, the distance between pulpal floor to furcation was approximately 1.7 mm, and the average height of the pulp chamber was observed to be in the range of two to three mm. The key measurements involved in access cavity preparation were consistent across the different types of primary molars.


A systematic review of clinical outcomes for patients diagnosed with skin cancer spinal metastases.
OBJECT Surgical procedures and/or adjuvant therapies are effective modalities for the treatment of symptomatic spinal metastases. However, clinical results specific to the skin cancer spinal metastasis cohort are generally lacking. The purpose of this study was to systematically review the literature for treatments, clinical outcomes, and survival following the diagnosis of a skin cancer spinal metastasis and evaluate prognostic factors in the context of spinal skin cancer metastases stratified by tumor subtype. METHODS The authors performed a literature review using PubMed, Embase, CINAHL, and Web of Science to identify articles since 1950 that reported survival, clinical outcomes, and/or prognostic factors for the skin cancer patient population with spinal metastases. The methodological quality of reviews was assessed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) tool. RESULTS Sixty-five studies met the preset criteria and were included in the analysis. Of these studies, a total of 25, 40, 25, and 12 studies included patients who underwent some form of surgery, radiotherapy, chemotherapy, or observation alone, respectively. Sixty-three of the 65 included studies were retrospective in nature (Class of Evidence [CoE] IV), and the 2 prospective studies were CoE II. Based on the studies analyzed, the median overall survival for a patient with a spinal metastasis from a primary skin malignancy is 4.0 months; survival by tumor subtype is 12.5 months for patients with basal cell carcinoma (BCC), 4.0 months for those with melanoma, 4.0 months for those with squamous cell carcinoma, 3.0 months for those with pilomatrix carcinoma, and 1.5 months for those with Merkel cell carcinoma (p < 0.0001). The overall percentage of known continued disease progression after spine metastasis diagnosis was 40.1% (n = 244/608, range 25.0%-88.9%), the rate of known recurrence of the primary skin cancer lesion was 3.5% (n = 21/608, range 0.2%-100.0%), and the rate of known spine metastasis recurrence despite treatment for all skin malignancies was 2.8% (n = 17/608, range 0.0%-33.3%). Age greater than 65 years, sacral spinal involvement, presence of a neurological deficit, and nonambulatory status were associated with decreased survival in patients diagnosed with a primary skin cancer spinal metastasis. All other clinical or prognostic parameters were of low or insufficient strength. CONCLUSIONS Patients diagnosed with a primary skin cancer metastasis to the spine have poor overall survival with the exception of those with BCC. The median duration of survival for patients who received surgical intervention alone, medical management (chemotherapy and/or radiation) alone, or the combination of therapies was similar across interventions. Age, spinal region, and neurological status may be associated with poor survival following surgery.


Optimization and enhancement of H&E stained microscopical images by applying bilinear interpolation method on lab color mode.
Hematoxylin & Eosin (H&E) is a widely employed technique in pathology and histology to distinguish nuclei and cytoplasm in tissues by staining them in different colors. This procedure helps to ease the diagnosis by enhancing contrast through digital microscopes. However, microscopic digital images obtained from this technique usually suffer from uneven lighting, i.e. poor Koehler illumination. Several off-the-shelf methods particularly established to correct this problem along with some popular general commercial tools have been examined to find out a robust solution. First, the characteristics of uneven lighting in pathological images obtained from the H&E technique are revealed, and then how the quality of these images can be improved by employing bilinear interpolation based approach applied on the channels of Lab color mode is explored without losing any essential detail, especially for the color information of nuclei (hematoxylin stained sections). Second, an approach to enhance the nuclei details that are a fundamental part of diagnosis and crucially needed by the pathologists who work with digital images is demonstrated. Merits of the proposed methodology are substantiated on sample microscopic images. The results show that the proposed methodology not only remedies the deficiencies of H&E microscopical images, but also enhances delicate details. Non-uniform illumination problems in H&E microscopical images can be corrected without compromising crucial details that are essential for revealing the features of tissue samples.


Words by the tail: Assessing lexical diversity in scholarly titles using frequency-rank distribution tail fits.
This research assesses the evolution of lexical diversity in scholarly titles using a new indicator based on zipfian frequency-rank distribution tail fits. At the operational level, while both head and tail fits of zipfian word distributions are more independent of corpus size than other lexical diversity indicators, the latter however neatly outperforms the former in that regard. This benchmark-setting performance of zipfian distribution tails proves extremely handy in distinguishing actual patterns in lexical diversity from the statistical noise generated by other indicators due to corpus size fluctuations. From an empirical perspective, analysis of Web of Science (WoS) article titles from 1975 to 2014 shows that the lexical concentration of scholarly titles in Natural Sciences & Engineering (NSE) and Social Sciences & Humanities (SSH) articles increases by a little less than 8% over the whole period. With the exception of the lexically concentrated Mathematics, Earth & Space, and Physics, NSE article titles all increased in lexical concentration, suggesting a probable convergence of concentration levels in the near future. As regards to SSH disciplines, aggregation effects observed at the disciplinary group level suggests that, behind the stable concentration levels of SSH disciplines, a cross-disciplinary homogenization of the highest word frequency ranks may be at work. Overall, these trends suggest a progressive standardization of title wording in scientific article titles, as article titles get written using an increasingly restricted and cross-disciplinary set of words.


HEXIM1 and NEAT1 Long Non-coding RNA Form a Multi-subunit Complex that Regulates DNA-Mediated Innate Immune Response.
The DNA-mediated innate immune response underpins anti-microbial defenses and certain autoimmune diseases. Here we used immunoprecipitation, mass spectrometry, and RNA sequencing to identify a ribonuclear complex built around HEXIM1 and the long non-coding RNA NEAT1 that we dubbed the HEXIM1-DNA-PK-paraspeckle components-ribonucleoprotein complex (HDP-RNP). The HDP-RNP contains DNA-PK subunits (DNAPKc, Ku70, and Ku80) and paraspeckle proteins (SFPQ, NONO, PSPC1, RBM14, and MATRIN3). We show that binding of HEXIM1 to NEAT1 is required for its assembly. We further demonstrate that the HDP-RNP is required for the innate immune response to foreign DNA, through the cGAS-STING-IRF3 pathway. The HDP-RNP interacts with cGAS and its partner PQBP1, and their interaction is remodeled by foreign DNA. Remodeling leads to the release of paraspeckle proteins, recruitment of STING, and activation of DNAPKc and IRF3. Our study establishes the HDP-RNP as a key nuclear regulator of DNA-mediated activation of innate immune response through the cGAS-STING pathway.


Laboratory and field evaluation of a SAW microsensor array for measuring perchloroethylene in breath.
This article describes the laboratory and field performance evaluation of a small prototype instrument employing an array of six polymer-coated surface acoustic wave (SAW) sensors and a thermal desorption preconcentration unit for rapid analysis of perchloroethylene in breath. Laboratory calibrations were performed using breath samples spiked with perchloroethylene to prepare calibration standards spanning a concentration range of 0.1-10 ppm. A sample volume of 250 mL was preconcentrated on 40 mg of Tenax GR at a flow rate of 100 mL/min, followed by a dry air purge and thermal desorption at a temperature of 200 degrees C. The resulting pulse of vapor was passed over the sensor array at a flow rate of 20 mL/min and sensor responses were recorded and displayed using a laptop computer. The total time per analysis was 4.5 min. SAW sensor responses were linear, and the instrument's limit of detection was estimated to be 50 ppb based on the criterion that four of the six sensors show a detectable response. Field performance was evaluated at a commercial dry-cleaning operation by comparing prototype instrument results for breath samples with those of a portable gas chromatograph (NIOSH 3704). Four breath samples were collected from a single subject over the course of the workday and analyzed using the portable gas chromatograph (GC) and SAW instruments. An additional seven spiked breath samples were prepared and analyzed so that a broader range of perchloroethylene concentrations could be examined. Linear regression analysis showed excellent agreement between prototype instrument and portable GC breath sample results with a correlation coefficient of 0.99 and a slope of 1.04. The average error for the prototype instrument over a perchloroethylene breath concentration range of 0.9-7.2 ppm was 2.6% relative to the portable GC. These results demonstrate the field capabilities of SAW microsensor arrays for rapid analysis of organic vapors in breath.


Interpretation of Depression Detection Models via Feature Selection Methods.
Given the prevalence of depression worldwide and its major impact on society, several studies employed artificial intelligence modelling to automatically detect and assess depression. However, interpretation of these models and cues are rarely discussed in detail in the AI community, but have received increased attention lately. In this study, we aim to analyse the commonly selected features using a proposed framework of several feature selection methods and their effect on the classification results, which will provide an interpretation of the depression detection model. The developed framework aggregates and selects the most promising features for modelling depression detection from 38 feature selection algorithms of different categories. Using three real-world depression datasets, 902 behavioural cues were extracted from speech behaviour, speech prosody, eye movement and head pose. To verify the generalisability of the proposed framework, we applied the entire process to depression datasets individually and when combined. The results from the proposed framework showed that speech behaviour features (e.g. pauses) are the most distinctive features of the depression detection model. From the speech prosody modality, the strongest feature groups were F0, HNR, formants, and MFCC, while for the eye activity modality they were left-right eye movement and gaze direction, and for the head modality it was yaw head movement. Modelling depression detection using the selected features (even though there are only 9 features) outperformed using all features in all the individual and combined datasets. Our feature selection framework did not only provide an interpretation of the model, but was also able to produce a higher accuracy of depression detection with a small number of features in varied datasets. This could help to reduce the processing time needed to extract features and creating the model.


Salvianolic Acid B-Alleviated Angiotensin II Induces Cardiac Fibrosis by Suppressing NF-κB Pathway In Vitro.
BACKGROUND Salvianolic acid B (SalB) is the representative component of phenolic acids derived from the roots and rhizomes of Salvia miltiorrhiza Bge (Labiatae), which has been used widely in Asian countries for clinical therapy of various cardiovascular dysfunction-related diseases. However, cardiac protection effects and the underlying mechanism for clinical application are still poorly understood. Here, we investigated the potential anti-myocardial fibrosis effect and mechanism of SalB on Angiotensin II (Ang II)-induced cardiac fibrosis in vitro. MATERIAL AND METHODS The proliferation and migration capacity of cardiac fibroblasts (CFBs) were measured by MTT assay and scratch analysis, respectively. The colorimetric assay determined the hydroxyproline content in medium. Western blotting detected the protein expressions of nuclear transcription factor-kappa B (NF-κB) pathway-associated proteins, fibronectin (FN), collagen type I (Coll I), α-smooth muscle actin (α-SMA), and connective tissue growth factor (CTGF). The expression of α-SMA protein was observed by immunofluorescence staining. qRT-PCR detected the mRNA expression of NF-κB. RESULTS SalB attenuated Ang II-induced the proliferation and the migration ability of CFBs. Ang II-induced the extracellular matrix protein Coll I, FN, and α-SMA, the pro-fibrotic cytokine CTGF protein expression was inhibited, and the nuclear translocation of NF-κB p65 subunit was reduced by SalB. Western blotting and qRT-PCR confirmed that SalB blocked the activation of NF-κB induced by Ang II. PDTC (the NF-κB inhibitor) also inhibited proliferation of CFBs and reduced α-SMA and Coll I expression induced by Ang II. CONCLUSIONS SalB can alleviate Ang II-induced cardiac fibrosis via suppressing the NF-κB pathway in vitro.


Vibration effects on static balance and strength.
The purpose of this study was to investigate the effects of a vibration training protocol and a conventional strength training program consisting of similar exercises on knee extensors and flexors strength and postural sway in middle-aged women. 38 women were randomly assigned into a Vibration Group (n=12, static and dynamic exercises on a vibration plate, frequency: 15-25 Hz, amplitude: 2-12.8 cm), a Strength Group (n=16, same exercises without vibration) and a Control Group (n=10). Both experimental groups trained for 12 weeks (3 sessions/w). Static balance was assessed in 3 tasks of increasing difficulty: Normal Quiet Stance, Sharpened Tandem, and One-Legged Stance. Postural sway was evaluated using the Centre of Pressure variations in the Anterior/Posterior and Medio/Lateral direction. Eccentric and concentric strength of knee extensors and flexors was recorded using a Cybex dynamometer. After vibration training, postural sway significantly decreased in both directions for the vibration group in all tasks (p<0.05), whereas no significant differences were observed for the other groups. Isokinetic strength significantly (p<0.05) increased for both experimental groups at selected angular velocities. It was concluded that side-alternating vibration could have beneficial effects on static balance control for middle-aged women. Gains in isokinetic strength were quite similar for both experimental groups.


Post-infectious olfactory loss: a cohort study and update.
Post-infectious olfactory loss is defined as an olfactory dysfunction in the course of an upper respiratory tract infection. Quantitative olfactory dysfunction is usually moderate to severe, with many patients experiencing a qualitative disorder such as parosmia. Diagnosis is made on the basis of patient history, normal clinical examination (no inflammatory disease in the olfactory cleft) and decreased olfactory function. This paper provides an update of pathophysiology, clinical management and prognosis, and also looks at the clinical characteristic of a cohort of 122 patients from our department. Results from orthonasal and retronasal testing, chemosensory event-related potentials and olfactory bulb volume confirmed previous findings: our post-infectious olfactory patients were middle-aged women (sex ratio 2.4; mean age 53.9), with 47.5% and 18% of them complaining of parosmia and phantosmia respectively. More of them were hyposmic than anosmic (64.7% and 35.3% respectively) and 18 suffered repeat episodes. Olfactory bulb volume was correlated to psychophysical olfactory testing and orthonasal to retronasal scores. Olfactory-event-related potentials were found in about one-third of the patients and the vast majority of them had reproducible intranasal trigeminal event-related potentials. As there is no proven medical therapy for this disease, complete clinical evaluation of the patients may help to counsel patients about the recovery prognosis that applies to one-third of them.


Are digital health interventions valuable to support patients with cancer and caregivers? An umbrella review of web-based and app-based supportive care interventions.
Digital health technologies have expanded tremendously in the last two decades, creating an emerging research and clinical field. They are regarded as cost-effective, and their use in healthcare is prioritized by many countries. However, the constant evolution of these technologies has led to an abundance of related literature. Thus, we conducted an umbrella review to identify and characterize digital supportive care interventions for patients with cancer and their relatives. A preregistered umbrella review was conducted (PROSPERO registration number CRD42022333110). Five databases were searched (Embase, PsycINFO, PubMed, CINAHL, and the Cochrane Library). To be considered, studies had to be systematic reviews or meta-analyses, be performed on pediatric or adult patients with cancer or survivors or their relatives, report results on web-based or app-based supportive care interventions, and measure psychological, functional, or behavioral variables or quality of life related to cancer. The methodological quality of the studies was assessed using the AMSTAR-2 tool. Twenty eligible studies were identified. Most of the included studies reported results from adult patients with cancer. Globally, digital interventions were shown to be effective for physical activity in patients with cancer but had mixed results regarding emotional outcomes and quality of life. Additionally, a lack of methodological quality was noted for most of the included reviews. Digital supportive care interventions could be an effective tool in cancer care for some outcomes. Recommendations have been formulated for further research in this field using adapted methodologies for the development of digital health interventions.


Transcatheter versus surgical aortic valve replacement in patients with severe aortic stenosis at low and intermediate risk: systematic review and meta-analysis.
To examine the effect of transcatheter aortic valve implantation (TAVI) versus surgical replacement of an aortic valve (SAVR) in patients with severe aortic stenosis at low and intermediate risk of perioperative death. Systematic review and meta-analysis DATA SOURCES: Medline, Embase, and Cochrane CENTRAL. Randomized trials of TAVI compared with SAVR in patients with a mean perioperative risk of death <8%. Two reviewers independently extracted data and assessed risk of bias for outcomes important to patients that were selected a priori by a parallel guideline committee, including patient advisors. We used the GRADE system was used to quantify absolute effects and quality of evidence. 4 trials with 3179 patients and a median follow-up of two years were included. Compared with SAVR, transfemoral TAVI was associated with reduced mortality (risk difference per 1000 patients: -30, 95% confidence interval -49 to -8, moderate certainty), stroke (-20, -37 to 1, moderate certainty), life threatening bleeding (-252, -293 to -190, high certainty), atrial fibrillation (-178, -150 to -203, moderate certainty), and acute kidney injury (-53, -39 to -62, high certainty) but increased short term aortic valve reintervention (7, 1 to 21, moderate certainty), permanent pacemaker insertion (134, 16 to 382, moderate certainty), and moderate or severe symptoms of heart failure (18, 5 to 34, moderate certainty). Compared with SAVR, transapical TAVI was associated higher mortality (57, -16 to 153, moderate certainty, P=0.015 for interaction between transfemoral versus transapical TAVI) and stroke (45, -2 to 125, moderate certainty, interaction P=0.012). No study reported long term follow-up, which is particularly important for structural valve deterioration. Many patients, particularly those who have a shorter life expectancy or place a lower value on the risk of long term valve degeneration, are likely to perceive net benefit with transfemoral TAVI versus SAVR. SAVR, however, performs better than transapical TAVI, which is of interest to patients who are not candidates for transfemoral TAVI. PROSPERO CRD42016042879.


Ferroplasma acidiphilum gen. nov., sp. nov., an acidophilic, autotrophic, ferrous-iron-oxidizing, cell-wall-lacking, mesophilic member of the Ferroplasmaceae fam. nov., comprising a distinct lineage of the Archaea.
An isolate of an acidophilic archaeon, strain YT, was obtained from a bioleaching pilot plant. The organism oxidizes ferrous iron as the sole energy source and fixes inorganic carbon as the sole carbon source. The optimal pH for growth is 1.7, although growth is observed in the range pH 1.3 to 2.2. The cells are pleomorphic and without a cell wall. 16S rRNA gene sequence analysis showed this strain to cluster phylogenetically within the order 'Thermoplasmales' sensu Woese, although with only 89.9 and 87.2% sequence identity, respectively, to its closest relatives, Picrophilus oshimae and Thermoplasma acidophilum. Other principal differences from described species of the 'Thermoplasmales' are autotrophy (strain YT is obligately autotrophic), the absence of lipid components typical of the ' Thermoplasmales' (no detectable tetraethers) and a lower temperature range for growth (growth of strain YT occurs between 15 and 45 degrees C). None of the sugars, amino acids, organic acids or other organic compounds tested was utilized as a carbon source. On the basis of the information described above, the name Ferroplasma acidiphilum gen. nov., sp. nov. is proposed for strain YT within a new family, the Ferroplasmaceae fam. nov. Strain YT is the type and only strain of F. acidiphilum. This is the first report of an autotrophic, ferrous-iron-oxidizing, cell-wall-lacking archaeon.


Using economy of means to evolve transition rules within 2D cellular automata.
Running a cellular automaton (CA) on a rectangular lattice is a time-honored method for studying artificial life on a digital computer. Commonly, the researcher wishes to investigate some specific or general mode of behavior, say, the ability of a coherent pattern of points to glide within the lattice, or to generate copies of itself. This technique has a problem: how to design the transitions table-the set of distinct rules that specify the next content of a cell from its current content and that of its near neighbors. Often the table is painstakingly designed manually, rule by rule. The problem is exacerbated by the potentially vast number of individual rules that need be specified to cover all combinations of center and neighbors when there are several symbols in the alphabet of the CA. In this article a method is presented to have the set of rules evolve automatically while running the CA. The transition table is initially empty, with rules being added as the need arises. A novel principle drives the evolution: maximum economy of means-maximizing the reuse of rules introduced on previous cycles. This method may not be a panacea applicable to all CA studies. Nevertheless, it is sufficiently potent to evolve sets of rules and associated patterns of points that glide (periodically regenerate themselves at another location) and to generate gliding "children" that then "mate" by collision.


α-cell glucokinase suppresses glucose-regulated glucagon secretion.
Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype.


Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.


Structural determinants for specific recognition by T4 endonuclease V.
DNA glycosylases catalyze the scission of the N-glycosyl bond linking either a damaged or mismatched base to the DNA sugar phosphate backbone. T4 endonuclease V is a glycosylase/apurinic (AP) lyase that is specific for UV light-induced cis-syn pyrimidine dimers. As a proposed transition state analog/inhibitor for glycosylases, a phosphoramidite derivative containing a pyrrolidine residue has been synthesized. The binding of endonuclease V to this duplex was analyzed by gel mobility shift assays and resulted in a single stable complex of reduced mobility and an apparent Kd of 17 nM. To assess the importance of the positive charge for specific binding, studies using other non-cleavable substrate analogs were performed. Wild type T4 endonuclease V shows an 8-fold decreased affinity for a tetrahydrofuran as compared with the pyrrolidine residue, demonstrating the significance of the positive charge for recognition. A 2-fold increase in binding affinity for a reduced AP site was observed. Similar assays using catalytically compromised mutants (E23Q and E23D) of endonuclease V demonstrate altered affinities for the pyrrolidine as well as tetrahydrofuran and reduced AP sites. This approach has provided insight into the structural mechanism by which specific lesions are targeted by the protein as well as the structural determinants of the DNA required for specific recognition by T4 endonuclease V.


Microbial communities of three sympatric Australian stingless bee species.
Bacterial symbionts of insects have received increasing attention due to their prominent role in nutrient acquisition and defense. In social bees, symbiotic bacteria can maintain colony homeostasis and fitness, and the loss or alteration of the bacterial community may be associated with the ongoing bee decline observed worldwide. However, analyses of microbiota associated with bees have been largely confined to the social honeybees (Apis mellifera) and bumblebees (Bombus spec.), revealing--among other taxa--host-specific lactic acid bacteria (LAB, genus Lactobacillus) that are not found in solitary bees. Here, we characterized the microbiota of three Australian stingless bee species (Apidae: Meliponini) of two phylogenetically distant genera (Tetragonula and Austroplebeia). Besides common plant bacteria, we find LAB in all three species, showing that LAB are shared by honeybees, bumblebees and stingless bees across geographical regions. However, while LAB of the honeybee-associated Firm4-5 clusters were present in Tetragonula, they were lacking in Austroplebeia. Instead, we found a novel clade of likely host-specific LAB in all three Australian stingless bee species which forms a sister clade to a large cluster of Halictidae-associated lactobacilli. Our findings indicate both a phylogenetic and geographical signal of host-specific LAB in stingless bees and highlight stingless bees as an interesting group to investigate the evolutionary history of the bee-LAB association.


Development of ceftazidime resistance in an acute Burkholderia pseudomallei infection.
Burkholderia pseudomallei, a bacterium that causes the disease melioidosis, is intrinsically resistant to many antibiotics. First-line antibiotic therapy for treating melioidosis is usually the synthetic β-lactam, ceftazidime (CAZ), as almost all B. pseudomallei strains are susceptible to this drug. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, which can lead to mortality if therapy is not switched to a different drug in a timely manner. Serial B. pseudomallei isolates obtained from an acute Thai melioidosis patient infected by a CAZ susceptible strain, who ultimately succumbed to infection despite being on CAZ therapy for the duration of their infection, were analyzed. Isolates that developed CAZ resistance due to a proline to serine change at position 167 in the β-lactamase PenA were identified. Importantly, these CAZ resistant isolates remained sensitive to the alternative melioidosis treatments; namely, amoxicillin-clavulanate, imipenem, and meropenem. Lastly, real-time polymerase chain reaction-based assays capable of rapidly identifying CAZ resistance in B. pseudomallei isolates at the position 167 mutation site were developed. The ability to rapidly identify the emergence of CAZ resistant B. pseudomallei populations in melioidosis patients will allow timely alterations in treatment strategies, thereby improving patient outcomes for this serious disease.


Brownmillerite thin films as fast ion conductors for ultimate-performance resistance switching memory.
An oxide-based resistance memory is a leading candidate to replace Si-based flash memory as it meets the emerging specifications for future memory devices. The non-uniformity in the key switching parameters and low endurance in conventional resistance memory devices are preventing its practical application. Here, a novel strategy to overcome the aforementioned challenges has been unveiled by tuning the growth direction of epitaxial brownmillerite SrFeO2.5 thin films along the SrTiO3 [111] direction so that the oxygen vacancy channels can connect both the top and bottom electrodes rather directly. The controlled oxygen vacancy channels help reduce the randomness of the conducting filament (CF). The resulting device displayed high endurance over 106 cycles, and a short switching time of ∼10 ns. In addition, the device showed very high uniformity in the key switching parameters for device-to-device and within a device. This work demonstrates a feasible example for improving the nanoscale device performance by controlling the atomic structure of a functional oxide layer.


Plasma noradrenaline and renovascular hypertension in the rat.
1. Plasma noradrenaline was measured in groups of rats up to 4 weeks after application of a renal artery clip. 2. When renal artery clipping was accoumpanied by contralateral nephrectomy (one-kidney model) plasma noradrenaline was significantly higher in hypertensive rats than in sham-operated control rats at 7, 14 and 28 days. 3. Plasma noradrenaline was not altered at any time examined in the two-kidney model (unilateral clip and contralateral kidney left in situ). 4. Neurogenic mechanisms mediated by the peripheral sympathetic nervous system appear to participate in the development of one-kidney renovascular hypertension, but do not play a significant role in the two-kidney model.


Hypertension and chronic kidney disease: controversies in pathogenesis and treatment.
The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.


Use of cognitive-behavioural arthritis education programmes in newly diagnosed rheumatoid arthritis.
To identify the effect of attending a cognitive-behavioural arthritis education programme on the health status of participants with newly diagnosed rheumatoid arthritis (RA) compared with a control group. Randomized controlled trial. Hospital based. Newly diagnosed with RA. Participation in either a cognitive-behavioural arthritis education programme or a standard arthritis education programme (control group). Sessions for both groups lasted for 2 hours per week for four weeks. Subjects were examined at home by an assessor blinded to group allocation, prior to and three and six months following attendance. The main outcome measure was the Physical Function subscale of the Arthritis Impact Measurement Scale Two. Other outcome measures included erythrocyte sedimentation rate (ESR), joint count scores, assessments of pain and psychological status. Fifty-four subjects (mean time since diagnosis 4.5 months) took part. Baseline analysis revealed that the control group had significantly better levels of functional ability (U = 185; p = 0.009) and lower levels of helplessness (U = 168; p = 0.002) prior to intervention. This difference remained unchanged three months later. Six months following the intervention no significant differences were noted between the groups for any measure of health status. There were no significant changes in health status over time in either group. Attending a cognitive-behavioural arthritis education programme had no significant effect on the health status of individuals newly diagnosed with RA. The move to early use of these programmes should be examined further, with a larger sample size and longer duration of follow-up.


Radiometric description of intensity and coherence in generalized holographic axicon images.
The characteristics of extended-range focal-line images generated in partially coherent light by annular-aperture logarithmic axicons are analyzed in terms of a certain generalized radiometric model. This radiometric description, which makes use of radiance propagation along geometric rays, is valid in the asymptotic short-wavelength limit, and it yields both the spectral density and the spatial coherence distributions of the images. The radio metrically obtained values on the image axis and in transverse planes are assessed against direct partially coherent wave-theoretical calculations. It is shown that the radiometric technique produces remarkably accurate results for the intensity and the spatial coherence profiles. Compared with diffraction calculations, the radiometric method is much faster, especially in conditions of relatively incoherent illumination.


Scattering of a partially coherent Gaussian-Schell beam from a diffuse target in slant atmospheric turbulence.
On the basis of the extended Huygens-Fresnel principle, the scattering of partially coherent Gaussian-Schell-model (GSM) beams from a diffuse target in slant double-passage atmospheric turbulence is studied and compared with that of fully coherent Gaussian beams. Using the cross-spectral density function of the GSM beams, we derive the expressions of the mutual coherence function, angle-of-arrival fluctuation, and covariance and variance of the intensity of the scattered field, taking into account the fluctuations of both the log-amplitude and phase. The numerical results are presented, and the influences of the wavelength, propagation distance, and waist radius on scattering properties are discussed. The perturbation region of the normalized intensity variance of the partially coherent GSM beam is smaller than that of the fully coherent Gaussian beam at the middle turbulence level. The normalized intensity variance of long-distance beam propagation is smaller than that of beam propagation along a short distance.


Major depression and generalized anxiety disorder. Same genes, (partly) different environments?
Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.


Management of malignant pleural effusion: challenges and solutions.
Malignant pleural effusion (MPE) is a sign of advanced cancer and is associated with significant symptom burden and mortality. To date, management has been palliative in nature with a focus on draining the pleural space, with therapies aimed at preventing recurrence or providing intermittent drainage through indwelling catheters. Given that patients with MPEs are heterogeneous with respect to their cancer type and response to systemic therapy, functional status, and pleural milieu, response to MPE therapy is also heterogeneous and difficult to predict. Furthermore, the impact of therapies on important patient outcomes has only recently been evaluated consistently in clinical trials and cohort studies. In this review, we examine patient outcomes that have been studied to date, address the question of which are most important for managing patients, and review the literature related to the expected value for money (cost-effectiveness) of indwelling pleural catheters relative to traditionally recommended approaches.


Robert Koch: Nobel laureate and controversial figure in tuberculin research.
Tuberculosis has been a major cause of death for centuries. Likewise, anthrax has posed a deadly threat to both farm animals and humans and today poses a threat as a weapon of biological warfare. Cholera, which wreaked havoc in the East and threatened to enter Europe, also posed a deadly threat. The causes of these diseases remained mysteries for centuries. Nobel laureate Robert Koch (1843-1910), often called the founder of medical bacteriology, is credited with discovering the tubercle bacillus, Mycobacterium tuberculosis; with demonstrating for the first time in history the life cycle of the anthrax bacillus under controlled in vitro conditions; and with identifying Vibrio cholorae as the cause of cholera. In later life, he also was at the center of several controversies. This article provides a brief summary of Koch's exploration into bacteriology and, especially, his experience with tuberculosis and the controversies that developed in the latter part of his life, as well as his childhood and early adult years and the development of his now well-known "postulates."


HbA(1c) values for defining diabetes and impaired fasting glucose in Asian Indians.
To determine the glycosylated haemoglobin (HbA(1c)) cut-points for diabetes and impaired fasting glucose (IFG) among Asian Indians. Participants (n=525) were a random sample selected from the India Health Study. Based on history and fasting plasma glucose (FPG), participants were classified into known diabetes, newly diagnosed diabetes (NDD), impaired fasting glucose (IFG) [ADA and WHO criteria] or normal fasting glucose (NFG). Receiver Operating Characteristic curves were used to identify the optimum sensitivity and specificity for defining HbA(1c) cut-points for NDD and IFG against the FPG criteria. There were 64 participants with a known history of diabetes. Of the remaining 461, IFG was present in 44.7% (ADA) and 18.2% (WHO), and 10.4% were NDD. Mean HbA(1c) were 5.4 (±0.04)% for NFG; 5.7 (±0.06)% among IFG-ADA, 5.8 (±0.09)% among IFG-WHO; 7.5 (±0.33)% for NDD and 8.4 (±0.32)% for known diabetes. Optimal HbA(1c) cut-point for NDD was 5.8% (sensitivity=75%, specificity=75.5%, AUC=0.819). Cut-point for IFG (ADA) was 5.5% (sensitivity=59.7%, specificity=59.9%, AUC=0.628) and for IFG (WHO) was 5.6% (sensitivity=60.7%, specificity=65.1%, AUC=0.671). In this study population from north and south regions of India, the HbA(1c) cut-point that defines NDD (≥5.8%) was much lower than that proposed by an international expert committee and the American Diabetes Association (≥6.5%). A cut-point of ≥5.5% or ≥5.6% defined IFG, and was slightly lower than the ≥5.7% for high risk proposed, but accuracy was less than 70%.


The effects of erythrocyte membranes on the nucleation of sickle hemoglobin.
Pathology in sickle cell disease begins with nucleation-dependent polymerization of deoxyhemoglobin S into stiff, rodlike fibers that deform and rigidify red cells. We have measured the effect of erythrocyte membranes on the rate of homogeneous nucleation in sickle hemoglobin, using preparations of open ghosts (OGs) with intact cytoskeletons from sickle (SS) and normal adult (AA) red cells. Nucleation rates were measured by inducing polymerization by laser photolysis of carboxy sickle hemoglobin and observing stochastic variation of replicate experiments of the time for the scattering signals to reach 10% of their respective maxima. By optical imaging of membrane fragments added to a hemoglobin solution we contrast the rate of nucleation immediately adjacent to membrane fragments with nucleation in a region of the same solution but devoid of membranes. From analysis of 29,272 kinetic curves obtained, we conclude that the effect of AA OGs is negligible (10% enhancement of nucleation rates +/-20%), whereas SS OGs caused 80% enhancement (+/-20%). In red cells, where more membrane surface is available to Hb, this implies enhancement of nucleation by a factor of 6. These experiments represent a 10-fold improvement in precision over previous approaches and are the first direct, quantitative measure of the impact of erythrocyte membranes on the homogeneous nucleation process that is responsible for polymer initiation in sickle cell disease.