Pose Invariant Embedding for Deep Person Re-identification.
Pedestrian misalignment, which mainly arises from detector errors and pose variations, is a critical problem for a robust person re-identification (re-ID) system. With poor alignment, the feature learning and matching process might be largely compromised. To address this problem, this paper introduces the pose invariant embedding (PIE) as a pedestrian descriptor. First, in order to align pedestrians to a standard pose, the PoseBox structure is introduced, which is generated through pose estimation followed by affine transformations. Second, to reduce the impact of pose estimation errors and information loss during PoseBox construction, we design a PoseBox fusion (PBF) CNN architecture that takes the original image, the PoseBox, and the pose estimation confidence as input. The proposed PIE descriptor is thus defined as the fully connected layer of the PBF network for the retrieval task. Experiments are conducted on the Market-1501, CUHK03-NP, and DukeMTMC-reID datasets. We show that PoseBox alone yields decent re-ID accuracy, and that when integrated in the PBF network, the learned PIE descriptor produces competitive performance compared with the state-of-the-art approaches.


The electrochemistry of size dependent graphene via liquid phase exfoliation: capacitance and ionic transport.
Recently, graphene-based materials have become ubiquitous in electrochemical devices including electrochemical sensors, electrocatalysts, capacitive and membrane desalination and energy storage devices. However, many of the electrochemical properties of graphene (particularly the capacitance and ionic transport) are not yet fully understood. This paper explores the capacitance and ionic transport properties of size dependent graphene (from 100 nm to 1 μm) prepared through the liquid phase exfoliation of graphite in which the size of graphene was finely selected using a multi-step centrifugation technique. Our experiment was then expanded to include basal plane graphene using highly ordered pyrolytic graphite as a model electrode, describing the assumed theoretical graphene capacitance (quoted as 550 F g-1 or 21 μF cm-2) and the electrochemical surface area of the carbon-based materials. This work improves our understanding of graphene electrochemistry (capacitance and ion transport), which should lead to the continuing development of many high-performance electrochemical devices, especially supercapacitors, capacitive desalination and ion-based selective membranes.


Enantioselective Separation of 4,8-DHT and Phytotoxicity of the Enantiomers on Various Plant Species.
As a candidate for bioherbicide, 4,8-dihydroxy-1-tetralone (4,8-DHT) was isolated from Caryospora callicarpa epicarp and its two enantiomers, S-(+)-isosclerone and R-(-)-regiolone, were separated by chiral high-performance liquid chromatography (HPLC) on a Chiralcel OD column with chiral stationary phase (CSP)-coated cellulose-tris(3,5-dimethylphenylcarbamate). Then, the phytotoxicity of 4,8-DHT and its enantiomers toward the seeds germination and seedling growth of the five tested plant species, including lettuce (Latuca sativa), radish (Raphanus sativus), cucumber (Cucumis sativus), onion (Allium cepa), and wheat (Triticum aestivum), were investigated and the results indicated a hormesis at low concentration of 4,8-DHT and its enantiomers, but a retardant effect at high concentration. Between the two enantiomers of 4,8-DHT, the S-(+)-isosclerone was more toxic to seeds germination and seedling growth of the five tested plant species than the R-(-)-regiolone, and also the phytotoxicity of S-(+)-isosclerone varied with different plants. For example, S-(+)-isosclerone was the most active to seedling growth of lettuce, indicating that S-(+)-isosclerone had specific effects on different organisms. Thus, all of the chirality and concentration of 4,8-DHT, as well as the affected plant species, need to be taken into consideration in the development and utilization of 4,8-DHT.


Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives.
Sophoridine is a natural quinolizidine alkaloid and a bioactive ingredient that can be isolated and identified from certain herbs, including Sophora flavescens Alt, Sophora alopecuroides L, and Sophora viciifolia Hance. In recent years, this quinolizidine alkaloid has gained widespread attention because of its unique structure and minimal side effects. Modern pharmacological investigations have uncovered sophoridine's multiple wide range biological activities, such as anti-cancer, anti-inflammatory, anti-viral, anti-arrhythmia, and analgesic functions, among others. These pharmacological activities and beneficial effects point to sophoridine as a strong potential therapeutic candidate for the treatment of various diseases, including several cancer types, hepatitis B virus, enterovirus 71, coxsackievirus B3, cerebral edema, cancer pain, heart failure, acute myocardial ischemia, arrhythmia, inflammation, acute lung injury, and osteoporosis. The data showed that sophoridine had adverse reactions, including hepatotoxicity and neurotoxicity. Additionally, analyses of sophoridine's safety, bioavailability, and pharmacokinetic parameters in animal models of research have been limited, especially in the clinic, as have been investigations on its structure-activity relationship. In this article, we comprehensively summarize the biological activities, toxicity, and pharmacokinetic characteristics of sophoridine and its derivatives, as currently reported in publications, as we attempt to provide an overall perspective on sophoridine analogs and the prospects of its application clinically.


Dominant inhibitory mutations in the Mg(2+)-binding site of RasH prevent its activation by GTP.
We have previously demonstrated that substitution of Asn for Ser at position 17 of RasH yields a dominant inhibitory protein whose expression in cells interferes with endogenous Ras function (L. A. Feig, and G. M. Cooper, Mol. Cell. Biol. 8:3235-3243, 1988). Subsequent structural studies have shown that the hydroxyl group of Ser-17 contributes to the binding of Mg2+ associated with bound nucleotide. In this report, we show that more subtle amino acid substitutions at this site that would be expected to interfere with complexing Mg2+, such as Cys or Ala, also generated dominant inhibitory mutants. In contrast, a Thr substitution that conserves a reactive hydroxyl group maintained normal Ras function. These results argue that the defect responsible for the inhibitory activity is improper coordination of Mg2+. Preferential affinity for GDP, observed in the original Asn-17 mutant, was found exclusively in inhibitory mutants. However, this binding specificity did not completely block the mutant proteins from binding GTP in vivo since introduction of the autophosphorylation site, Thr-59, in 17N Ras resulted in the phosphorylation of the double mutant in cells. Furthermore, inhibitory mutants failed to activate a model downstream target, yeast adenylate cyclase, even when bound to GTP. Thus, the consequence of improper complexing of Mg2+ was to lock the protein in a constitutively inactive state. A model is presented to explain how these properties could cause the mutant protein to inhibit the activation of endogenous Ras by competing for a guanine nucleotide-releasing factor.


Nucleolar localization of human hepatitis B virus capsid protein.
Wild-type human hepatitis B virus (HBV) exhibits selective export of virions containing mature genomes. In contrast, changing an isoleucine to a leucine at amino acid 97 (I97L) of the HBV core antigen (HBcAg) causes it to release immature genomes. To elucidate the structure-function relationship of HBcAg at amino acid 97, we systematically replaced the isoleucine residue at this position with 18 other amino acids via mutagenesis. Twelve of the 18 mutants exhibited no significant phenotype, while five new mutants displayed strong phenotypes. The I97D mutant had a near lethal phenotype, the I97P mutant exhibited a significantly reduced level of virion secretion, and the I97G mutant lacked the full-length relaxed circular form of viral DNA. The tip of the spike of the capsid particle is known to contain a predominant B-cell epitope. However, the recognition of this exposed epitope by an anti-HBc antibody appeared to be affected by the I97E mutation or by histidine tagging at the C terminus of mutant HBcAg, which is presumably in the capsid interior. Surprisingly, the nuclear HBcAg of mutants I97E and I97W, produced from either a replicon or an expression vector, was found to be colocalized with nucleolin and B23 at a frequency of nearly 100% by confocal immunofluorescence microscopy. In contrast, this colocalization occurred with wild-type HBcAg only to a limited extent. We also noted that nucleolin-colocalizing cells were often binucleated or apoptotic, suggesting that the presence of HBcAg in the nucleolus may perturb cytokinesis. The mechanism of this phenomenon and its potential involvement in liver pathogenesis are discussed. To our knowledge, this is the first report of nucleolar HBcAg in culture.


Malignant melanoma in Puerto Rico: an update.
A study about the incidence of malignant melanoma in Puerto Rico during the calendar year 1996 was carried out compiling the information submitted by pathological reports to the Puerto Rico Cancer Registry and identifying similar reports at other pathology laboratories. A total of 107 new cases were documented in 1996, resulting in an incidence of 3.03 (+/- 17.9) per 100,000 persons for that particular year. The age of the patients fluctuated between 19 and 88 years with a mean of 61.3 years, most of them being between 50 and 80 years. More than half of the cases (54.2%) were located in the head and neck, and the extremities. Thickness measurement of the neoplasm was reported in only 42% of the cases. In 60% of those cases in which the tumor thickness was reported, it was found to be less than 1.49 mm. Previous data in Puerto Rico from the years 1981 to 1986 had shown a tendency to an increase in the incidence of melanoma per 100,000 inhabitants rising 1.20 to 1.52 respectively. The present study reflects a continuation of the same pattern, with a two-fold increase in the last 10 years (from 1.52 to 3.03).


Refractive index measurement of the isolated crystalline lens using optical coherence tomography.
An optical coherence tomography system has been developed that was designed specifically for imaging the isolated crystalline lens. Cross-sectional OCT images were recorded on 40 lenses from 32 human donors with an age range of 6-82 years. A method has been developed to measure the axial thickness and average refractive index of the lens from a single recorded image. The measured average group refractive index at the measurement wavelength of 825 nm was converted to the average phase refractive index at 589 nm using lens dispersion data from the literature. The average refractive index for all lenses measured was 1.408+/-0.005 which agrees well with recent MRI measurements of the lens index gradient. A linear regression of the data resulted in a statistically significant decrease in the average refractive index with age, but a simple linear model was insufficient to explain the age dependence. The results presented here suggest that the peak refractive index in the nucleus is closer to 1.420, rather than the previously accepted value of 1.406.


Evidence for parallel evolution of a gene involved in the regulation of spermatogenesis.
PHD finger protein 7 (Phf7) is a male germline specific gene in Drosophila melanogaster that can trigger the male germline sexual fate and regulate spermatogenesis, and its human homologue can rescue fecundity defects in male flies lacking this gene. These findings prompted us to investigate conservation of reproductive strategies through studying the evolutionary origin of this gene. We find that Phf7 is present only in select species including mammals and some insects, whereas the closely related G2/M-phase specific E3 ubiquitin protein ligase (G2e3) is in the genome of most metazoans. Interestingly, phylogenetic analyses showed that vertebrate and insect Phf7 genes did not evolve from a common Phf7 ancestor but rather through independent duplication events from an ancestral G2e3 This is an example of parallel evolution in which a male germline factor evolved at least twice from a pre-existing template to develop new regulatory mechanisms of spermatogenesis.


Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis.
Ulcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability. We investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method. An increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations. Our data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.


Leukemogenesis caused by incapacitated GATA-1 function.
GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allele or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-1 activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.


Adaptation and Validation of the Spanish Version of Decisional Conflict Scale in People with Migraine in Spain.
We aimed to validate the Spanish version of the Decisional Conflict Scale (DCS) and analyze its psychometric properties in people with migraine. The DCS validation comprised two phases. First, a translation and cross-cultural adaptation following the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Good Practices: 1-preparation, 2-independent forward translation, 3-reconciliation, 4-back-translation, 5-harmonization, 6-clinical review, and 7-content validation in a group of migraine patients. Second, the analysis of the psychometric properties. The reliability or internal consistency of the DCS scale and subscales was assessed using Cronbach's α value. The item-subscale correlation was also evaluated. A floor and ceiling effects for DCS score was considered when at least 15% of respondents obtained DCS >90 (ceiling) or <10 (floor). The construct validity was studied through the correlation between the DCS subscales and by the correlation between the DCS and other questionnaires (Decision Self-Efficacy Scale [DSES] and 9-item Shared Decision-Making [SDM-Q-9]). Spearman's coefficients were estimated for the correlations. The cross-cultural adaptation was conducted on 17 patients who completed the questionnaire in a mean of 2.4 ±1.1 minutes. Generally, more than 75% of them considered that DCS items were adequate, easy to understand, and relevant. The psychometric properties were evaluated in a sample of n=128 patients. Accordingly, the internal consistency of DCS was high, with a Cronbach's α of 0.97 for the scale and between 0.87 to 0.96 for subscales. Also, a slight floor effect was observed, with 24.2% of patients having DCS scores <10. The correlation between subscales exceeded Spearman's coefficient of 0.7. Whereas the correlation between the DCS and the other questionnaires was generally moderate (Spearman's coefficient >0.4). The Spanish version (Spain) of the DCS has very acceptable psychometric properties (reliability and construct validity) and good potential for assessing decisional conflicts among migraine patients.


Trapping and thermal migration of the first- and second-row atoms in Ar, Kr and Xe crystals.
Trapping and temperature-induced migration (TIM) of the first- and second-row atoms A from H to Ne in the face-centered cubic rare gas RG = Ar, Kr and Xe crystals are investigated within the classical crystal model parameterized by the empirically modified pairwise potentials. New ab initio coupled cluster A-RG potentials computed in a uniform way for all the atoms A are used to represent the atom-crystal interactions. Absolute and relative stabilities of the substitutional and interstitial trapping sites, their structures, interstitial migration pathways, related activation energies and rough estimates of the TIM rates are obtained. The isotropic model, which neglects non-zero atomic electronic orbital momentum, reveals that migration of interstitial atoms along the network of conjugated fcc octahedral voids is the generic case for atomic mobility. Anisotropic interactions with a crystal inherent to P-state atoms B, C, O and F are accounted for using the non-relativistic diatomics-in-molecule method. Depending on its sign, interaction anisotropy can alter the structures of interstitial trapping sites and transition states remarkably. This, in turn, can dramatically affect the TIM rates. Comparison with reliable experimental data available for oxygen and hydrogen indicates a systematic overestimation of the measured activation energies, by 30% at worst. A comprehensive literature review accomplished for other atoms reveals a lack of information on the TIM processes and rates, though makes it possible to verify a part of the present results on the trapping site energies and structures.


Bitopertin in Negative Symptoms of Schizophrenia-Results From the Phase III FlashLyte and DayLyte Studies.
There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24. The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated. These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia.


Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies.
52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.


Histopathological changes in myocardial tissue due to coronary venous hypertension.
In chronic venous insufficiency (CVI), an increase in venous pressure causes the passage of intravascular blood cells and molecules into the surrounding tissues and induces histopathological changes in the lower extremities, leading to increased pigmentation in the legs, ulceration, and tissue loss to various degrees. This study aimed to investigate whether an increase in venous pressure in the coronary veins can lead to the aforementioned histopathological changes. Twenty-four New Zealand rabbits were divided into the following three groups: experimental model of coronary venous hypertension (CVH) (n = 8), sham group (n = 8), and control group (n = 8). After 21 days postoperatively, tissue samples from each group were compared for perivascular inflammation, erythrocyte extravasation, macrophage infiltration, and hemosiderin deposits by histopathological scoring under a light microscope. Matrix metalloproteinase-2 (MMP-2) activation was evaluated using immunohistochemical staining. In the CVH group, hemosiderin accumulation was significantly higher than in the sham and control groups (1.0 (1.0-3.0), 0.0 (0.0-1.0), 0.0 (0.0-0.0); p < 0.001). Immunohistochemically, in the CVH group, MMP-2 levels were significantly higher than in the sham and control groups (2.0 (1.0-3.0), 0.0 (0.0-1.0), 0.0 (0.0-0.0); p < 0.001). This experimental study showed for the first time the histopathological and immunohistochemical changes in myocardial tissue, similar to those observed in CVI, as a result of increased coronary venous pressure due to coronary vein ligation. Further studies are needed to understand the clinical implications of these results.


Screening for chlamydia and/or gonorrhea in primary health care: protocol for systematic review.
Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly reported sexually transmitted infections in Canada. Existing national guidance on screening for these infections was not based on a systematic review, and recommendations as well as implementation considerations (e.g., population groups, testing and case management) should be explicit and reflect the quality of evidence. The aim of this systematic review is to synthesize research on screening for these infections in sexually active individuals within primary care. We will also review evidence on how people weigh the relative importance of the potential outcomes from screening, rated as most important by the Canadian Task Force on Preventive Health Care (CTFPHC) with input from patients and stakeholders. We have developed a peer-reviewed strategy to comprehensively search MEDLINE, Embase, Cochrane Library, CINAHL, and PsycINFO for English and French literature published 1996 onwards. We will also search trial registries and conference proceedings, and mine references lists. Screening, study selection, risk of bias assessments, and quality of findings across studies (for each outcome) will be independently undertaken by two reviewers with consensus for final decisions. Data extraction will be conducted by one reviewer and checked by another for accuracy and completeness. The CTFPHC and content experts will provide input for decisions on study design (i.e., when and whether to include uncontrolled studies for screening effectiveness) and for interpretation of the findings. The results section of the review will include a description of all studies, results of all analyses, including planned subgroup and sensitivity analyses, and evidence profiles and summary of findings tables incorporating assessment based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods to communicate our confidence in the estimates of effect. We will compare our findings to others and discuss limitations of the review and available literature. The findings will be used by the CTFPHC-supplemented by consultations with patients and stakeholders and from other sources on issues of feasibility, acceptability, costs/resources, and equity-to inform recommendations on screening to support primary health care providers in delivering preventive care. International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42018100733.


Mechanisms of action of nonpeptide hormones on resveratrol-induced antiproliferation of cancer cells.
Nonpeptide hormones, such as thyroid hormone, dihydrotestosterone, and estrogen, have been shown to stimulate cancer proliferation via different mechanisms. Aside from their cytosolic or membrane-bound receptors, there are receptors on integrin αv β3 for nonpeptide hormones. Interaction between hormones and integrin αv β3 can induce signal transduction and eventually stimulate cancer cell proliferation. Resveratrol induces inducible COX-2-dependent antiproliferation via integrin αv β3 . Resveratrol and hormone-induced signals are both transduced by activated extracellular-regulated kinases 1 and 2 (ERK1/2); however, hormones promote cell proliferation, while resveratrol induces antiproliferation in cancer cells. Hormones inhibit resveratrol-stimulated phosphorylation of p53 on Ser15, resveratrol-induced nuclear COX-2 accumulation, and formation of p53-COX-2 nuclear complexes. Subsequently, hormones impair resveratrol-induced COX-2-/p53-dependent gene expression. The inhibitory effects of hormones on resveratrol action can be blocked by different antagonists of specific nonpeptide hormone receptors but not integrin αv β3 blockers. Results suggest that nonpeptide hormones inhibit resveratrol-induced antiproliferation in cancer cells downstream of the interaction between ligand and receptor and ERK1/2 activation to interfere with nuclear COX-2 accumulation. Thus, the surface receptor sites for resveratrol and nonpeptide hormones are distinct and can induce discrete ERK1/2-dependent downstream antiproliferation biological activities. It also indicates the complex pathways by which antiproliferation is induced by resveratrol in various physiological hormonal environments. .


Biallelic inherited SCN8A variants, a rare cause of SCN8A-related developmental and epileptic encephalopathy.
Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.


An Integrated Power-Efficient Active Rectifier With Offset-Controlled High Speed Comparators for Inductively Powered Applications.
We present an active full-wave rectifier with offset-controlled high speed comparators in standard CMOS that provides high power conversion efficiency (PCE) in high frequency (HF) range for inductively powered devices. This rectifier provides much lower dropout voltage and far better PCE compared to the passive on-chip or off-chip rectifiers. The built-in offset-control functions in the comparators compensate for both turn-on and turn-off delays in the main rectifying switches, thus maximizing the forward current delivered to the load and minimizing the back current to improve the PCE. We have fabricated this active rectifier in a 0.5-μm 3M2P standard CMOS process, occupying 0.18 mm(2) of chip area. With 3.8 V peak ac input at 13.56 MHz, the rectifier provides 3.12 V dc output to a 500 Ω load, resulting in the PCE of 80.2%, which is the highest measured at this frequency. In addition, overvoltage protection (OVP) as safety measure and built-in back telemetry capabilities have been incorporated in our design using detuning and load shift keying (LSK) techniques, respectively, and tested.


Molecular Breeding for Nutritionally Enriched Maize: Status and Prospects.
Maize is a major source of food security and economic development in sub-Saharan Africa (SSA), Latin America, and the Caribbean, and is among the top three cereal crops in Asia. Yet, maize is deficient in certain essential amino acids, vitamins, and minerals. Biofortified maize cultivars enriched with essential minerals and vitamins could be particularly impactful in rural areas with limited access to diversified diet, dietary supplements, and fortified foods. Significant progress has been made in developing, testing, and deploying maize cultivars biofortified with quality protein maize (QPM), provitamin A, and kernel zinc. In this review, we outline the status and prospects of developing nutritionally enriched maize by successfully harnessing conventional and molecular marker-assisted breeding, highlighting the need for intensification of efforts to create greater impacts on malnutrition in maize-consuming populations, especially in the low- and middle-income countries. Molecular marker-assisted selection methods are particularly useful for improving nutritional traits since conventional breeding methods are relatively constrained by the cost and throughput of nutritional trait phenotyping.


Structural evolution induced by Au atom diffusion in Ag2S.
Atom diffusion processes govern the structure and composition of core-shell nanomaterial, which play a crucial role in determining their properties. By using aberration-corrected high-resolution transmission electron microscopy and X-ray absorption near-edge structure spectroscopy in combination with in situ X-ray diffraction, we confirm that single-atom diffusion of Au to Ag2S occurs, and that the transition from the Au@Ag2S core-shell nanostructure to AuAgS-AuAgx or Ag3AuS2-AuAgx heterostructures was observed. Moreover, the phase of the ternary sulfide induced by Au single-atom diffusion in Ag2S is determined by the ratio of Au and Ag, thus exhibiting a significant difference in the photocatalytic activity performance.


Charge-transfer induced magnetic field effects of nano-carbon heterojunctions.
Room temperature magnetic field effects have not been definitively observed in either single-walled carbon nanotubes (SWCNTs) or C₆₀ under a small magnetic field due to their weak hyperfine interaction and slight difference of g-factor between positive and negative polarons. Here, we demonstrate charge-transfer induced magnetic field effects in nano-carbon C₆₀-SWCNT bulk heterojunctions at room temperature, where the mechanism of magnetic field effects is verified using excited state transition modeling. By controlling SWCNT concentrations and interfacial interactions, nano-carbon heterojunctions exhibit tunability of charge-transfer density and room temperature magnetoconductance of 2.8% under 100 mT external magnetic field. External stimuli, such as electric field and photoexcitation, also play an important role in controlling the magnetic field effects of nano-carbon heterojunctions, which suggests that these findings could enable the control of optoelectronic properties of nano-carbon heterojunctions.


Physical complications in acute lung injury survivors: a two-year longitudinal prospective study.
Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life. Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and health-related quality of life and their associations with critical illness and ICU exposures. A multisite prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. Thirteen ICUs from four academic teaching hospitals. Two hundred twenty-two survivors of acute lung injury. None. At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness); 6-minute walk distance, and the Medical Outcomes Short-Form 36 health-related quality of life survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness. Muscle weakness is common after acute lung injury, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after acute lung injury. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.


Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.
Acute Respiratory Distress Syndrome (ARDS) is characterized by lung injury and damage to the alveolar type II cells. This study sought to determine if endogenous surfactant is altered in ARDS. Bronchoalveolar lavage was performed in patients at-risk to develop ARDS (AR, n = 20), with ARDS (A, n = 66) and in normal subjects (N, n = 29). The crude surfactant pellet was analyzed for total phospholipids (PL), individual phospholipids, SP-A, SP-B, and minimum surface tension (STmin). PL was decreased in both AR and A (3.48 +/- 0.61 and 2.47 +/- 0.40 mumol/ml, respectively) compared to N (7.99 +/- 0.60 mumol/ml). Phosphatidylcholine was decreased in A (62.64 +/- 2.20% PL) compared to N (76.27 +/- 2.05% PL). Phosphatidylglycerol was 11.58 +/- 1.21% PL in N and was decreased to 6.48 +/- 1.43% PL in A. SP-A was 123.64 +/- 20.66 micrograms/ml in N and was decreased to 49.28 +/- 21.68 micrograms/ml in AR and to 29.88 +/- 8.49 micrograms/ml in A. SP-B was 1.28 +/- 0.33 micrograms/ml in N and was decreased to 0.57 +/- 0.24 micrograms/ml in A. STmin was increased in AR (15.1 +/- 2.53 dyn/cm) and A (29.04 +/- 2.05 dyn/cm) compared to N (7.44 +/- 1.61 dyn/cm). These data demonstrate that the chemical composition and functional activity of surfactant is altered in ARDS. Several of these alterations also occur in AR, suggesting that these abnormalities occur early in the disease process.


Association of Promoter Methylation Patterns with Expression of MAPK14 in Tissue of Papillary Thyroid Cancer Patients.
Thyroid cancer is one of the most prevalent malignancies worldwide. Genetic and epigenetic alterations are one of the main causes of thyroid tumor that is responsible to the activation of oncogenes as well as the inactivation of tumor suppressor genes. This research aimed to investigate the relationship of promoter methylation patterns with the expression of P38α in Iranian patients with thyroid cancer. We collected 40 thyroid tumor samples and 40 adjacent normal thyroid samples from 40 Iranian patients with papillary thyroid cancer. The promoter methylation pattern of P38α gene was investigated by methylation-sensitive high-resolution melting (MS-HRM) method. Moreover, mRNA expression of P38α was investigated by Real-Time PCR method. Further validation of the obtained results was performed by the Cancer Genome Atlas (TCGA) dataset. The obtained results indicated that the expression of the P38α (MAPK-14) gene in the thyroid cancer sample was considerably higher than tumor margin sample. Also, P38α gene promoter methylation was higher in thyroid margin tissue as compared to tumor tissue. These results were additionally confirmed by TCGA analysis. The receiver operating characteristic (ROC) curve analysis showed a high accuracy of P38α gene expression as a diagnostic biomarker for thyroid malignancy. Our study demonstrated that the P38α expression level gene was associated with thyroid cancer pathogenesis among the Iranian population. We suggested that this gene expression might be used as a biomarker for diagnosis of thyroid tumor.


Autoradiographic studies of the synthesis of RNA and protein as a function of cell volume in Streptococcus faecium.
Mid-exponential-phase cultures were either labeled continuously with tritiated leucine and uracil or pulse-labeled with tritiated leucine. The amount of leucine and uracil incorporated into protein or RNA per cell was determined by grain counts of autoradiographs of cells seen in electron micrographs; the volume of each cell was determined by three-dimensional reconstruction. The average number of autoradiographic grains around cells continuously labeled with uracil and leucine increased linearly with cell volume. In contrast, while the average grain count around cells pulse-labeled with leucine increased in a near-linear fashion over most of the volume classes, less than the expected number of grains were seen around cells in large- and small-size classes. The distribution of grains around cells from both the continuously and pulse-labeled populations could be fit at the 5% confidence level with a Poisson distribution modified to take into consideration the volume distribution of each population of cells analyzed. These findings suggested that large changes in the density of RNA and protein do not occur in most cells as they increase in size; however, there may be decreases in the rate of protein synthesis in some large and small cells. The decrease in the rate of protein synthesis appears consistent with the hypothesis that new sites of envelope growth must be introduced into cells that are close to the division event to restore rapid growth.


[Origin and the functional role of adrenergic fibers of the vagus nerve in cats].
Origin of adrenergic fibres of vagus is studied. They are shown to appear in the thoracic vagus through caudal anastomosis introduction. The observations indicated that axons of spinal neurons and neurons of the ganglion stellate passed through caudal anastomosis and entered a thoracic vagus nerve. Stimulation of the thoracic vagus in cats after atropine sulphate injection increases the heart rate.


Risk Stratification in Orthopaedics.
Proper predictive tools are essential to guide patient selection, optimization, category of surgical admission (inpatient, outpatient surgery), and discharge disposition, and predict the risk of readmissions and complications after orthopaedic procedures. Therefore, identification and optimization of patients' perioperative risk for surgery is essential, and understanding these basic concepts is crucial to maximizing patient care quality. It is important to define risk, stratify the existing preoperative attributes, and review key concepts of patient-specific risk calculation and documentation.


[Use of molecular methods in food microbiology with the example of probiotic use of lactobacilli].
The aim of molecular methods in food microbiology is the identification or strain specific differentiation of microorganisms. Identification methods include besides taxonomic purposes also the detection of virulence genes or resistance markers. Strain specific differentiation is used for epidemiological investigations or the quality control of technologically used bacteria. Probiotic strains of the Lactobacillus acidophilus-group were investigated with different molecular methods: for identification proteinfingerprinting and RAPD-PCR (Random Amplified Polymorphic DNA-PCR) were applied, for strain specific differentiation pulsed field gel electrophoresis (PFGE) and again RAPD-PCR were used. The molecular methods applied should be chosen depending on the objective (identification, differentiation) and with respect to the organism to be tested. In case of probiotic lactic acid bacteria like the L. acidophilus-group proteinfingerprinting has proved to be successful for identification and with some limitation also RAPD-PCR. For differentiation PFGE is suitable as well as RAPD-PCR. Those methods differ substantially in their work load and in personal requirements, and show different power of discrimination and reproducibility within and between laboratories. This should be considered while choosing the appropriate method.


Galectin-3 stimulates cell proliferation.
Galectin-3, a beta-galactoside-binding protein, has been shown to be involved in multiple biological processes through interaction with its complementary glycoconjugates. Here we provide the first evidence of galectin-3 as a mitogen. Incubation of quiescent cultures of normal human lung fibroblast IMR-90 cells with recombinant galectin-3 (rgalectin-3) stimulated DNA synthesis as well as cell proliferation in a dose-dependent manner. This mitogenic activity was dependent on the lectin property of galectin-3, as it could be significantly inhibited by lactose, a disaccharide competitive for carbohydrate-binding by galectin-3. Chemical cross-linking and affinity-purification experiments identified binding of rgalectin-3 to cell surface glycoproteins, which were not recognized by antibodies directed against lysosome-associated membrane proteins (LAMPs), putative cellular ligands for galectin-3. Moreover, pulse-chase analysis revealed no secretion of galectin-3 by IMR-90 cells. These results indicate that galectin-3 is a mitogen capable of stimulating fibroblast cell proliferation in a paracrine fashion through interaction with cell surface glycoconjugates different from LAMPs and suggest a possible involvement of galectin-3 in tissue remodeling.


APID2NET: unified interactome graphic analyzer.
Exploration and analysis of interactome networks at systems level requires unification of the biomolecular elements and annotations that come from many different high-throughput or small-scale proteomic experiments. Only such integration can provide a non-redundant and consistent identification of proteins and interactions. APID2NET is a new tool that works with Cytoscape to allow surfing unified interactome data by querying APID server (http://bioinfow.dep.usal.es/apid/) to provide interactive analysis of protein-protein interaction (PPI) networks. The program is designed to visualize, explore and analyze the proteins and interactions retrieved, including the annotations and attributes associated to them, such as: GO terms, InterPro domains, experimental methods that validate each interaction, PubMed IDs, UniProt IDs, etc. The tool provides interactive graphical representation of the networks with all Cytoscape capabilities, plus new automatic tools to find concurrent functional and structural attributes along all protein pairs in a network. http://bioinfow.dep.usal.es/apid/apid2net.html. Installation Guide and User's Guide are supplied at the Web site indicated above.


How to Represent Part-Whole Hierarchies in a Neural Network.
This article does not describe a working system. Instead, it presents a single idea about representation that allows advances made by several different groups to be combined into an imaginary system called GLOM.1 The advances include transformers, neural fields, contrastive representation learning, distillation, and capsules. GLOM answers the question: How can a neural network with a fixed architecture parse an image into a part-whole hierarchy that has a different structure for each image? The idea is simply to use islands of identical vectors to represent the nodes in the parse tree. If GLOM can be made to work, it should significantly improve the interpretability of the representations produced by transformer-like systems when applied to vision or language.


Predicting nodal metastases in squamous cell carcinoma of the oral tongue using artificial intelligence.
The presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. Cases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. Eighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. A CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.


Location of Helicoverpa zea (Lepidoptera: Noctuidae) larvae on different plant parts of determinate and indeterminate soybean.
Helicoverpa zea (Boddie) is a damaging pest of many crops including soybean, Glycine max (L.), especially in the southern United States. Previous studies have concluded that oviposition and development of H. zea larvae mirror the phenology of soybean, with oviposition occurring during full bloom, younger larvae developing on blooms and leaves, intermediate aged larvae developing on varying tissue types, and older larvae developing on flowers and pods. In a field trial, we investigated the presence of natural infestations of H. zea larvae by instar in determinate and indeterminate soybean varieties. In complementary experiments, we artificially infested H. zea and allowed them to oviposit on plants within replicated cages (one with a determinate variety and two with an indeterminate variety). Plants were sampled weekly during the time larvae were present. In the natural infestation experiment, most larvae were found on blooms during R3 and were early to middle instars; by R4, most larvae were found on leaves and were middle to late instars. In contrast, in the cage study, most larvae were found on leaves regardless of soybean growth stage or larval stage. Determinate and indeterminate growth habit did not impact larval preference for different soybean tissue types. Our studies suggest H. zea larvae prefer specific tissue types, but also provide evidence that experimental design can influence the results. Finally, our finding of larval preference for leaves contrasts with findings from previous studies.


[Relationships between ectoparasites and grooming behavior of Tylonycteris pachypus and T. robustula].
Grooming behavior is evolved in animals in response to the costs associated with ectoparasites. In this study, ecotparasite densities and grooming behavior-including licking and scratching-of wild-caught lesser bamboo bat (Tylonycteris pachypus) and greater bamboo bat (T. robustula) were analyzed. The results indicated that both the frequencies and durations of licking were higher than those of scratching in both bat species, though T. pachypus licked more but scratched less than T. robustula. There were no difference in the durations of licking and scratching between the two bat species, and the durations and frequencies of grooming behavior of the two bat species were irrelevant with ectoparasite densities. These findings suggest that the grooming behavior of T. pachypus and T. robustula might be modulated by both the central control (programmed grooming) model and the peripheral stimulation (stimulus driven) model.


Frontiers in Dissecting and Managing Brassica Diseases: From Reference-Based RGA Candidate Identification to Building Pan-RGAomes.
The Brassica genus contains abundant economically important vegetable and oilseed crops, which are under threat of diseases caused by fungal, bacterial and viral pathogens. Resistance gene analogues (RGAs) are associated with quantitative and qualitative disease resistance and the identification of candidate RGAs associated with disease resistance is crucial for understanding the mechanism and management of diseases through breeding. The availability of Brassica genome assemblies has greatly facilitated reference-based quantitative trait loci (QTL) mapping for disease resistance. In addition, pangenomes, which characterise both core and variable genes, have been constructed for B. rapa, B. oleracea and B. napus. Genome-wide characterisation of RGAs using conserved domains and motifs in reference genomes and pangenomes reveals their clustered arrangements and presence of structural variations. Here, we comprehensively review RGA identification in important Brassica genome and pangenome assemblies. Comparison of the RGAs in QTL between resistant and susceptible individuals allows for efficient identification of candidate disease resistance genes. However, the reference-based QTL mapping and RGA candidate identification approach is restricted by the under-represented RGA diversity characterised in the limited number of Brassica assemblies. The species-wide repertoire of RGAs make up the pan-resistance gene analogue genome (pan-RGAome). Building a pan-RGAome, through either whole genome resequencing or resistance gene enrichment sequencing, would effectively capture RGA diversity, greatly expanding breeding resources that can be utilised for crop improvement.


Fluoride ion donor properties of TcO2F3 and ReO2F3: X-ray crystal structures of MO2F3.SbF5 (M = Tc, Re) and TcO2F3.XeO2F2 and Raman and NMR spectroscopic characterization of MO2F3.PnF5 (Pn = As, Sb), [ReO2F2(CH3CN)2][SbF6], and [Re2O4F5][Sb2F11].
The fluoride ion donor properties of TcO2F3 and ReO2F3 toward AsF5, SbF5, and XeO2F2 have been investigated, leading to the formation of TcO2F3.PnF5 and ReO2F3.PnF5 (Pn = As, Sb) and TcO2F3.XeO2F2, which were characterized in the solid state by Raman spectroscopy and X-ray crystallography. TcO2F3.SbF5 crystallizes in the monoclinic system P2(1)/n, with a = 7.366(2) A, b = 10.441(2) A, c = 9.398(2) A, beta = 93.32(3) degrees, V = 721.6(3) A3, and Z = 4 at 24 degrees C, R1 = 0.0649, and wR2 = 0.1112. ReO2F3.SbF5 crystallizes in the monoclinic system P2(1)/c, with a = 5.479(1) A, b = 10.040(2) A, c = 12.426(2) A, beta = 99.01(3) degrees, V = 675.1(2) A3, and Z = 4 at -50 degrees C, R1 = 0.0533, and wR2 = 0.1158. TcO2F3.XeO2F2 crystallizes in the orthorhombic system Cmc2(1), with a = 7.895(2) A, b = 16.204(3) A, c = 5.198(1) A, beta = 90 degrees, V = 665.0(2) A3, and Z = 4 at 24 degrees C, R1 = 0.0402, and wR2 = 0.0822. The structures of TcO2F3.SbF5 and ReO2F3.SbF5 consist of infinite chains of alternating MO2F4 and SbF6 units in which the bridging fluorine atoms on the antimony are trans to each other. The structure of TcO2F3.XeO2F2 comprises two distinct fluorine-bridged chains, one of TcO2F3 and the other of XeO2F2 bridged by long Tc-F...Xe contacts. The oxygen atoms of the group 7 metals in the three structures are cis to each other and to two terminal fluorine atoms and trans to the bridging fluorine atoms. The 19F NMR and Raman spectra of TcO2F3.PnF5 and ReO2F3.PnF5 in SbF5 and PnF5-acidified HF solvents are consistent with dissociation of the adducts into cis-MO2F2(HF)2+ cations and PnF6- anions. The energy-minimized geometries of the free MO2F2+ cations and their HF adducts, cis-MO2F2(HF)2+, have been calculated by local density functional theory (LDFT), and the calculated vibrational frequencies have been used as an aid in the assignment of the Raman spectra of the solid MO2F3.PnF5 adducts and their PnF5-acidified HF solutions. In contrast, ReO2F3.SbF5 ionizes in SO2ClF solvent to give the novel Re2O4F5+ cation and Sb2F11- anion. The 19F NMR spectrum of the cation is consistent with two ReO2F2 units joined by a fluorine bridge in which the oxygen atoms are assumed to lie in the equatorial plane. The [ReO2F2(CH3CN)2][SbF6] salt was formed upon dissolution of ReO2F3.SbF5 in CH3CN and was characterized by 1H, 13C, and 19F NMR and Raman spectroscopies. The ReO2F2(CH3CN)2+ cation is a pseudooctahedral cis-dioxo arrangement in which the CH3CN ligands are trans to the oxygens and the fluorines are trans to each other.


Estrogen potentiates vasopressin-induced contraction of female rat aorta by enhancing cyclooxygenase-2 and thromboxane function.
To determine the roles of estrogen and constrictor prostanoids in vasopressin (VP)-induced contraction of female rat aorta, vascular reactivity to VP was determined in thoracic aortas of intact, ovariectomized, and ovariectomized + estrogen-replaced female rats in the presence of indomethacin (Indo), NS-398, SQ-29,548, or vehicle control. The effects of estrogen on vascular reactivity to the thromboxane A(2) analog U-46619 were also examined. Maximal contractile response to VP in intact female rats (5,567 +/- 276 mg/mg of aortic ring wt) was markedly attenuated by ovariectomy (2,485 +/- 394 mg; P < 0.001) and restored by estrogen replacement with 17beta-estradiol (5,059 +/- 194 mg; P > 0.1). Indo and NS-398 significantly attenuated maximal responses to VP in intact female rats to a similar extent [3,176 +/- 179 (P < 0.0001) and 3,258 +/- 152 mg (P < 0.0001), respectively]. Ovariectomy abolished and estrogen replacement restored the inhibitory effects of Indo, NS-398, and SQ-29,548. Contractile responses of rat aorta to U-46619 were significantly greater (P < 0.0001) in females (5,040 +/- 238 mg) than in males (3,679 +/- 96 mg). Ovariectomy markedly attenuated (3,923 +/- 84 mg; P < 0.01) and estrogen replacement restored (5,024 +/- 155 mg; P > 0.1) responses to U-46619 in female aortas. These data reveal that estrogen is an important regulator of the contractile responses of female rat aorta to VP, which appears to potentiate both cyclooxygenase-2 and constrictor prostanoid function in the vascular wall.


Fuzzy ensemble clustering based on random projections for DNA microarray data analysis.
Two major problems related the unsupervised analysis of gene expression data are represented by the accuracy and reliability of the discovered clusters, and by the biological fact that the boundaries between classes of patients or classes of functionally related genes are sometimes not clearly defined. The main goal of this work consists in the exploration of new strategies and in the development of new clustering methods to improve the accuracy and robustness of clustering results, taking into account the uncertainty underlying the assignment of examples to clusters in the context of gene expression data analysis. We propose a fuzzy ensemble clustering approach both to improve the accuracy of clustering results and to take into account the inherent fuzziness of biological and bio-medical gene expression data. We applied random projections that obey the Johnson-Lindenstrauss lemma to obtain several instances of lower dimensional gene expression data from the original high-dimensional ones, approximately preserving the information and the metric structure of the original data. Then we adopt a double fuzzy approach to obtain a consensus ensemble clustering, by first applying a fuzzy k-means algorithm to the different instances of the projected low-dimensional data and then by using a fuzzy t-norm to combine the multiple clusterings. Several variants of the fuzzy ensemble clustering algorithms are proposed, according to different techniques to combine the base clusterings and to obtain the final consensus clustering. We applied our proposed fuzzy ensemble methods to the gene expression analysis of leukemia, lymphoma, adenocarcinoma and melanoma patients, and we compared the results with other state of the art ensemble methods. Results show that in some cases, taking into account the natural fuzziness of the data, we can improve the discovery of classes of patients defined at bio-molecular level. The reduction of the dimension of the data, achieved through random projections techniques, is well-suited to the characteristics of high-dimensional gene expression data, thus resulting in improved performance with respect to single fuzzy k-means and with respect to ensemble methods based on resampling techniques. Moreover, we show that the analysis of the accuracy and diversity of the base fuzzy clusterings can be useful to explain the advantages and the limitations of the proposed fuzzy ensemble approach.


Hub Genes in Stable QTLs Orchestrate the Accumulation of Cottonseed Oil in Upland Cotton via Catalyzing Key Steps of Lipid-Related Pathways.
Upland cotton is the fifth-largest oil crop in the world, with an average supply of nearly 20% of vegetable oil production. Cottonseed oil is also an ideal alternative raw material to be efficiently converted into biodiesel. However, the improvement in kernel oil content (KOC) of cottonseed has not received sufficient attention from researchers for a long time, due to the fact that the main product of cotton planting is fiber. Previous studies have tagged QTLs and identified individual candidate genes that regulate KOC of cottonseed. The regulatory mechanism of oil metabolism and accumulation of cottonseed are still elusive. In the current study, two high-density genetic maps (HDGMs), which were constructed based on a recombinant inbred line (RIL) population consisting of 231 individuals, were used to identify KOC QTLs. A total of forty-three stable QTLs were detected via these two HDGM strategies. Bioinformatic analysis of all the genes harbored in the marker intervals of the stable QTLs revealed that a total of fifty-one genes were involved in the pathways related to lipid biosynthesis. Functional analysis via coexpression network and RNA-seq revealed that the hub genes in the co-expression network that also catalyze the key steps of fatty acid synthesis, lipid metabolism and oil body formation pathways (ACX4, LACS4, KCR1, and SQD1) could jointly orchestrate oil accumulation in cottonseed. This study will strengthen our understanding of oil metabolism and accumulation in cottonseed and contribute to KOC improvement in cottonseed in the future, enhancing the security and stability of worldwide food supply.


Induction of beta-glucosidases in Neurospora crassa.
The induction of beta-glucosidases (EC 184.108.40.206) was studied in Neurospora crassa. Cellobiase was induced by cellobiose, but other inducers had little effect on this enzyme. Cellobiase activity was very low in all stages of the vegetative life cycle in the absence of di-beta-glucoside inducer. Aryl-beta-glucosidase was semiconstitutive at late stages of culture growth prior to conidiation. At early stages, aryl-beta-glucosidase was induced by cellobiose, laminaribiose, and gentiobiose, and weakly induced by galactose, amino sugars, and aryl-beta-glucosides. The induction properties of the beta-glucosidases are compared with those of the other disaccharidases of Neurospora. The induction of beta-glucosidases was inhibited by glucose, 2-deoxy-d-glucose, and sodium acetate. Sodium phosphate concentrations between 0.01 and 0.1 M stimulated induction of both enzymes, while concentrations above 0.1 M were inhibitory. The optimal condition for induction of both beta-glucosidases was pH 6.0. Cellobiase induction was relatively more inhibited than aryl-beta-glucosidase in the range of pH 6.0 to 8.0.


IMASIS computer-based medical record project: dealing with the human factor.
The Institut Municipal d'Assistència Sanitària (IMAS) is a health care organization in Barcelona, comprising two general hospitals, a psychiatric hospital, a surgical clinic, a geriatric center, some primary care clinics, and a research institute. Since 1984, IMAS has been engaged in creating a multicenter integrated hospital information system (IMASIS). Currently, IMASIS offers the possibility to manage administrative data, laboratory results, pathology and cytology reports, radiology reports, and pharmacy inpatient orders; it also shares this information on-line among IMAS centers. IMASIS users may also work with a word processor, a spreadsheet, a database, or a statistical package and have access to MEDLINE. A second phase of IMASIS development began in December 1993 focused on clinical information management. The goal was to move towards an integrated multimedia medical record [1]. As a first step, the implementation experiences of the most advanced hospital information systems around the world were studied. Some of these experiences detected behavioral, cultural, and organizational factors [2] as the main sources of delay, or even failure, in HIS projects. A preliminary analysis to define such factors, assess their potential impact, and introduce adequate measures to deal with them seemed unavoidable before structuring of the project. In our approach to physician attitudes analysis, two survey techniques were applied. First, every hospital service head was contacted to schedule an interview, with either a service representative or a group of staff physicians and residents. The aim was to provide detailed information about project objectives and collect personal opinions, problems encountered in the current HIS, and specific needs of every medical and surgical specialty (including imaging needs). Every service head was asked to distribute a questionnaire among all clinicians, which assessed frequency of use of IMASIS current applications, user's satisfaction level, problems to be solved in utilization of the system, errors detected in the systems' database, and the personal interest in participating in the IMASIS project. The questionnaire was also intended to be a tool to monitor IMASIS evolution. Our study showed that medical staff had a lack of information about the current HIS, leading to a poor utilization of some system options. Another major characteristic, related to the above, was the feeling that the project would negatively affect the organization of work at the hospitals. A computer-based medical record was feared to degrade physician-patient relationship, introduce supplementary administrative burden in clinicians day-to-day work, unnecessarily slow history taking, and imply too-rigid patterns of work. The most frequent problems in using the current system could be classified into two groups: problems related to lack of agility and consistency in user interface design, and those derived from lack of a common patient identification number. Duplication of medical records was the most frequent error detected by physicians. Analysis of physicians' attitudes towards IMASIS revealed a lack of confidence globally. This was probably the consequence of two current features: a lack of complete information about IMASIS possibilities and problems faced when using the system. To deal with such factors, three types of measures have been planned. First, an effort is to be done to ensure that every physician is able to adequately use the current system and understands long-term benefits of the project. This task will be better accomplished by personal interaction between clinicians and a physician from the Informatics Department than through formal teaching of IMASIS. Secondly, a protocol for evaluating the HIS is being developed and will be systematically applied to detect both database errors and systemUs design pitfalls. Finally, the IMASIS project has to find a convenient point for starting, to offer short-term re


Temperament and Early Stuttering Development: Cross-Sectional Findings From a Community Cohort.
The purpose of this study was to ascertain if there is an association between stuttering severity and behaviors and the expression of temperament characteristics, including precursors of anxiety. We studied temperament characteristics of a prospectively recruited community cohort of children who stutter (N = 173) at ages 3, 4, and 6 years using the Short Temperament Scale STS (Prior, Sanson, Smart & Oberklaid, 2000). Six of 131 statistical tests of association between stuttering severity and behaviors and temperament traits were statistically significant at the 5% level, which was no more than expected by chance alone. On the basis of parent responses to the STS, preschoolers who exhibited different levels of stuttering severity and behaviors did not generally express temperament traits differently from one another. Stuttering severity and stuttering behaviors were not associated with the precursors of anxiety. Overall, taking multiple tests into consideration, results show little evidence of association between stuttering severity and temperament up to 4 years of age or between stuttering behaviors and temperament up to 6 years of age.


Mixed orthogonal frequency coded SAW RFID tags.
Orthogonal frequency coded (OFC) SAW radio-frequency identification (RFID) tags are currently being explored as a multi-sensor platform because of their passive spread-spectrum operation, low loss, and resilience in harsh environments. Ongoing research continues to search for robust device embodiments that increase the number of identifiable codes, in the presence of intersymbol interference, while maintaining reasonable device lengths. This paper presents a technique that shortens the SAW response length while preserving code diversity and bandwidth by utilizing a multi-track SAW configuration. These new devices allow the time response of multiple OFC chips to overlap and yield a mixed-frequency chip having the sum of the chip bandwidths but shorter overall time response. The theoretical development is presented and examples are discussed for these new mixed orthogonal frequency coded (MOFC) SAW devices. Experimental results for MOFC sensors, fabricated on YZ-LiNbO3, with a 7% fractional bandwidth and five chip frequencies in three cells, provide a good contrast to similar OFC designs. Experimental results are presented for the simultaneous operation of eight wireless temperature sensors--four OFC and four MOFC--in a 915-MHz wireless correlator receiver system, highlighting the ability of these devices to operate in the same system.


A facile synthesis of Fe3O4/nitrogen-doped carbon hybrid nanofibers as a robust peroxidase-like catalyst for the sensitive colorimetric detection of ascorbic acid.
In recent years, the fabrication of functional nanostructures with multicomponents for a variety of novel biosensors has received considerable attention due to their synergistic improved sensitivity. Herein, we report a facile approach for the preparation of Fe3O4/nitrogen-doped carbon (Fe3O4/N-C) hybrid nanofibers, and construct a sensing platform for the sensitive colorimetric detection of H2O2 and ascorbic acid (AA). During the synthetic process, a discontinuous layer of polypyrrole (PPy) is first polymerized in situ on the surface of the α-Fe2O3 nanofibers under hydrothermal reaction using α-Fe2O3 nanofibers as both a template and an oxidant. Then the prepared α-Fe2O3/PPy nanofibers are converted into Fe3O4/N-C hybrid nanofibers through pyrolysis with a thermochemical reduction process. The resulting Fe3O4/N-C hybrid nanofibers are used as a novel peroxidase mimic towards the oxidation of 3,3,5,5-tetramethylbenzidine (TMB) in the presence of H2O2, with a superior catalytic activity over individual α-Fe2O3 nanofibers, α-Fe2O3/PPy nanofibers, Fe3O4/C nanofibers, and commercial Fe3O4 nanoparticles. Based on the high peroxidase-like activity of Fe3O4/N-C hybrid nanofibers, a sensing platform for the colorimetric detection of AA is developed. A good linear relationship from 0 to 50 μM and a detection limit of 0.04 μM are achieved. This work offers a new method for the preparation of Fe3O4/N-C hybrid nanofibers and presents new potential applications in biosensing, medical diagnostics and environmental monitoring.


Second primary cancers in non-Hodgkin lymphoma: Bidirectional analyses suggesting role for immune dysfunction.
Second primary cancers (SPCs) account for an increasing proportion of all cancer diagnoses. It is unlikely that prior therapy is solely responsible for SPC risk. To investigate risk of SPC after diagnosis of non-Hodgkin lymphoma (NHL) and 10 of its subtypes we conducted a novel bidirectional analysis, SPCs after NHL and NHL as SPC. Using the Swedish Family-Cancer Database, we identified 19,833 individuals with primary NHL diagnosed between 1993 and 2015. We calculated relative risks (RRs) of SPCs in NHL survivors and, for bi-directional analysis, risk of NHL as SPC. The overall RRs were significantly bidirectionally increased for NHL and 7 cancers. After diagnosis of NHL risks were increased for upper aerodigestive tract (RR = 1.96), colorectal (1.35), kidney (3.10), bladder (1.54) and squamous cell skin cancer (SCC) (4.12), melanoma (1.98) and Hodgkin lymphoma (9.38). The concordance between RRs for each bidirectional association between NHL and 31 different cancers was highly significant (r = 0.86, p < 0.0001). Melanoma was bidirectionally associated with all 10 subtypes of NHL. The observed bidirectional associations between NHL and cancer suggest that therapy-related carcinogenic mechanisms cannot solely explain the findings. Considering that skin SCC and melanoma are usually treated by surgery and that these cancers and NHL are most responsive of any cancer to immune suppression, the consistent bidirectional results provide population-level evidence that immune suppressed state is a key underlying mechanism in the context of SPCs. Furthermore, the quantified risks for NHL subtypes have direct clinical application in the management of NHL patients.


HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.
The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem−/− mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.


CrMP-Sol database: classification, bioinformatic analyses and comparison of cancer-related membrane proteins and their water-soluble variant designs.
Membrane proteins are critical mediators for tumor progression and present enormous therapeutic potentials. Although gene profiling can identify their cancer-specific signatures, systematic correlations between protein functions and tumor-related mechanisms are still unclear. We present here the CrMP-Sol database ( https://bio-gateway.aigene.org.cn/g/CrMP ), which aims to breach the gap between the two. Machine learning was used to extract key functional descriptions for protein visualization in the 3D-space, where spatial distributions provide function-based predictive connections between proteins and cancer types. CrMP-Sol also presents QTY-enabled water-soluble designs to facilitate native membrane protein studies despite natural hydrophobicity. Five examples with varying transmembrane helices in different categories were used to demonstrate the feasibility. Native and redesigned proteins exhibited highly similar characteristics, predicted structures and binding pockets, and slightly different docking poses against known ligands, although task-specific designs are still required for proteins more susceptible to internal hydrogen bond formations. The database can accelerate therapeutic developments and biotechnological applications of cancer-related membrane proteins.


Electrocochleography as a diagnostic and intraoperative adjunct in superior semicircular canal dehiscence syndrome.
To determine the electrocochleographic characteristics of ears with superior semicircular canal dehiscence (SSCD) and to examine its use for intraoperative monitoring in canal occlusion procedures. Case series. Academic medical center. Thirty-three patients (45 ears) had clinical and computed tomographic evidence of SSCD; 8 patients underwent intraoperative electrocochleography (ECoG) during superior canal occlusion; 9 patients underwent postoperative ECoG after SSCD occlusion. Diagnostic, intraoperative, and postoperative extratympanic ECoG; middle fossa or transmastoid occlusion of the superior semicircular canal. Summating potential (SP) to action potential (AP) ratio, as measured by ECoG, and alterations in SP/AP during canal exposure and occlusion. Using computed tomography as the standard, elevation of SP/AP on ECoG demonstrated 89% sensitivity and 70% specificity for SSCD. The mean SP/AP ratio among ears with SSCD was significantly higher than that among unaffected ears (0.62 versus 0.29, p < 0.0001). During occlusion procedures, SP/AP increased on exposure of the canal lumen (mean change ± standard deviation, 0.48 ± 0.30). After occlusion, SP/AP dropped below the intraoperative baseline in most cases (mean change, -0.23 ± 0.52). All patients experienced symptomatic improvement. All patients who underwent postoperative ECoG 1 to 3 months after SSCD repair maintained SP/AP of 0.4 or lesser. These findings expand the differential diagnosis of abnormal ECoG. In conjunction with clinical findings, ECoG may support a clinical diagnosis of SSCD. Intraoperative ECoG facilitates dehiscence documentation and allows the surgeon to confirm satisfactory canal occlusion.


Nail disorders in patients with chronic renal failure undergoing hemodialysis.
Chronic renal failure affects almost all the systems of the body, including the skin and appendages. The nail disorders most commonly found in patients with chronic renal failure are half and half nails, absent lunula and splinter hemorrhages. To evaluate the spectrum and the frequency of nail disorders in patients with chronic renal failure submitted to hemodialysis and compare them with a paired sample from the general population. A case-controlled study paired for gender and age was conducted in which nail disorders were investigated in the two groups. At least one nail disorder was found in 86% of the hemodialysis patients and in 75% of subjects in the control group. Absent lunula (62.9%) and half and half nails (14.4%) were more common in the hemodialysis group compared to the control group and this difference was statistically significant (p < 0.05). Longitudinal striae were more common in the control group compared to the hemodialysis group (24.1%). Absent lunula and half and half nails were the most common nail disorders found in patients on hemodialysis, corroborating the findings of previous studies. Longitudinal striae were more common in the control group and future studies may clarify whether structural abnormalities such as absent lunula may be related to this finding.


Enzymatic correction of interference in the kinetic Jaffé reaction for determining creatinine in plasma.
We evaluated a simple, specific method for measuring plasma creatinine concentration, involving enzymatic degradation of creatinine before analysis by a kinetic Jaffé reaction. The enzymes--prepared in a dry, stable form--are convenient to use and eliminate the need to correct for sample dilution. As little as 50 microL of plasma is required, making the procedure ideal for use with samples from children. Between-day precision studies for determination of plasma creatinine at concentrations of 70 and 470 mumol/L yielded CVs of 7.8 and 4.3%, respectively. Analytical recovery of creatinine added to plasma samples ranged from 94 to 113%. Linear regression analysis demonstrated excellent agreement between results by this method and those by a "high performance" liquid-chromatographic technique.


[Human rights and their relationship with patient's rights].
This historical article reviews the most important milestones in the evolution of human and patient's rights. The latter have derived from human rights and have followed a similar historical evolution, but in markedly different times. This has lead to the persistence of monarchic type, paternalistic clinical relationship forms in republican societies. The acceptance of informed consent and patient's rights has been a democratization of clinical relationships. On the other hand the right to body health management is a real cultural revolution. The democratization of clinical relationship is in agreement with our technical, pluralist and secularized times.


Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.
As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.


Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency.
Neuroendocrine control of reproduction by brain-secreted pulses of gonadotropin-releasing hormone (GnRH) represents a longstanding puzzle about extracellular signal decoding mechanisms. GnRH regulates the pituitary gonadotropin's follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are heterodimers specified by unique β subunits (FSHβ/LHβ). Contrary to Lhb, Fshb gene induction has a preference for low-frequency GnRH pulses. To clarify the underlying regulatory mechanisms, we developed three biologically anchored mathematical models: 1) parallel activation of Fshb inhibitory factors (e.g. inhibin α and VGF nerve growth factor-inducible), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. growth differentiation factor 9). Simulations with all three models recapitulated the Fshb expression levels obtained in pituitary gonadotrope cells perifused with varying GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration, and pulse frequency revealed that the apparent frequency-dependent pattern of Fshb expression in model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed "true" pulse frequency sensing. To resolve which components of this GnRH signal induce Fshb, we developed a high-throughput parallel experimental system. We analyzed over 4,000 samples in experiments with varying near-physiological GnRH concentrations and pulse patterns. Whereas Egr1 and Fos genes responded only to variations in average GnRH concentration, Fshb levels were sensitive to both average concentration and true pulse frequency. These results provide a foundation for understanding the role of multiple regulatory factors in modulating Fshb gene activity.


Positive affect and disability among older Mexican Americans with arthritis.
To examine the relationship between positive affect and subsequent functional disability in older Mexican Americans with self-reported physician-diagnosed arthritis. We conducted a 2-year prospective cohort study using a population-based sample of 1,084 noninstitutionalized Mexican American subjects aged > or =65 years residing in 5 southwestern states. Measures included self-reported diagnoses of various medical conditions, functional ability, body mass index, and ratings of positive and negative affect. For 937 subjects with arthritis who reported no limitations in activities of daily living (ADLs) at baseline, 697 remained ADL independent, 84 became ADL dependent, 41 died, and 115 were lost to followup 2 years later. There was a significant association between high positive affect (score = 12) and reduced risk of ADL disability 2 years later, controlling for baseline sociodemographic variables, medical conditions, and negative affect (odds ratio 0.46, 95% confidence interval 0.22-0.94). There was an interaction effect between positive affect and sex, with positive affect having a larger effect in reducing risk of ADL dependence in men than in women. High positive affect was associated with lower incidence of ADL disability in older Mexican Americans with self-reported physician-diagnosed arthritis. The strength of the positive affect is stronger in men than in women.


Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: A polysomnographic randomized, double-blind, placebo-controlled study.
To evaluate the efficacy of pramipexole on polysomnographic measures, patient ratings and a clinical rating in Japanese patients with primary restless legs syndrome (RLS). Patients with moderate to severe RLS having periodic limb movements in bed index (PLMI)>or=5 were randomly assigned to receive pramipexole or placebo in a 6-week, double-blind, placebo-controlled study with forced titration from 0.125 to 0.75mg/day. Both polysomnography (PSG) and the suggested immobilization test (SIT) were performed at baseline and 6weeks after starting treatment. The analysis of covariance of log-transformed PLMI showed that the adjusted means at the end of study were significantly smaller in the pramipexole group than in the placebo group (p=0.0019). In all patients, variables on SIT did not show any differences between the two groups, whereas a significant improvement was shown in the pramipexole group compared with the placebo group for patients with a SIT-PLM index at baseline >or=15. Pramipexole group showed a significant reduction in the International Restless Legs Syndrome Study Group rating scale (IRLS; p=0.0005), a significant improvement in both Patient Global Impression (PGI; p<0.0001) and Clinical Global Impressions (CGI-I; p=0.0488), and a significantly greater mean reduction in the Pittsburgh Sleep Quality Index (PSQI; p=0.0016), when compared with those of placebo group at week 6. Pramipexole is highly efficacious in the reduction of PLMI and in the improvement of subjective severity of RLS and subjective sleep disturbance caused by the disorder.


A Transferable Coarse Grain Non-bonded Interaction Model For Amino Acids.
The large quantity of protein sequences being generated from genomic data has greatly outpaced the throughput of experimental protein structure determining methods and consequently brought urgency to the need for accurate protein structure prediction tools. Reduced resolution, or coarse grained (CG) models, have become a mainstay in computational protein structure prediction perfoming among the best tools available. The quest for high quality generalized CG models presents an extremely challenging yet popular endeavor. To this point, a CG based interaction potential is presented here for the naturally occurring amino acids. In the present approach, three to four heavy atoms and associated hydrogens are condensed into a single CG site. The parameterization of the site-site interaction potential relies on experimental data thus providing a novel approach that is neither based on all-atom (AA) simulations nor experimental protein structural data. Specifically, intermolecular potentials, which are based on Lennard-Jones (LJ) style functional forms, are parameterized using thermodynamic data including surface tension and density. Using this approach, an amino acid potential dataset has been developed for use in modeling peptides and proteins. The potential is evaluated here by comparing the solvent accessible surface area (SASA) to AA representations and ranking of protein decoy data sets provided by Decoys 'R' Us. The model is shown to perform very well compared to other existing prediction models for these properties.


Advances in systemic therapy for the first-line treatment of unresectable HCC.
Introduction: Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide. In recent years, several drugs have been approved in first- and second-line setting. Currently, several phase-III trials are ongoing with combinations of checkpoint inhibitors, tyrosine kinase inhibitors (TKI) and anti-angiogenic antibodies, which will most likely increase therapeutic options in frontline therapy in the near future.Areas covered: This review summarizes the standard of care in first-line systemic therapy for patients with advanced HCC and provides an outlook on the most promising combinations currently tested in prospective trials.Expert opinion: The recent approval of novel substances has substantially changed the field of palliative treatment strategies in patients with advanced HCC. Immuno-oncology (IO)-based combination therapies will become the next standard of care in frontline HCC. The potent anti-tumor efficacy and good tolerability of these therapies will increase the use of upfront systemic therapy in patients with intermediate stage HCC.


The use of iliac stem prosthesis for acetabular defects following resections for periacetabular tumors.
The management of pelvic tumors is a challenge for orthopaedic oncologists due to the complex anatomy of the pelvis and the need to have extensive exposure. Various reconstructive techniques have been proposed with poor functional results and a high percentage of complications. Our purpose is to determine the functional results and the rate of complications of iliac stem prosthesis for acetabular defects following resections for periacetabular tumors. Between 1999 and 2012, 45 patients underwent pelvic resections for periacetabular bone tumors followed by reconstruction with stem cup prosthesis. The most common diagnosis was CS (chondrosarcoma, 29 cases), followed by OS (osteosarcoma, 9 cases) and metastasis (3 cases). In 33 cases, this implant was associated with massive bone allografts. Minimum follow-up required to evaluate functional outcome was 2 years. We classified pelvic resections according to Enneking and Dunham's classification and we used MSTS (musculoskeletal tumor system) score to evaluate functional outcomes. Sixteen patients died of their disease, three were lost to follow-up, four are alive with disease, and twenty-two are alive with no evidence of disease. Fifteen patients had local recurrence. Sixteen patients had bone or lung metastasis. We have had 6 infections, 2 aseptic loosening, and 2 cases of hip dislocation. Iliac sovracetabular osteotomy was fused in all cases at 10 months from surgery. Functional results were good or excellent in 25 of 31 patients with long-term follow-up (77%), with a percentage similar to that reported in the literature. The use of iliac stem prosthesis is a simple reconstructive technique that reduces operative times and risk of infection. It allows having good results and low rate of complications, but it should be performed in selected cases and centres of reference.


Exploring gender and thematic differences in qualitative assessments of internal medicine resident performance.
Evidence suggests gender disparities in medical education assessment, including differences in ratings of competency and narrative comments provided in resident performance assessments. This study explores how gender manifests within the content of qualitative assessments (i.e., narrative comments or performance feedback) of resident performance. Qualitative content analysis was used to explore gender-based differences in narrative comments included in faculty assessments of resident performance during inpatient medicine rotations at six Internal Medicine residency programs, 2016-2017. A blinded, multi-analyst approach was employed to identify themes across comments. Patterns in themes with resident gender and post-graduate year (PGY) were explored, focusing on PGY2 and PGY3 when residents are serving in the team leader role. Data included 3,383 evaluations with narrative comments of 385 men (55.2%) and 313 women residents (44.8%). There were thematic differences in narrative comments received by men and women residents and how these themes manifested within comments changed with training time. Compared to men, comments about women had a persistent relationship-orientation and emphasized confidence over training including as interns and in PGY2 and PGY3, when serving as team leader. The relationship-orientation was characterized not only by the residents' communal attributes but also their interpersonal and communication skills, including efforts supporting others and establishing the tone for the team. Comments about women residents often highlighted confidence, including recommendations around behaviors that convey confidence in decision-making and team leadership. There were gender-based thematic differences in qualitative assessments. Comments about women resident team leaders highlight relationship building skills and urge confidence and actions that convey confidence as team leader. Persistent attention to communal skills suggests gendered expectations for women resident team leaders and a lost opportunity for well-rounded feedback to the disadvantage of women residents. These findings may inform interventions to promote equitable assessment, such as providing feedback across the competencies.


Correlation of serum prostate specific antigen and quantitative immunohistochemistry.
Serum prostate specific antigen (PSA) in patients with prostate carcinoma is influenced by prostate size, transition zone volume, and tumor differentiation and volume. Immunohistochemistry studies have demonstrated an inverse correlation between PSA staining intensity and tumor grade, yet to our knowledge tissue expression of PSA has never been correlated with serum PSA. In 47 radical prostatectomy cases serum PSA was corrected for gland size and tumor volume. Standard immunohistochemistry staining techniques were applied to specimens using monoclonal antibodies to PSA and cytokeratin CAM5.2. Color images of PSA and CAM5.2 immunohistochemistry stained slides were digitally acquired and analyzed using a standard image analysis system. Representative tumor foci in each slide were imaged with a 20x objective and 10x eyepiece. Staining extent and intensity of the tumor epithelium were measured, and stromal elements and luminal areas were excluded from analysis. For each case quantitative PSA staining intensity was expressed relative to keratin staining in adjacent benign epithelium. Gland volume and tumor volume independently correlated with serum PSA. Furthermore, tissue PSA intensity inversely correlated with histological grade of the tumor (p <0.00001). After gland size, tumor volume and grade were considered, corrected quantitative tissue PSA intensity did not significantly correlate with corrected serum PSA. Immunohistochemistry expression of tissue PSA in prostate carcinoma cannot be used to explain variations in serum PSA. This discrepancy may relate to differences between the amount of PSA produced by prostatic tumors and the amount secreted, and/or the sensitivity of detecting various tissue isoforms of PSA with immunohistochemistry.


PIRPLE: a penalized-likelihood framework for incorporation of prior images in CT reconstruction.
Over the course of diagnosis and treatment, it is common for a number of imaging studies to be acquired. Such imaging sequences can provide substantial patient-specific prior knowledge about the anatomy that can be incorporated into a prior-image-based tomographic reconstruction for improved image quality and better dose utilization. We present a general methodology using a model-based reconstruction approach including formulations of the measurement noise that also integrates prior images. This penalized-likelihood technique adopts a sparsity enforcing penalty that incorporates prior information yet allows for change between the current reconstruction and the prior image. Moreover, since prior images are generally not registered with the current image volume, we present a modified model-based approach that seeks a joint registration of the prior image in addition to the reconstruction of projection data. We demonstrate that the combined prior-image- and model-based technique outperforms methods that ignore the prior data or lack a noise model. Moreover, we demonstrate the importance of registration for prior-image-based reconstruction methods and show that the prior-image-registered penalized-likelihood estimation (PIRPLE) approach can maintain a high level of image quality in the presence of noisy and undersampled projection data.