Defect-unbinding transitions and inherent structures in two dimensions

We present a large-scale (36000-particle) computational study of the "inherent structures" (IS) associated with equilibrium, two-dimensional, one-component Lennard-Jones systems. Our results provide strong support both for the inherent-structures theory of classical fluids, and for the KTHNY theory of two-stage melting in two dimensions. This support comes from the observation of three qualitatively distinct "phases" of inherent structures: a crystal, a "hexatic glass", and a "liquid glass". We also directly observe, in the IS, analogs of the two defect-unbinding transitions (respectively, of dislocations, and disclinations) believed to mediate the two equilibrium phase transitions. Each transition shows up in the inherent structures---although the free disclinations in the "liquid glass" are embedded in a percolating network of grain boundaries. The bond-orientational correlation functions of the inherent structures show the same progressive loss of order as do the three equilibrium phases: long-range to quasi-long-range to short-range.Comment: RevTeX, 8 pages, 15 figure

Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis

Biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Amongst these, polyarticular Juvenile-Idiopathic Arthritis (pJIA) and Rheumatoid Arthritis (RA) display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. Mechanisms and determinants of this heterogeneous response are diverse and complex, such that development of true “precision”-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in polyarticular JIA in comparison to what is known in RA. Although some biomarkers have been identified that stratify for the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centered and clinically-based approach, i.e. personalized instead of biomarker-based precision medicine in JIA

Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects

Cama de frango como substrato para a produção de biogás após diferentes períodos de estocagem.

RESUMO: Na avicultura a cama de frango é produzida sazonalmente, em função do modo de produção. Para obter energia do biogás por meio da biodigestão da cama de frango, de forma contínua, o armazenamento do resíduo pode ser uma solução. Ensaios de Potencial Bioquímico de Metano (BMP) foram utilizados neste trabalho para estimar a capacidade de produção de biogás e metano da cama de frango removida após o sexto lote de reutilização e a diferentes tempos de armazenamento após a coleta, assim, verificar a viabilidade de utilização da cama de frango como um substrato em unidade produtora de biogás. A produção de biogás e metano, nas amostras em diferentes períodos de armazenamento, foi comparada: antes de armazenar 245 LN biogas.kgSV adic-1 e 159 LN CH4.kgSV adic-11, seis meses com 252 LN biogas.kgSV adic-1 e 160 LN CH4.kgSV adic-1 e um ano 209 LN biogas.kgSV adic-1 e 117 LNCH4.kgSV adic-1, demonstrando que o período de armazenamento é caracterizado por uma relativa perda do conteúdo de matéria orgânica após um ano, contudo, não há diferença significativa entre a produção de biogás e metano após seis meses armazenada e antes de armazenar. Verificou-se a viabilidade da estocagem de cama de frango do sexto lote de reutilização, no período de seis meses, sem perda significativa de matéria orgânica para a conversão em biogás e metano. ABSTRACT: In poultry litter is produced seasonally due to production mode. To get energy from biogas through the bio digestion of poultry litter, continuously, the storage of the residue can be a solution. Biochemical Methane Potential (BMP) assays were used in this study to estimate the production of biogas and methane poultry litter removed after the sixth lot of reuse and in different storage times after collect, so check the feasibility of use poultry litter as a feedstock in biogas producer unit. The production of biogas and methane in the samples in different periods of storage was compared: before storage 245 LN biogas.kgVS add-1 E 159 LN C H4 kg SV add-1, six months with 252 LN biogas.kgVS add-1 e 160 LN C H4 kg SV add-1 and a year 209 LN biogas.kgVS add-1 and one year 117 LN C H4 kg SV add-1, demonstrating that the storage period is characterized by a relative loss of content of organic matter after a year, however there's no significant difference between the production of biogas and methane in six months storaged and before storage . It was verified the viability of storage of poultry litter of the sixth lot of reuse, in the six-month period, without significant loss of organic matter for conversion to biogas and methane

Association of Atopobium vaginae, a recently described metronidazole resistant anaerobe, with bacterial vaginosis

BACKGROUND: Bacterial vaginosis (BV) is a polymicrobial syndrome characterized by a change in vaginal flora away from predominantly Lactobacillus species. The cause of BV is unknown, but the condition has been implicated in diverse medical outcomes. The bacterium Atopobium vaginae has been recognized only recently. It is not readily identified by commercial diagnostic kits. Its clinical significance is unknown but it has recently been isolated from a tuboovarian abcess. METHODS: Nucleotide sequencing of PCR amplified 16S rRNA gene segments, that were separated into bands within lanes on polyacrylamide gels by denaturing gradient gel electrophoresis (DGGE), was used to examine bacterial vaginal flora in 46 patients clinically described as having normal (Lactobacillus spp. predominant; Nugent score ≤ 3) and abnormal flora (Nugent score ≥ 4). These women ranged in age from 14 to 48 and 82% were African American. RESULTS: The DGGE banding patterns of normal and BV-positive patients were recognizably distinct. Those of normal patients contained 1 to 4 bands that were focused in the centre region of the gel lane, while those of BV positive patients contained bands that were not all focused in the center region of the gel lane. More detailed analysis of patterns revealed that bands identified as Atopobium vaginae were present in a majority (12/22) of BV positive patients, while corresponding bands were rare (2/24) in normal patients. (P < 0.001) Two A. vaginae isolates were cultivated from two patients whose DGGE analyses indicated the presence of this organism. Two A. vaginae 16S rRNA gene sequences were identified among the clinical isolates. The same two sequences were obtained from DGGE bands of the corresponding vaginal flora. The sequences differed by one nucleotide over the short (~300 bp) segment used for DGGE analysis and migrated to slightly different points in denaturing gradient gels. Both isolates were strict anaerobes and highly metronidazole resistant. CONCLUSION: The results suggest that A. vaginae may be an important component of the complex bacterial ecology that constitutes abnormal vaginal flora. This organism could play a role in treatment failure if further studies confirm it is consistently metronidozole resistant

The Human Phenotype Ontology in 2024: phenotypes around the world

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Triple negative breast cancer: proposals for a pragmatic definition and implications for patient management and trial design.

In trials in triple negative breast cancer (TNBC), oestrogen and progesterone receptor negativity should be defined as < 1% positive cells. Negativity is a ratio of <2 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less. In routine practice, immunohistochemistry is acceptable given stringent quality assurance. Triple negativity emerging after neoadjuvant treatment differs from primary TN and such patients should not enter TNBC trials. Patients relapsing with TN metastases should be eligible even if their primary was positive. Rare TN subtypes such as apocrine, adenoid-cystic and low-grade metaplastic tumours should be excluded. TN and basal-like (BL) signatures overlap but are not equivalent. Since the significance of basal cytokeratin or EGFR overexpression is not known and we lack validated assays, these features should not be used to subclassify TN tumours. Tissue collection in trials is mandatory so the effect on outcome of different tumour phenotypes and BRCA mutation can be explored. No prospective studies have established that TN tumours have particular sensitivity or resistance to any specific chemotherapy agent or radiation. TNBC patients should be treated according to tumour and clinical characteristics