Current applications of quantitative methods pharmacology and machine mastering models over illnesses

Assigning new sequences to known protein families and subfamilies is a prerequisite for many functional, comparative and evolutionary genomics analyses. Such assignment is commonly achieved by looking for the closest sequence in a reference database, using a method such as BLAST. However, ignoring the gene phylogeny can be misleading because a query sequence does not necessarily belong to the same subfamily as its closest sequence. For example, a hemoglobin which branched out prior to the hemoglobin alpha/beta duplication could be closest to a hemoglobin alpha or beta sequence, whereas it is neither. To overcome this problem, phylogeny-driven tools have emerged but rely on gene trees, whose inference is computationally expensive.
Here, we first show that in multiple animal and plant datasets, 18 to 62% of assignments by closest sequence are misassigned, typically to an over-specific subfamily. Then, we introduce OMAmer, a novel alignment-free protein subfamily assignment method, which limits over-specific subfamily assignments and is suited to phylogenomic databases with thousands of genomes. OMAmer is based on an innovative method using evolutionarily-informed k-mers for alignment-free mapping to ancestral protein subfamilies. Histone Methyltransferase inhibitor Whilst able to reject non-homologous family-level assignments, we show that OMAmer provides better and quicker subfamily-level assignments than approaches relying on the closest sequence, whether inferred exactly by Smith-Waterman or by the fast heuristic DIAMOND.
OMAmer is available from the Python Package Index (as omamer), with the source code and a precomputed database available at https//github.com/DessimozLab/omamer.
Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.Tuberculosis is a chronic inflammatory disease caused by Mycobacterium tuberculosis. When tuberculosis invades the human body, innate immunity is the first line of defense. However, how the innate immune microenvironment responds remains unclear. In this research, we studied the function of each type of cell and explained the principle of an immune microenvironment. Based on the differences in the innate immune microenvironment, we modularized the analysis of the response of five immune cells and two structural cells. The results showed that in the innate immune stress response, the genes CXCL3, PTGS2 and TNFAIP6 regulated by the nuclear factor kappa B(NK-KB) pathway played a crucial role in fighting against tuberculosis. Based on the active pathway algorithm, each immune cell showed metabolic heterogeneity. Besides, after tuberculosis infection, structural cells showed a chemotactic immunity effect based on the co-expression immunoregulatory module.With the increasing volume of high-throughput sequencing data from a variety of omics techniques in the field of plant-pathogen interactions, sorting, retrieving, processing and visualizing biological information have become a great challenge. Within the explosion of data, machine learning offers powerful tools to process these complex omics data by various algorithms, such as Bayesian reasoning, support vector machine and random forest. Here, we introduce the basic frameworks of machine learning in dissecting plant-pathogen interactions and discuss the applications and advances of machine learning in plant-pathogen interactions from molecular to network biology, including the prediction of pathogen effectors, plant disease resistance protein monitoring and the discovery of protein-protein networks. The aim of this review is to provide a summary of advances in plant defense and pathogen infection and to indicate the important developments of machine learning in phytopathology.The Nef protein of human and simian immunodeficiency viruses boosts viral pathogenicity through its interactions with host cell proteins. By combining the polyvalency of its large unstructured regions with the binding selectivity and strength of its folded core domain, Nef can associate with many different host cell proteins, thereby disrupting their functions. For example, the combination of a linear proline-rich motif and hydrophobic core domain surface allows Nef to bind tightly and specifically to SH3 domains of Src family kinases. We investigated whether the interplay between Nef's flexible regions and its core domain could allosterically influence ligand selection. We found that the flexible regions can associate with the core domain in different ways, producing distinct conformational states that alter the way in which Nef selects for SH3 domains and exposes some of its binding motifs. The ensuing crosstalk between ligands might promote functionally coherent Nef-bound protein ensembles by synergizing certain subsets of ligands while excluding others. We also combined proteomic and bioinformatics analyses to identify human proteins that select SH3 domains in the same way as Nef. We found that only 3% of clones from a whole-human fetal library displayed Nef-like SH3 selectivity. However, in most cases, this selectivity appears to be achieved by a canonical linear interaction rather than by a Nef-like 'tertiary' interaction. Our analysis supports the contention that Nef's mode of hijacking SH3 domains is a virus-specific adaptation with no or very few cellular counterparts. Thus, the Nef tertiary binding surface is a promising virus-specific drug target.Neuritin is a member of the neurotrophic factor family, which plays an important role in the promotion and development of the nervous system. Neuritin is also involved in angiogenesis. Neuritin was recently found to be a negative regulatory factor of the Notch 1 signaling pathway. Notch signaling pathway is known as a regulatory pathway of angiogenesis. Thus, neuritin may play a role in angiogenesis through the Notch signaling pathway. In the present study, we investigated the expressions of neuritin and Notch signaling pathway factors in the pulmonary vascular tissue. The results showed that neuritin expression was increased in the paraneoplastic vascular tissue and decreased in the lung cancer vascular tissue. The neuritin expression was increased with the increase of vascular tissue density, and a negative correlation between neuritin expression and delta-like ligand 4 (DLL4) was identified in vascular tissues of lung cancer. Overexpression of neuritin in human umbilical vein endothelial cells (HUVECs) inhibited the expressions of Notch signaling pathway-associated factors, including DLL4, NICD, and Hes-1, and promoted the migration and tubular formation of HUVECs. In conclusion, our results indicated that neuritin is involved in angiogenesis and may play a role in angiogenesis through the Notch signaling pathway. This study provides a theoretical basis for clinical anti-angiogenesis therapy.
Adjuvant chemotherapy is the standard of care for resected pancreatic ductal adenocarcinoma (PDAC) based on level 1 evidence, but some studies suggest that a neoadjuvant approach (which is standard for borderline resectable PDAC) may be preferable for upfront resectable PDAC. An in-depth review was conducted of all randomized clinical trials that investigated neoadjuvant and adjuvant treatment of patients with resectable or resected PDAC, focusing on trial design, characteristics of enrolled population, and long-term outcomes.
The existing resectable PDAC trials have good internal validity but variable applicability because of their restrictive eligibility criteria. In these trials, overall survival is the criterion standard end point, but disease-free survival is more feasible, proximate, and specific to the assigned intervention (at the cost of subjective outcome assessment) and thus an acceptable end point in certain contexts. The prolonged survival in the PRODIGE 24 trial highlights both the success ogly encouraged.
This review found that adjuvant chemotherapy with mFOLFIRINOX is currently the standard of care in fit patients with resected PDAC; however, the role of neoadjuvant treatment is expanding. Precision oncology may help individualize the treatment regimen and sequence and improve outcomes. Enrollment of patients with resectable PDAC in clinical trials is strongly encouraged.
Ulceration is a common complication of infantile hemangioma (IH), which leads to substantial morbidity. Ulceration in IH has not been systematically studied since the advent of β-blocker therapy for IH.
To examine treatment interventions used for ulceration in IH and identify clinical prognostic indicators of healing time.
A retrospective, multicenter cohort study was conducted on 436 consecutive patients with a clinical diagnosis of ulcerated IH and available clinical photographs. Patients receiving care at tertiary referral centers evaluated between 2012 and 2016 were included; statistical and data analysis were performed from February 7 to April 27, 2020.
Clinical characteristics, treatment interventions, course, complications, and resource use were analyzed. Treatment interventions for ulceration in IH included local (wound care, topical), systemic (β-blocker, corticosteroids), and procedural (pulsed-dye laser).
The primary end point was time to complete or nearly complete ulceration healing. Clfound that a subset of patients with IH ulceration continued to experience prolonged IH healing times. Larger IH size appears to be a poor prognostic factor for time to heal. For patients requiring systemic therapy, initiation of propranolol at lower doses (≤1 mg/kg/d) should be considered.
Despite the use of β-blockers, this cohort study found that a subset of patients with IH ulceration continued to experience prolonged IH healing times. Larger IH size appears to be a poor prognostic factor for time to heal. For patients requiring systemic therapy, initiation of propranolol at lower doses (≤1 mg/kg/d) should be considered.
Portal vein embolization (PVE) has been implemented in patients with extensive colorectal liver metastases to increase the number of patients able to undergo liver resection. Liver transplant could be an alternative in selected patients with extensive liver-only disease, and we have recently shown promising survival outcomes.
To compare overall survival (OS) among patients with colorectal cancer and high liver metastasis tumor load who were treated with liver transplant or with PVE and liver resection.
This comparative effectiveness research study assessed 50 patients with colorectal cancer liver metastases who were previously enrolled in liver transplant studies between November 2006 and August 2019 at Oslo University Hospital in Norway. Those patients were compared with a retrospective cohort of 53 patients in the Oslo University Hospital PVE database from March 2006 through November 2015 with similar selection criteria who underwent PVE and liver resection.
The OS among patients with high tumor loa with nonresectable disease, an extensive liver tumor load, and left-sided primary tumors had long OS after liver transplant, exceeding the survival outcome for those patients treated with PVE and liver resection.
Early-stage melanoma, among the most common cancers in the US, is typically treated with wide local excision. However, recent advances in immunohistochemistry have led to an increasing number of these cases being excised via Mohs micrographic surgery (MMS). Although studies of resections for other cancers have reported that facility-level factors are associated with patient outcomes, it is not yet established how these factors may affect outcomes for patients treated with Mohs micrographic surgery.
To evaluate the association of treatment center academic affiliation and case volume with long-term patient survival after MMS for T1a-T2a invasive melanoma.
In a retrospective cohort study, 4062 adults with nonmetastatic, T1a-T2a melanoma diagnosed from 2004 to 2014 and treated with MMS in the National Cancer Database (NCDB) were identified. The NCDB includes all reportable cases from Commission on Cancer-accredited facilities and is estimated to capture approximately 50% of all incident melanomas in the US.