Abstract
Motivation
Accurate prediction and interpretation of ligand bioactivities are essential for virtual screening and drug discovery. Unfortunately, many important drug targets lack experimental ...data about the ligand bioactivities; this is particularly true for G protein-coupled receptors (GPCRs), which account for the targets of about a third of drugs currently on the market. Computational approaches with the potential of precise assessment of ligand bioactivities and determination of key substructural features which determine ligand bioactivities are needed to address this issue.
Results
A new method, SED, was proposed to predict ligand bioactivities and to recognize key substructures associated with GPCRs through the coupling of screening for Lasso of long extended-connectivity fingerprints (ECFPs) with deep neural network training. The SED pipeline contains three successive steps: (i) representation of long ECFPs for ligand molecules, (ii) feature selection by screening for Lasso of ECFPs and (iii) bioactivity prediction through a deep neural network regression model. The method was examined on a set of 16 representative GPCRs that cover most subfamilies of human GPCRs, where each has 300–5000 ligand associations. The results show that SED achieves excellent performance in modelling ligand bioactivities, especially for those in the GPCR datasets without sufficient ligand associations, where SED improved the baseline predictors by 12% in correlation coefficient (r2) and 19% in root mean square error. Detail data analyses suggest that the major advantage of SED lies on its ability to detect substructures from long ECFPs which significantly improves the predictive performance.
Availability and implementation
The source code and datasets of SED are freely available at https://zhanglab.ccmb.med.umich.edu/SED/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Although the taxonomy of
has been extensively scrutinized, significant uncertainty remains regarding the generic boundaries and composition of this large and heterogeneous taxon. Here we used the ...amino acid and nucleotide sequences of 106 conserved proteins from 92 species to infer robust maximum likelihood phylogenies with which to investigate the generic structure of
sensu lato. These data unambiguously supported five distinct lineages, of which four correspond to
sensu stricto and the newly introduced genera
,
, and
. The fifth lineage was represented by
. Based on these findings, we propose 13 new combinations for those species previously described as members of
but that form part of
. These findings also suggest revision of the taxonomic status of
as it is does not form part of any of the genera currently recognized in
sensu lato. From a phylogenetic point of view,
sensu stricto has a sister relationship with the
+
clade. Also, the lineages represented by
and
, respectively, emerged prior to the radiation of the
sensu stricto+
+
clade. Our findings therefore constitute a solid framework, not only for supporting current and future taxonomic decisions, but also for studying the evolution of this assemblage of medically, industrially and agriculturally important species.
Background Ongoing evaluation of biological agents in patients with moderate‐to‐severe psoriasis is needed to support their long‐term use.
Objective To evaluate long‐term efficacy and safety of ...ustekinumab through 5 years in the PHOENIX 1 study.
Methods Patients were randomized to placebo or ustekinumab (45 mg or 90 mg) at Weeks 0, 4 and every‐12‐weeks thereafter; placebo patients crossed‐over to ustekinumab at Week 12. Clinical response through Week 244 was evaluated using the Psoriasis Area and Severity Index (PASI) in the Overall Population (i.e. patients receiving ≥1 dose of ustekinumab), Initial Responders (i.e. PASI 75 responders Weeks 28/40 re‐randomized at Week 40 to continue every‐12‐week maintenance) and Partial Responders (i.e. <PASI 75 responders adjusted to every‐8‐week maintenance at Weeks 28 or 40). Safety endpoints were evaluated through Week 264 for the Overall Population.
Results Overall, 68.7% (517/753) of ustekinumab‐treated patients completed treatment through Week 244. Initial clinical responses were generally maintained through Week 244 (PASI 75: 63.4% and 72.0%; PASI 90: 39.7% and 49.0%; PASI 100: 21.6% and 26.4%) for patients receiving 45 mg and 90 mg, respectively. Similarly, PASI 75 responses were generally maintained among Initial Responders 79.1% (45 mg) and 80.8% (90 mg) and Partial Responders 57.6% (45 mg) and 55.1% (90 mg). With 3104 patient‐years of follow‐up, rates of overall adverse events (AEs), serious AEs, serious infections, malignancies and major adverse cardiovascular events were generally consistent over time and comparable between doses.
Conclusions Through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response and a safety profile consistent with previous reports.
Efficient derivation of neural cells from human embryonic stem cells (hESCs) remains an unmet need for the treatment of neurological disorders. The limiting factors for current methods include being ...labor-intensive, time-consuming and expensive. In this study, we hypothesize that the substrate topography, with optimal geometry and dimension, can modulate the neural fate of hESCs and enhance the efficiency of differentiation. A multi-architectural chip (MARC) containing fields of topographies varying in geometry and dimension was developed to facilitate high-throughput analysis of topography-induced neural differentiation in vitro. The hESCs were subjected to “direct differentiation”, in which small clumps of undifferentiated hESCs were cultured directly without going through the stage of embryoid body formation, on the MARC with N2 and B27 supplements for 7days. The gene and protein expression analysis indicated that the anisotropic patterns like gratings promoted neuronal differentiation of hESCs while the isotropic patterns like pillars and wells promoted the glial differentiation of hESCs. This study showed that optimal combination of topography and biochemical cues could shorten the differentiation period and allowed derivation of neurons bearing longer neurites that were aligned along the grating axis. The MARC platform would enable high-throughput screening of topographical substrates that could maximize the efficiency of neuronal differentiation from pluripotent stem cells.
Weekly PM2.5 samples were simultaneously collected at a semi-residential (Tsinghua University) and a downtown (Chegongzhuang) site in Beijing from August 2001 through September 2002. The ambient mass ...concentration and chemical composition of PM2.5 were determined. Analyses including elemental composition, water-soluble ions, and organic and elemental carbon were performed. The annual average concentrations of PM2.5 were 96.5 microg m(-3) and 106.9 microg m(-3) at CGZ and HU site, respectively. More than 80% of the PM2.5 mass concentrations were explained by carbonaceous species, secondary particles, crustal matters and trace elements at the two sites. Carbonaceous species were the most abundant components, constituting about 45% and 48% of the total PM2.5 mass concentrations at CGZ and THU site, respectively. SO4(2-), NO3- and NH4+ were three major ions, accounting for 37%, 23% and 20%, respectively, of the total mass of inorganic water-soluble ions.
Abstract
Background
Fetal docosahexaenoic acid (DHA) supply relies on preferential transplacental transfer, which is regulated by placental DHA lipid metabolism. Maternal hyperglycemia and obesity ...associate with higher birthweight and fetal DHA insufficiency but the role of placental DHA metabolism is unclear.
Methods
Explants from 17 term placenta were incubated with
13
C-labeled DHA for 48 h, at 5 or 10 mmol/L glucose treatment, and the production of 17 individual newly synthesized
13
C-DHA labeled lipids quantified by liquid chromatography mass spectrometry.
Results
Maternal BMI positively associated with
13
C-DHA-labeled diacylglycerols, triacylglycerols, lysophospholipids, phosphatidylcholine and phosphatidylethanolamine plasmalogens, while maternal fasting glycemia positively associated with five
13
C-DHA triacylglycerols. In turn,
13
C-DHA-labeled phospholipids and triacylglycerols positively associated with birthweight centile. In-vitro glucose treatment increased most
13
C-DHA-lipids, but decreased
13
C-DHA phosphatidylethanolamine plasmalogens. However, with increasing maternal BMI, the magnitude of the glucose treatment induced increase in
13
C-DHA phosphatidylcholine and
13
C-DHA lysophospholipids was curtailed, with further decline in
13
C-DHA phosphatidylethanolamine plasmalogens. Conversely, with increasing birthweight centile glucose treatment induced increases in
13
C-DHA triacylglycerols were exaggerated, while glucose treatment induced decreases in
13
C-DHA phosphatidylethanolamine plasmalogens were diminished.
Conclusions
Maternal BMI and glycemia increased the production of different placental DHA lipids implying impact on different metabolic pathways. Glucose-induced elevation in placental DHA metabolism is moderated with higher maternal BMI. In turn, findings of associations between many DHA lipids with birthweight suggest that BMI and glycemia promote fetal growth partly through changes in placental DHA metabolism.
Abstract
Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased ...fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with
13
C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized
13
C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most
13
C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased
13
C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased
13
C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.
Meticillin-resistant Staphylococcus aureus (MRSA) infections are rampant in hospitals and residential care homes for the elderly (RCHEs).
To analyse the prevalence of MRSA colonization among ...residents and staff, and degree of environmental contamination and air dispersal of MRSA in RCHEs.
Epidemiological and genetic analysis by whole-genome sequencing (WGS) in 12 RCHEs in Hong Kong.
During the COVID-19 pandemic (from September to October 2021), 48.7% (380/781) of RCHE residents were found to harbour MRSA at any body site, and 8.5% (8/213) of staff were nasal MRSA carriers. Among 239 environmental samples, MRSA was found in 39.0% (16/41) of randomly selected resident rooms and 31.3% (62/198) of common areas. The common areas accessible by residents had significantly higher MRSA contamination rates than those that were not accessible by residents (37.2%, 46/121 vs. 22.1%, 17/177, P=0.028). Of 124 air samples, nine (7.3%) were MRSA-positive from four RCHEs. Air dispersal of MRSA was significantly associated with operating indoor fans in RCHEs (100%, 4/4 vs. 0%, 0/8, P=0.002). WGS of MRSA isolates collected from residents, staff and environmental and air samples showed that ST 1047 (CC1) lineage 1 constituted 43.1% (66/153) of all MRSA isolates. A distinctive predominant genetic lineage of MRSA in each RCHE was observed, suggestive of intra-RCHE transmission rather than clonal acquisition from the catchment hospital.
MRSA control in RCHEs is no less important than in hospitals. Air dispersal of MRSA may be an important mechanism of dissemination in RCHEs with operating indoor fans.
Background:
Although percutaneous surgery for the treatment of hallux valgus is popular in Europe, there is sparse English written literature documenting its efficacy. This study described the ...operative techniques using percutaneous basal closing wedge osteotomy of the first metatarsal in correction of moderate to severe hallux valgus (HV) and its short-term clinical outcomes. We postulated that satisfactory correction of hallux valgus (HV) angle, intermetatarsal (IM) angle, and patients’ clinical outcomes could be achieved with this technique.
Methods:
We conducted a retrospective review of 25 feet in 23 patients who underwent a percutaneous basal closing wedge osteotomy of the first metatarsal (MT1) combined with a mini-open modified McBride procedure and mini-open resection of medial eminence. Follow-up averaged 21.5 months. Radiographic outcomes included pre- and postoperative HV angle, IM angle, absolute and relative shortening of MT1, and time to union. American Orthopaedic Foot & Ankle Society (AOFAS) scores were compared between pre- and postoperatively.
Results:
The average HV angle improved from 39.4 (range, 29-58.3) degrees preoperatively to 14.7 (range, 0.1-23.2) degrees postoperatively (P < .05). IM angle improved from 14.9 (range, 6.7-22.4) degrees to 6.6 (range, 0.9-14.8) degrees (P < .05). The average absolute shortening was 3.8 (range, 0.27-12.91) mm and the relative shortening was 0.8 (range, 0.05-1.91) mm. There was no delayed union or malunion at the osteotomy site. The average AOFAS score improved from 39 (range, 12-50) to 81 (range, 70-93) (P < .05).
Conclusions:
Satisfactory hallux valgus deformity correction and patients’ outcomes were achieved with this technique. Our results are similar to results reported in other studies using open techniques. There was no malunion or delayed union of the osteotomy.
Level of Evidence:
Level IV, case series study.
Introduction
Non-prosthetic peri-implant fractures (NPPIFs) are an under-reported entity. Management is challenging because of alterations in anatomy, the presence of orthopaedic implants and ...phenomena such as stress shielding, disuse osteopenia and fracture remodeling. The aims of this paper were to review patterns of injury, management and outcomes and to propose a classification system to aid further research.
Materials and methods
This study is a multi-centered retrospective case series. Patients were identified from the orthopaedic department trauma databases of public hospitals in Singapore and individual surgeon case series of members of the Singapore Orthopaedic Research Collaborative (SORCE) group.
Results
We collected a series of 60 NPPIFs in 53 patients. 38 fractures involved the femur, 12 the radius/ulna, 5 humeri, 3 tibia/fibula and 1 clavicle. 39 patients had fractures around plates and screws, 12 around nails, and 3 around screws. Fractures were managed with a variety of surgical techniques. Six patients had surgical complications with refracture in four and non-union in two cases. Two patients had multiple refractures (total 12 additional fractures). All surgical complications required further surgery. Three patients had deep vein thrombosis and one patient died of post-operative pneumonia. Fractures were classified according to the initial implant (plate or nail), the position of the new fracture relative to the original implant (at the tip or distant) and the status of the original fracture (healed, not healed or failing). Surgical strategies for common subtypes were reviewed.
Conclusions
This study represents the largest series in the literature. NPPIFs are a challenging clinical problem with a high rate of post-operative complications. They are distinct from peri-prosthetic fractures and should be understood as a separate entity. We, therefore, propose a novel classification system. Further research is needed to determine the optimal treatment for the various subtypes.
Level of evidence
Therapeutic Level IV—case series.
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