bluuebunny/crossref_metadata_2025_split huggingface dataset:
3DLigandSite: structure-based prediction of protein–ligand binding sites
Authors: McGreig Jake E , Uri Hannah , Antczak Magdalena , Sternberg Michael J E , Michaelis Martin , Wass Mark N 
Published: April 2022

Abstract
3DLigandSite is a web tool for the prediction of ligand-binding sites in proteins. Here, we report a significant update since the first release of 3DLigandSite in 2010. The overall methodology remains the same, with candidate binding sites in proteins inferred using known binding sites in related protein structures as templates. However, the initial structural modelling step now uses the newly available structures from the AlphaFold database or alternatively Phyre2 when AlphaFold structures are not available. Further, a sequence-based search using HHSearch has been introduced to identify template structures with bound ligands that are used to infer the ligand-binding residues in the query protein. Finally, we introduced a machine learning element as the final prediction step, which improves the accuracy of predictions and provides a confidence score for each residue predicted to be part of a binding site. Validation of 3DLigandSite on a set of 6416 binding sites obtained 92% recall at 75% precision for non-metal binding sites and 52% recall at 75% precision for metal binding sites. 3DLigandSite is available at https://www.wass-michaelislab.org/3dligandsite. Users submit either a protein sequence or structure. Results are displayed in multiple formats including an interactive Mol* molecular visualization of the protein and the predicted binding sites.
The Importance of the C-Terminal Cys Pair of Phosphoribulokinase in Phototrophs in Thioredoxin-Dependent Regulation
Authors: Fukui Kazuha , Yoshida Keisuke , Yokochi Yuichi , Sekiguchi Takatoshi , Wakabayashi Ken-ichi , Hisabori Toru , Mihara Shoko 
Published: April 2022

Abstract
Phosphoribulokinase (PRK), one of the enzymes in the Calvin–Benson cycle, is a well-known target of thioredoxin (Trx), which regulates various enzyme activities by the reduction of disulfide bonds in a light-dependent manner. PRK has two Cys pairs conserved in the N-terminal and C-terminal regions, and the N-terminal one near the active site is thought to be responsible for the regulation. The flexible clamp loop located between the N-terminal two Cys residues has been deemed significant to Trx-mediated regulation. However, cyanobacterial PRK is also subject to Trx-dependent activation despite the lack of this clamp loop. We, therefore, compared Trx-mediated regulation of PRK from the cyanobacterium Anabaena sp. PCC 7120 (A.7120_PRK) and that from the land plant Arabidopsis thaliana (AtPRK). Interestingly, peptide mapping and site-directed mutagenesis analysis showed that Trx was more effective in changing the redox states of the C-terminal Cys pair in both A.7120_PRK and AtPRK. In addition, the effect of redox state change of the C-terminal Cys pair on PRK activity was different between A.7120_PRK and AtPRK. Trx-mediated redox regulation of the C-terminal Cys pair was also important for complex dissociation/formation with CP12 and glyceraldehyde 3-phosphate dehydrogenase. Furthermore, in vivo analysis of the redox states of PRK showed that only one disulfide bond is reduced in response to light. Based on the enzyme activity assay and the complex formation analysis, we concluded that Trx-mediated regulation of the C-terminal Cys pair of PRK is important for activity regulation in cyanobacteria and complex dissociation/formation in both organisms.
Digital image analysis of intraepithelial B-lymphocytes to assess lymphoepithelial lesions in salivary glands of Sjögren’s syndrome patients
Authors: van Ginkel Martha S , van der Sluis Tineke , Bulthuis Marian L C , Buikema Henk J , Haacke Erlin A , Arends Suzanne , Harder Stine , Spijkervet Fred K L , Bootsma Hendrika , Vissink Arjan , Kroese Frans G M , van der Vegt Bert 
Published: April 2022

Abstract

Objective
Salivary glands of primary SS (pSS) patients characteristically harbour periductal infiltrates, in which lymphoepithelial lesions (LELs) can develop. LELs are composed of hyperplastic ductal epithelium with infiltrating lymphocytes and may assist in the challenging diagnostic process of pSS. As manual identification of LELs remains difficult, we aimed to identify LELs by using an objective digital image analysis (DIA) algorithm that detects intraepithelial lymphocytes.

Methods
A virtual triple-staining technique developed for this study was used to count intraepithelial lymphocytes in consecutive slides stained for CD3 (T-lymphocytes), high-molecular-weight cytokeratin (hmwCK) (striated ducts) and CD20 (B-lymphocytes) in labial and parotid gland biopsies in a diagnostic cohort of 109 sicca patients. Patients were classified as having pSS or non-SS according to the ACR-EULAR classification criteria.

Results
T-lymphocytes were detected in almost all analysed ducts of pSS and non-SS sicca patients, whereas intraepithelial B-lymphocytes were present in 59–68% of labial and parotid gland biopsies of pSS patients, against only 2–3% of patients classified as non-SS. Intraepithelial B-lymphocytes were found in almost all striated ducts with hyperplasia (LELs). Remarkably, ∼25% of analysed striated ducts without hyperplasia of pSS patients also contained B-lymphocytes (precursor-LELs). Furthermore, presence of intraepithelial B-lymphocytes was associated with clinical parameters of pSS (i.e. serology).

Conclusion
The presence of intraepithelial B-lymphocytes in salivary gland biopsies of sicca patients is a clear indicator of pSS and can be used as an objective alternative to LEL scoring. Therefore, identification of B-lymphocyte–containing ducts should be added to the diagnostic histopathological work-up of patients suspected of pSS.
Survival analysis of mortality and development of lupus nephritis in patients with systemic lupus erythematosus up to 40 years of follow-up
Authors: Luo Weike , Farinha Filipa , Isenberg David A , Rahman Anisur 
Published: April 2022

Abstract

Objectives
Patients with SLE have increased mortality compared with age- and sex-matched controls. LN is a severe manifestation of SLE and an important cause of death. We carried out a retrospective survival analysis to investigate factors that could influence the risk of mortality and LN in a large multi-ethnic cohort of patients with SLE.

Methods
By careful review of medical records, we identified 496 patients with SLE for whom we had complete information regarding the period of observation and occurrence of death and nephritis. Patients were stratified into groups according to sex, ethnicity, age at start of follow-up and time period of diagnosis. Kaplan–Meier analysis was used to investigate differences between the groups.

Results
Of the 496 patients in the study, 91 (18.3%) died, 165 (33.3%) developed LN and 33 (6.7%) developed end-stage renal failure. There was no difference between men and women in either mortality or development of LN. Caucasian patients were significantly less likely to develop LN than other ethnic groups (P &lt; 0.0001) but not less likely to die. Patients diagnosed before the median age of 28 years were significantly more likely to develop LN (P &lt; 0.0001) but significantly less likely to die (P = 0.0039) during the period of observation. There has been a significant improvement in survival in patients diagnosed between 1978 and 1989 and those diagnosed between 2006 and 2011 (P = 0.019).

Conclusion
In our cohort, non-Caucasian ethnicity and younger age at diagnosis are associated with the risk of developing LN. There is evidence of improvement in survival of patients with SLE over time.
Impact of COVID-19 and COVID-19 vaccination on high-risk patients with antiphospholipid syndrome: a nationwide survey
Authors: Pengo Vittorio , Del Ross Teresa , Tonello Marta , Andreoli Laura , Tincani Angela , Gresele Paolo , Silvestri Elena , Simioni Paolo , Campello Elena , Hoxha Ariela , Falanga Anna , Ghirarduzzi Angelo , Denas Gentian ,   COVID-19 APS collaborators, Semeraro Paolo , Bertocchi Stefania , Paciullo Francesco , Veropalumbo Maria Rosaria 
Published: April 2022

AbstractObjectivesPatients with APS and triple-positive for aPL are at high risk of recurrent events. As COVID-19 and COVID-19 vaccination may induce thrombotic complications, the objective of the study was to assess the course of COVID-19 and adverse events after vaccination in these patients.MethodsThis is a nationwide multicentre survey conducted in nine APS referral centres by means of a questionnaire. Included patients are thrombotic APS with triple-positive aPL confirmed 12 weeks apart. Reference specialist physicians used a four-graded scale of severity for COVID-19 [from 0 (asymptomatic) to 3 (hospitalization in intensive care unit)] and a six-graded scale for adverse reactions to vaccination [from 0 (transient local injection site sign/symptoms) to 5 (potentially life-threatening reactions)]. Outcomes were considered within a 30-day period.ResultsOut of 161 patients interviewed, 18 (11%) had COVID-19. All of them fully recovered without any progression to severe disease nor thromboembolic event. A total of 146 patients received the first (92%) and 129 (80%) the second dose of vaccine; side effects were minimal and, in most cases (83% after the first and 68% after the second vaccination) limited to a sore arm. Fifteen patients (9%) were unvaccinated. Most of them raised doubts on the need for vaccination, complained of poor safety and in general were reluctant about COVID-19 vaccination.ConclusionPatients with triple-positive thrombotic APS did not suffer from severe COVID-19 outcomes. Importantly, COVID-19 vaccination was well tolerated. These data may reassure patients and physicians and contribute to reducing hesitancy in unvaccinated patients.
Low-dose glucocorticoids withdrawn in systemic lupus erythematosus: a desirable and attainable goal
Authors: Ji Lanlan , Gao Dai , Hao Yanjie , Huang Hong , Wang Yu , Deng Xuerong , Geng Yan , Zhang Zhuoli 
Published: April 2022

Abstract

Objectives
To assess the risk of flare in systemic lupus erythematosus (SLE) patients after low-dose glucocorticoid (GC) discontinuation and to evaluate the risk factors of flare.

Methods
SLE patients who ever discontinued GCs were identified from the Peking University First Hospital SLE cohort. The disease flare profile after GC discontinuation was analysed. The flare rate was analysed using Kaplan–Meier analysis. Cox regression was used to determine the effects of variables on SLE flare. A prognostic nomogram using Cox proportional hazards regression modelling was developed.

Results
A total of 132 SLE patients were eligible for the final analysis. They were followed up for a median of 21.8 months (interquartile range 9.01–36.7). The cumulative probability of flare after GC discontinuation was 8.3% at 6 months, 16.8% at 1 years and 27.5% at 2 years. In multivariate Cox analysis, hypocomplementemia and serologically active clinically quiescent (SACQ) were independent risk factors of flare [hazard ratio (HR0 2.53 (95% CI 1.32, 4.88); HR 3.17 (95% CI 1.44, 6.97), respectively]. Age ≥40 years at GC withdrawal and hydroxychloroquine (HCQ) usage were independent protective factors of flare [HR 0.53 (95% CI 0.29, 0.99); HR 0.32 (95% CI 0.17, 0.62), respectively]. The protective effect of HCQ was dosage related. From the perspective of different tapering strategies embodied as the duration from prednisone 5 mg/day to complete discontinuation, a slower tapering strategy (12–24 months) significantly reduced the risk of flare compared with a faster tapering strategy (&lt;3 months) [HR 0.30 (95% CI 0.11, 0.82), P = 0.019]. The prognostic nomogram including the aforementioned factors effectively predicted the 1 and 2 year probability of being flare-free.

Conclusion
Low-dose GC is feasibly discontinued in real-life settings. SACQ and younger age are potential risk factors of SLE flare, while HCQ use and slow GC tapering to withdrawal can reduce relapse. The visualized model we developed may help to predict the risk of flare among SLE patients who discontinued GC.
Case report and review of the literature: immune dysregulation in a large familial cohort due to a novel pathogenicRELAvariant
Authors: Lecerf Kelsey , Koboldt Daniel C , Kuehn Hye Sun , Jayaraman Vijayakumar , Lee Kristy , Mihalic Mosher Theresa , Yonkof Jennifer R , Mori Mari , Hickey Scott E , Franklin Samuel , Drew Joanne , Akoghlanian Shoghik , Sivaraman Vidya , Rosenzweig Sergio D , Wilson Richard K , Abraham Roshini S 
Published: April 2022

AbstractObjectiveTo explore and define the molecular cause(s) of a multi-generational kindred affected by Bechet’s-like mucocutaneous ulcerations and immune dysregulation.MethodsWhole genome sequencing and confirmatory Sanger sequencing were performed. Components of the NFκB pathway were quantified by immunoblotting, and function was assessed by cytokine production (IL-6, TNF-α, IL-1β) after lipopolysaccharide (LPS) stimulation. Detailed immunophenotyping of T-cell and B-cell subsets was performed in four patients from this cohort.ResultsA novel variant in the RELA gene, p. Tyr349LeufsTer13, was identified. This variant results in premature truncation of the protein before the serine (S) 536 residue, a key phosphorylation site, resulting in enhanced degradation of the p65 protein. Immunoblotting revealed significantly decreased phosphorylated [p]p65 and pIκBα. The decrease in [p]p65 may suggest reduced heterodimer formation between p50/p65 (NFκB1/RelA). Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T-cell populations in one patient (P1). P1 also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the other three patients.ConclusionFamily members with this novel RELA variant have a clinical phenotype similar to other reported RELA cases with predominant chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet’s syndrome and IBD. Here we describe the clinical, immunological and genetic evaluation of a large kindred to further expand identification of patients with autosomal dominant RELA deficiency, facilitating earlier diagnosis and intervention. The functional impairment of the canonical NFκB pathway suggests that this variant is causal for the clinical phenotype in these patients.
Evaluation and validation of the prognostic value of anti-MDA5 IgG subclasses in dermatomyositis-associated interstitial lung disease
Authors: Xu Yue-Tong , Zhang Ya-Mei , Yang Hong-Xia , Ye Li-Fang , Chen Fang , Lu Xin , Wang Guo-Chun , Peng Qing-Lin 
Published: April 2022

AbstractObjectiveTo investigate the association between the anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses and prognosis of patients with dermatomyositis (DM)-associated interstitial lung disease (ILD).MethodsThis retrospective study included 122 anti-MDA5 positive DM-ILD patients admitted from October 2017 to October 2020 as training cohort, and additional 68 patients from August 2014 to September 2017 as validation cohort. The levels of anti-MDA5 total IgG and IgG subclasses were measured using in-house enzyme-linked immunosorbent assays, and analysed in association with the patient prognosis.ResultsIn the training cohort, the concentrations of anti-MDA5 IgG1 and IgG3 in non-survivors were significantly higher than in survivors (P &lt; 0.05), whereas there were no significant differences in the IgG2 and IgG4 levels. Kaplan–Meier survival analysis revealed that the levels of anti-MDA5 total IgG, IgG1 and IgG3 were associated with mortality (P &lt; 0.05). Multivariate analysis revealed anti-MDA5 IgG1 &gt;13 U/ml and anti-MDA5 IgG3 &gt;11 U/ml were independent risk factors for death of DM-ILD patients (P &lt; 0.05). Anti-MDA5 IgG1 was confirmed as an independent risk factor in the validation cohort, while anti-MDA5 IgG3 was not. Anti-MDA5 IgG1 showed greater discriminable power for patient prognosis (Youden index 0.494) than anti-MDA5 total IgG, IgG3, or the combination of IgG1 and IgG3 (Youden index 0.356, 0.32 and 0.447, respectively).ConclusionAnti-MDA5 IgG1 and IgG3 are significantly associated with poor prognosis in DM-ILD patients, and anti-MDA5 IgG1 is more efficient as a prognostic biomarker in DM-ILD patients.
Robust, Universal Tree Balance Indices
Authors: Lemant Jeanne , Le Sueur Cécile , Manojlović Veselin , Noble Robert 
Published: April 2022

Abstract
Balance indices that quantify the symmetry of branching events and the compactness of trees are widely used to compare evolutionary processes or tree-generating algorithms. Yet, existing indices are not defined for all rooted trees, are unreliable for comparing trees with different numbers of leaves, and are sensitive to the presence or absence of rare types. The contributions of this article are twofold. First, we define a new class of robust, universal tree balance indices. These indices take a form similar to Colless’ index but can account for population sizes, are defined for trees with any degree distribution, and enable meaningful comparison of trees with different numbers of leaves. Second, we show that for bifurcating and all other full m-ary cladograms (in which every internal node has the same out-degree), one such Colless-like index is equivalent to the normalized reciprocal of Sackin’s index. Hence, we both unify and generalize the two most popular existing tree balance indices. Our indices are intrinsically normalized and can be computed in linear time. We conclude that these more widely applicable indices have the potential to supersede those in current use. [Cancer; clone tree; Colless index; Sackin index; species tree; tree balance.]
Phylogenetic Diversity Rankings in the Face of Extinctions: The Robustness of the Fair Proportion Index
Authors: Fischer Mareike , Francis Andrew , Wicke Kristina 
Published: April 2022

Abstract
Planning for the protection of species often involves difficult choices about which species to prioritize, given constrained resources. One way of prioritizing species is to consider their “evolutionary distinctiveness,” (ED) that is, their relative evolutionary isolation on a phylogenetic tree. Several evolutionary isolation metrics or phylogenetic diversity indices have been introduced in the literature, among them the so-called Fair Proportion (FP) index (also known as the ED score). This index apportions the total diversity of a tree among all leaves, thereby providing a simple prioritization criterion for conservation. Here, we focus on the prioritization order obtained from the FP index and analyze the effects of species extinction on this ranking. More precisely, we analyze the extent to which the ranking order may change when some species go extinct and the FP index is recomputed for the remaining taxa. We show that for each phylogenetic tree, there are edge lengths such that the extinction of one leaf per cherry completely reverses the ranking. Moreover, we show that even if only the lowest-ranked species goes extinct, the ranking order may drastically change. We end by analyzing the effects of these two extinction scenarios (extinction of the lowest-ranked species and extinction of one leaf per cherry) for a collection of empirical and simulated trees. In both cases, we can observe significant changes in the prioritization orders, highlighting the empirical relevance of our theoretical findings. [Biodiversity conservation; Fair Proportion index; phylogenetic diversity; species prioritization.]
Lateral Stress Radiographs of Lateral Compression Type 1 Pelvic Injuries, With the Injured Side Down or Up, Reliably Measure Occult Instability
Authors: Parry Joshua A. , Hadeed Michael M. , Strage Katya E. , Heare Austin , Stacey Stephen C. , Mauffrey Cyril 
Published: April 2022

Objectives:
To evaluate the interobserver reliability of measured displacement and occult instability of minimally displaced lateral compression type 1 (LC1) fractures on lateral stress radiographs (LSRs) and to compare differences in displacement between LSR with the injured side down (ID) and up (IU).

Design:
Retrospective review.

Setting:
Urban Level 1 trauma center.

Patients/Participants:
Twenty-three adult patients with minimally displaced (<1 cm) LC1 injuries.

Intervention:
None.

Main Outcome Measurements:
Three orthopaedic surgeons measured the distance between the radiographic teardrops on LSR and supine anteroposterior pelvic radiographs to calculate dynamic fracture displacement. The interobserver reliability of the measured displacement, a continuous variable, was assessed by calculating the intraclass correlation coefficient. The interobserver reliability of occult instability (≥10 mm of displacement on LSR), a categorical variable, was assessed by calculating the kappa value. Matched-pairs analysis was performed to calculate the mean difference of measurements between observers and between ID and IU LSR.

Results:
The interobserver reliability of the measured displacement was excellent (intraclass correlation coefficient 0.93). The mean difference in measurements between observers ranged from −1.8 to 0.96 mm. The mean difference in the measured displacement between ID and IU LSRs for each observer ranged from −0.6 to 0.3 mm. There was 83% (19/23 cases) agreement on the presence of occult instability (≥10 mm of displacement on LSR) on both ID and IU LSRs. The interobserver reliability of occult instability was moderate (kappa 0.76).

Conclusions:
Measured fracture displacement and occult instability of minimally displaced LC1 injuries were reliably measured and identified on LSR, regardless of the laterality.
The Progressive Loss Risk Scale for Hair Restoration Surgery
Authors: Stough Dow B. 
Published: April 2022

BACKGROUND
Limited information exists on the long-term risks to individuals undergoing procedures in hair restoration surgery. The short-term risks are well known and similar to other procedures in dermatologic surgery. The long-term risks of hair restoration surgery are seldom discussed between the physician and patient.

OBJECTIVE
The author sought to describe a classification system that can be used as a communication tool between physicians and patients to define the long-term risk involved with hair restoration surgery.

METHODS
The Progressive Loss (PL) Scale is an attempt at assessing the cosmesis because of future hair loss following a hair transplant procedure. The PL Risk Scale has designated 5 levels, 1 to 5, with each ascending level representing a higher level of risk. The PL Risk Scale can be assigned to an individual at the time of the assessment for hair restoration surgery.

RESULTS
Each patient can be assigned a risk level based on how future hair loss may affect the overall cosmetic result of their hair transplant. This risk is dependent on age, and specific for the area to be transplanted. The younger the age of the patient, the higher the risk. The larger the area to be transplanted, the higher the risk. It is not a static scale, because it will be affected by age, donor area, location of transplantation, and other mitigating factors.

CONCLUSION
Pattern baldness in men and women is progressive and unrelenting. The dichotomy of hair restoration surgery is that a satisfactory short-term outcome can evolve to disappointing results because of progressive hair loss. The PL Risk Scale can be assigned to every individual undergoing a hair restoration procedure. This scale assignment will convey to the patient their lifetime risk associated with any given surgical hair restoration procedure for that age and the specific area to be restored.