bluuebunny/crossref_metadata_2025_split huggingface dataset:
Botanical drugs: a new strategy for structure-based target prediction
Authors: Wei Xuxu , Wu Xiang , Cheng Zeyu , Wu Qingming , Cao Chen , Xu Xue , Shang Hongcai 
Published: September 2021

Abstract
Target identification of small molecules is an important and still changeling work in the area of drug discovery, especially for botanical drug development. Indistinct understanding of the relationships of ligand–protein interactions is one of the main obstacles for drug repurposing and identification of off-targets. In this study, we collected 9063 crystal structures of ligand-binding proteins released from January, 1995 to April, 2021 in PDB bank, and split the complexes into 5133 interaction pairs of ligand atoms and protein fragments (covalently linked three heavy atoms) with interatomic distance ≤5 Å. The interaction pairs were grouped into ligand atoms with the same SYBYL atom type surrounding each type of protein fragment, which were further clustered via Bayesian Gaussian Mixture Model (BGMM). Gaussian distributions with ligand atoms ≥20 were identified as significant interaction patterns. Reliability of the significant interaction patterns was validated by comparing the difference of number of significant interaction patterns between the docked poses with higher and lower similarity to the native crystal structures. Fifty-one candidate targets of brucine, strychnine and icajine involved in Semen Strychni (Mǎ Qián Zǐ) and eight candidate targets of astragaloside-IV, formononetin and calycosin-7-glucoside involved in Astragalus (Huáng Qí) were predicted by the significant interaction patterns, in combination with docking, which were consistent with the therapeutic effects of Semen Strychni and Astragalus for cancer and chronic pain. The new strategy in this study improves the accuracy of target identification for small molecules, which will facilitate discovery of botanical drugs.
A randomized clinical trial comparing early patient-reported pain after open anterior mesh repair versus totally extraperitoneal repair of inguinal hernia
Authors: Matikainen Markku , Vironen Jaana Hellevi , Silvasti Seppo , Ilves Imre , Kössi Jyrki , Kivivuori Antti , Paajanen Hannu 
Published: September 2021

Abstract

Background
This was a prospective, multicentre, non-blinded, randomized clinical trial involving two parallel groups of patients.

Methods
Adult patients with symptomatic unilateral primary inguinal hernia were included in this study. Patients were enrolled and treated in five Finnish hospitals. Eligible patients were randomized by use of a computer-based program to receiving either open anterior repair (modified Lichtenstein) with glue mesh fixation or totally extraperitoneal (TEP) repair. The primary aims were to compare 30-day patient-reported pain scores and return to work after surgery between the two groups.

Results
A total of 202 patients were randomized: 98 patients to TEP repair and 104 patients to open repair. All randomized patients received their allocated treatment. A total of 86 patients (88 per cent) in the TEP group and 94 patients (90 per cent) in the Lichtenstein group completed the 30-day follow-up. Patients experienced less early pain (P &lt; 0.001) and used less analgesics after TEP repair, compared to those who had modified Lichtenstein repair. Two patients in the TEP group and five in the Lichtenstein group developed superficial wound infection (P = 0⋅446). Only one reoperation was performed in the Lichtenstein group due to haematoma.

Conclusion
TEP inguinal hernia repair is associated with less early postoperative pain compared to the open glue mesh fixation technique.

Trial registration
NCT03566433 (http://www.clinicaltrials.gov).
Epilepsy in the mTORopathies: opportunities for precision medicine
Authors: Moloney Patrick B , Cavalleri Gianpiero L , Delanty Norman 
Published: September 2021

AbstractThe mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.
Contributions of Animal Studies to the Understanding of Infectious Diseases
Authors: Musher Daniel M , Arasaratnam Reuben J 
Published: September 2021

AbstractExperiments in animals have played an integral role in furthering basic understanding of the pathophysiology, host immune response, diagnosis, and treatment of infectious diseases. However, competing demands of modern-day clinical training and increasingly stringent requirements to perform animal research have reduced the exposure of infectious disease physicians to animal studies. For practitioners of infectious diseases and, especially, for contemporary trainees in infectious diseases, it is important to appreciate this historical body of work and its impact on current clinical practice. In this article, we provide an overview of some major contributions of animal studies to the field of infectious diseases. Areas covered include transmission of infection, elucidation of innate and adaptive host immune responses, testing of antimicrobials, pathogenesis and treatment of endocarditis, osteomyelitis, intra-abdominal and urinary tract infection, treatment of infection associated with a foreign body or in the presence of neutropenia, and toxin-mediated disease.
Squirrel Search Deer Hunting-Based Deep Recurrent Neural Network for Survival Prediction Using PAN-Cancer Gene Expression Data
Authors: Majji Ramachandro , Rajeswari R , Vidyadhari Ch , Cristin R 
Published: September 2021

Abstract
This paper devises a novel technique, namely Squirrel Search Deer Hunting-based deep recurrent neural network (SSDH-based DRNN) for cancer-survival rate prediction using gene expression (GE) data. Initially, the input GE data are transformed using the polynomial kernel data transformation. Then entropy-based Bayesian fuzzy clustering is employed for gene selection. Then, the selected features are strengthened through survival indicators based on time series data features, like simple moving average (SMA) and rate of change. Finally, the survival rate prediction is performed using a deep recurrent neural network (DRNN), in which the training is carried out with squirrel search deer hunting (SSDH). The proposed SSDH algorithm is devised by combining Squirrel Search Algorithm (SSA) and deer hunting optimization algorithm (DHOA). The performance of the proposed methodology is analyzed using Pan-Cancer (PANCAN) dataset with a prediction error of 4.05%, RMSE of 7.58, the accuracy of 90.98%, precision of 90.80%, recall of 92.03% and F1-score of 91.41%. The devised method with higher prediction accuracy and the lower prediction error is employed for the cancer survival prediction of the patients for the cancer prognosis. Besides, it will be helpful for the clinical management of cancer patients.
Pre-oviposition Period and Immature Development of Maconellicoccus hirsutus (Hemiptera: Pseudococcidae) on Cucurbita moschata ‘Black Futsu’ Squash
Authors: Ruais Danielle R , Ganjisaffar Fatemeh , Perring Thomas M 
Published: September 2021

Abstract
The developmental time of pink hibiscus mealybug, Maconellicoccus hirsutus (Green), immatures was investigated on the host plant Cucurbita moschata Duchesne ex Poiret variety ‘Black Futsu.’ Because host plant species influences developmental rates of M. hirsutus, understanding the life history of this specific host plant has implications for the mass rearing protocols of its natural enemy, Anagyrus callidus Triapitsyn, Andreason and Perring, currently being released in California, United States. Fruit from ‘Black Futsu’ squash were infested with first instar pink hibiscus mealybug and kept at 26.6 ± 2°C, 50 ± 10% RH, and 0:24 (L:D) h photoperiod for the duration of the experiment. Every 24 h the life stages of pink hibiscus mealybug individuals on the squash were recorded. After adult eclosion, observations of adult females continued until the first eggs hatched, which revealed an average pre-oviposition period of 7.2 ± 0.1 d and an average length of the egg stage of 7.0 ± 0.0 d. The average developmental times for both sexes were similar from the egg stage through the second instar. Third instar females took nearly twice as long (7.2 d) to develop into adults as did third instar males. However, females have just three immature instars while males have four. The males spent an average of 4.5 ± 0.3 d as third instars and 4.8 ± 0.4 d as fourth instars before developing into winged adults. On average, female immature developmental time was 27.8 ± 0.2 d from egg to adult and male developmental time was 29.4 ± 0.2 d from egg to adult. The implications of these results on rearing A. callidus are discussed.
Normal values and reference ranges for left atrial strain by speckle-tracking echocardiography: the Copenhagen City Heart Study
Authors: Nielsen Anne Bjerg , Skaarup Kristoffer Grundtvig , Hauser Raphael , Johansen Niklas Dyrby , Lassen Mats Christian Højbjerg , Jensen Gorm Boje , Schnohr Peter , Møgelvang Rasmus , Biering-Sørensen Tor 
Published: September 2021

Abstract

Aims
Left atrial (LA) function assessed by two-dimensional speckle-tracking echocardiography has shown increasing clinical and prognostic significance. We sought to establish age- and sex-based normative values of LA strain in the general population and to assess the prognostic yield of lower limits of normality of LA strain in relation to future atrial fibrillation (AF).

Methods and results
We determined normative values of peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and LA strain during the conduit phase (LACS) in 1641 healthy participants included in the fifth Copenhagen City Heart Study. In a secondary analysis, a validation cohort of 2016 participants, regardless of health status, were included to assess the prognostic value of the established reference values. In the healthy cohort, median age was 46 years (interquartile range 32–57), 62% were female. Median PALS, PACS, and LACS and corresponding limits of normality in the healthy participants were 39.4% (23.0–67.6%), 15.5% (6.4–28.0%), and 23.7% (8.8–44.8%), respectively. There was a tendency of lower values of PALS and LACS in males and older participants, while PACS tended to increase with advancing age. The established lower limits of normality showed high specificity (range 93–94%) regarding future AF, implying a low risk of developing AF in participants with LA strain above the lower limits of normality in their respective sex and age group.

Conclusion
We report normal values for LA strain stratified by sex and age. The lower limits of normality showed high specificity regarding future AF.
Left atrial strain predicts incident atrial fibrillation in the general population: the Copenhagen City Heart Study
Authors: Hauser Raphael , Nielsen Anne Bjerg , Skaarup Kristoffer Grundtvig , Lassen Mats Christian Højbjerg , Duus Lisa Steen , Johansen Niklas Dyrby , Sengeløv Morten , Marott Jacob Louis , Jensen Gorm , Schnohr Peter , Søgaard Peter , Møgelvang Rasmus , Biering-Sørensen Tor 
Published: September 2021

Abstract

Background
Left atrial (LA) strain parameters have been demonstrated to be valuable predictors of atrial fibrillation (AF) in several patient cohorts. The purpose of this study was to investigate whether LA strain, assessed by two-dimensional speckle-tracking echocardiography, can be used to predict the development of AF in the general population.

Methods and results
This prospective longitudinal study included 4466 participants from the fifth Copenhagen City Heart Study. All participants underwent a health examination, including echocardiographic measurements of LA strain. Participants with prevalent AF at baseline were excluded. The primary endpoint was incident AF. During a median follow-up period of 5.3 years, 154 (4.3%) participants developed AF. In univariable analysis, peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and LA strain during the conduit phase were significantly associated with the development of AF. PALS [hazard ratio (HR) 1.05, 95% confidence interval (CI) (1.03–1.07), P &lt; 0.001, per 1% decrease] and PACS (HR 1.08, 95% CI (1.05–1.12), P &lt; 0.001, per 1% decrease] remained independent predictors of AF in multivariable analysis. In addition, PALS and PACS remained significantly associated with AF development even in participants with normal-sized atria and normal left ventricular (LV) systolic function.

Conclusion
In the general population, PALS and PACS independently predict incident AF. These findings remained consistent even in participants with normal-sized LA and normal LV systolic function.
Cropping systems impact changes in soil fungal, but not prokaryote, alpha-diversity and community composition stability over a growing season in a long-term field trial
Authors: Finn Damien R , Lee Sungeun , Lanzén Anders , Bertrand Michel , Nicol Graeme W , Hazard Christina 
Published: September 2021

ABSTRACT
Crop harvest followed by a fallow period can act as a disturbance on soil microbial communities. Cropping systems intended to improve alpha-diversity of communities may also confer increased compositional stability during succeeding growing seasons. Over a single growing season in a long-term (18 year) agricultural field experiment incorporating conventional (CON), conservation (CA), organic (ORG) and integrated (INT) cropping systems, temporal changes in prokaryote, fungal and arbuscular mycorrhizal fungi (AMF) communities were investigated overwinter, during crop growth and at harvest. While certain prokaryote phyla were influenced by cropping system (e.g. Acidobacteria), the community as a whole was primarily driven by temporal changes over the growing season as distinct overwinter and crop-associated communities, with the same trend observed regardless of cropping system. Species-rich prokaryote communities were most stable over the growing season. Cropping system exerted a greater effect on fungal communities, with alpha-diversity highest and temporal changes most stable under CA. CON was particularly detrimental for alpha-diversity in AMF communities, with AMF alpha-diversity and stability improved under all other cropping systems. Practices that promoted alpha-diversity tended to also increase the similarity and temporal stability of soil fungal (and AMF) communities during a growing season, while prokaryote communities were largely insensitive to management.
Examination of Gene Loss in the DNA Mismatch Repair Pathway and Its Mutational Consequences in a Fungal Phylum
Authors: Phillips Megan A , Steenwyk Jacob L , Shen Xing-Xing , Rokas Antonis 
Published: September 2021

Abstract
The DNA mismatch repair (MMR) pathway corrects mismatched bases produced during DNA replication and is highly conserved across the tree of life, reflecting its fundamental importance for genome integrity. Loss of function in one or a few MMR genes can lead to increased mutation rates and microsatellite instability, as seen in some human cancers. Although loss of MMR genes has been documented in the context of human disease and in hypermutant strains of pathogens, examples of entire species and species lineages that have experienced substantial MMR gene loss are lacking. We examined the genomes of 1,107 species in the fungal phylum Ascomycota for the presence of 52 genes known to be involved in the MMR pathway of fungi. We found that the median ascomycete genome contained 49/52 MMR genes. In contrast, four closely related species of obligate plant parasites from the powdery mildew genera Erysiphe and Blumeria, have lost between five and 21 MMR genes, including MLH3, EXO1, and DPB11. The lost genes span MMR functions, include genes that are conserved in all other ascomycetes, and loss of function of any of these genes alone has been previously linked to increased mutation rate. Consistent with the hypothesis that loss of these genes impairs MMR pathway function, we found that powdery mildew genomes with higher levels of MMR gene loss exhibit increased numbers of mononucleotide runs, longer microsatellites, accelerated sequence evolution, elevated mutational bias in the A|T direction, and decreased GC content. These results identify a striking example of macroevolutionary loss of multiple MMR pathway genes in a eukaryotic lineage, even though the mutational outcomes of these losses appear to resemble those associated with detrimental MMR dysfunction in other organisms.
A mixture theory analysis for reflection phenomenon of homogeneous plane-P1-wave at the boundary of unsaturated porothermoelastic media
Authors: Liu Hongbo , Dai Guoliang , Zhou Fengxi , Cao Xiaolin 
Published: September 2021

SUMMARY
A mixture theory is employed to analyse the reflection behaviour of a homogeneous plane-P1-wave at the boundary of an unsaturated porothermoelastic medium. A non-isothermal dynamic model is employed which takes into account the interaction between the pore fluids and the solid phase of the porous material. In such an unsaturated porothermoelastic cases, the theoretical expressions of the amplitude reflectivity and energy ratio for five kinds of reflected waves generated by the incidence of homogeneous plane-P1-wave, that is reflected P1, P2, P3, S and thermal waves, are derived by taking into consideration of the traction-free, water-permeable, air-permeable and adiabatic boundary conditions. The numerical results are obtained and utilized to discuss the relationship between the amplitude reflectivity and energy ratio of each reflected wave and the thermophysical parameters of the unsaturated porothermoelastic media. The results show that the amplitude and energy carried by the incident wave are mainly occupied by reflected P1 wave and reflected S wave. The amplitude reflectivity and energy ratio of each reflected wave is not just related to the incident angle but also affected by the saturation, thermal expansion coefficient and initial reference temperature. The phase lags of the heat flux and temperature gradient and the thermal conductivity only have a large effect on the amplitude reflectivity and energy ratio of reflected thermal wave.
A joint inversion-segmentation approach to assisted seismic interpretation
Authors: Ravasi Matteo , Birnie Claire 
Published: September 2021

SUMMARY
Structural seismic interpretation and quantitative characterization are historically intertwined processes. The latter provides estimates of the properties of the subsurface, which can be used to aid structural interpretation alongside the original seismic data and a number of other seismic attributes. In this work, we redefine this process as an inverse problem which tries to jointly estimate subsurface properties (i.e. acoustic impedance) and a piece-wise segmented representation of the subsurface based on user-defined macroclasses. By inverting for the quantities simultaneously, the inversion is primed with prior knowledge about the regions of interest, whilst at the same time it constrains this belief with the actual seismic measurements. As the proposed functional is separable in the two quantities, these are optimized in an alternating fashion, where each subproblem is solved using the Primal-Dual algorithm. Subsequently, the final segmented model is used as input to an ad hoc workflow that extracts the perimeter of the detected shapes and produces a structural framework (i.e. seismic horizons) consistent with the estimated subsurface properties. The effectiveness of the proposed method is illustrated through numerical examples on synthetic and field data sets.
Association between Charlson Comorbidity Index and polypharmacy: a retrospective database study from Jordan
Authors: Arabyat Rasha M , Alazzam Ola M , Al-Azzam Sayer I , Nusair Mohammad B 
Published: September 2021

Abstract

Objectives
Polypharmacy is usually associated with duplication of therapy, unnecessary medications and adverse drug reactions. Therefore, it is crucial to study the factors that increase the risk of polypharmacy. The objective of this study was to assess the risk factors for polypharmacy (i.e. the concomitant use of at least five medications) with a special focus on comorbidity in Jordan.

Methods
Using a retrospective cross-sectional study design, medical records of patients (age ≥55 years), which covered slightly over one-fourth of the population, found in a national electronic healthcare database from 2018 to 2019 were retrieved. Polypharmacy, the main outcome, was defined as the current use of at least five medications (the patient should have at least one chronic condition, one medication refill and continuous use of the medication for at least 30 days). Comorbidity, the main exposure, was summarized using the Charlson Comorbidity Index (CCI). Potential predictors of polypharmacy were examined using a multivariable logistic regression analysis.

Key findings
An eligible sample of 113 834 individuals (mean age 68 years, 51.5% female) were included in the analysis, of whom 38% met the polypharmacy definition (28% were categorized as having major [5–9 medications] and 10.2% exhibited excessive polypharmacy [≥10 medications]). Approximately, 20% of the patients had a CCI of ≥1. The most significant predictors of polypharmacy were a CCI score between 3 and 4 (adjusted odds ratio [AOR] = 5.89; 95% CI, 5.10 to 6.80; P &lt; 0.001), gender (AOR = 0.86; 95% CI, 0.82 to 0.86; P &lt; 0.001), and age ≥75 years (AOR = 1.62; 95% CI, 1.57 to 1.67; P &lt; 0.001).

Conclusions
Polypharmacy is common among patients in Jordan. Comorbidity is positively, independently and strongly related to polypharmacy. Identifying groups who are at the greatest risk for polypharmacy can help optimize patients’ treatment, which can lead to better outcomes and improved quality of life.