bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploiting pretrained biochemical language models for targeted drug design
Authors: Uludoğan Gökçe , Ozkirimli Elif , Ulgen Kutlu O , Karalı Nilgün , Özgür Arzucan 
Published: September 2022

AbstractMotivationThe development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein–ligand pairs. On the other hand, large amounts of unlabelled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation and (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target-specific training. We also compare two decoding strategies to generate compounds: beam search and sampling.ResultsThe results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality.Availability and implementationThe source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials (i.e., data, models, and outputs) are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145.Supplementary informationSupplementary data are available at Bioinformatics online.
Preoperative risk factors for early recurrence after resection of perihilar cholangiocarcinoma
Authors: Yamamoto Ryusei , Sugiura Teiichi , Ashida Ryo , Ohgi Katsuhisa , Yamada Mihoko , Otsuka Shimpei , Aramaki Takeshi , Asakura Koiku , Uesaka Katsuhiko 
Published: September 2022

Abstract

Background
Early recurrence after curative resection of perihilar cholangiocarcinoma (PHCC) often occurs within a year of surgery. Preoperative predictors of early recurrence remain unclear. The aim of this study was to define reliable preoperative predictors of early recurrence.

Methods
Medical records and preoperative multidetector-row CT of patients with PHCC who underwent resection between 2002 and 2018 were reviewed. Clinical findings, tumour markers, and radiological appearances including a ‘periductal enation sign’ (PES) where there was evidence of soft tissue enhancement appearing to arise from the extrahepatic bile duct, were analysed.

Results
Among 261 patients who underwent resection for PHCC, 67 (25.7 per cent) developed early recurrence. Multivariable analysis identified four preoperative risk factors for early recurrence, namely carbohydrate antigen 19–9 (CA19-9) 37 U/ml or higher (OR 2.19, 95 per cent confidence interval (c.i.) 1.08 to 4.46), positive PES (OR 7.37, 95 per cent c.i. 2.46 to 22.10), mass-forming tumour (OR 4.46, 95 per cent c.i. 1.83 to 10.90), and luminal-occlusion tumour (OR 4.52, 95 per cent c.i. 2.11 to 9.68). The OR of preoperative risk factors were used to define four risk subgroups for early recurrence. The early recurrence rates in the low, moderate, high, and very-high risk groups were 0, 9.4 , 39.7, and 65.0 per cent respectively.

Conclusion
CA19-9, PES, mass-forming tumour, and luminal-occlusion tumour identify patients at higher risk for early recurrence after resection of PHCC.
The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity
Authors: Cisternas Pablo , Taylor Xavier , Martinez Pablo , Maldonado Orlando , Jury Nur , Lasagna-Reeves Cristian A 
Published: September 2022

AbstractAlzheimer’s disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents amyloid-beta-induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated amyloid-beta-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to amyloid-beta. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3. These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by amyloid-beta-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions.
Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response
Authors: Valli Atte , Kuuliala Krista , Virtanen Anniina , Kuuliala Antti , Palmroth Maaria , Peltomaa Ritva , Vidqvist Krista-Liisa , Leirisalo-Repo Marjatta , Silvennoinen Olli , Isomäki Pia 
Published: September 2022

Abstract
The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase—signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) &gt;3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P &lt; 0.001). Marked (&gt;20%) and statistically significant (P &lt; 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (&gt;50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.
Visually induced γ band rhythm in spatial summation beyond the receptive field in mouse primary visual cortex
Authors: Hou BoJun , Chen Ke , Jia Ang , Liu Shanshan , Bao Xiaojing , Liao Baitao , Zhao Yi Lei , Guo Daqing , Xia Yang , Yao Dezhong 
Published: September 2022

AbstractRecent studies in many kinds of mammals have established the existence of multiple γ rhythms in the cerebral cortex subserving different functions. In the primary visual cortex (V1), visually induced γ rhythms are dependent on stimulus features. However, experimental findings of γ power induced by varying the size of the drifting grating are inconsistent. Here, we reinvestigated the spatial summation properties of visually induced spike and γ rhythm activities in mouse V1. Our results show that drifting sinusoidal grating stimuli mainly induce 2 γ band rhythms, including a low-frequency band (25–45 Hz) and a high-frequency band (55–75 Hz). Unlike previous findings, we discovered that visually induced γ power could also exhibit extrareceptive field (ERF) modulatory properties. The modulation by ERF stimulation could be either suppressive, countersuppressive, or nonsuppressive, mostly similar to the local spike activity. Moreover, further analysis of the neuron group exhibiting surround suppression in both spike and γ activity revealed that the strength of the surround suppression and the receptive field size showed moderate correlations between measurements by spike and γ rhythm activity. Our findings improve the understanding of the characteristics and neural mechanisms of induced γ rhythms in visual spatial summation.
Age and the eGFR-dependent risk for adverse clinical outcomes
Authors: Liu Ping , Ravani Pietro 
Published: September 2022

ABSTRACT
Although the relative risk of kidney failure increases with more severe chronic kidney disease (CKD) independent of age, with older age the absolute risk of kidney failure at a given time horizon becomes smaller. In this article, we first review some epidemiological measures of outcome occurrence (absolute rate or risk) and association (relative measures: difference or ratio of rates or risks). We emphasize that relative measures need to be presented along with absolute measures to be understood and absolute risk is more helpful than absolute rate when making treatment decisions. We then apply these principles to the discussion of the absolute and relative rates or risks of kidney failure and death across categories of estimated glomerular filtration rate and age. Lastly, we discuss the implications of existing studies on whether the definition of CKD should account for age.
A thelytokous predatory mite is more cannibalistic towards distant kin
Authors: Zhang Keshi , Zhang Zhi-Qiang 
Published: September 2022

Abstract
Kin recognition has been widely observed in various taxa. Cannibalism avoidance may be a strong driver for the evolution of kin recognition, as it may avoid a reduction in inclusive fitness. Kin recognition has recently been observed in a generalist phytoseiid, Amblyseius herbicolus (Acari: Phytoseiidae). This study experimentally examined the degree of relatedness needed between prey larvae and cannibal adults of A. herbicolus for the occurrence of kin discrimination. The adults were individually placed in enclosed arenas with two prey, a daughter and a more distant related larva, to observe their cannibalizing choice. The adults of A. herbicolus did not discriminate between close relatives (daughter versus niece) but preferably cannibalized more distant kin (i.e., first and second cousins once removed). Phenotype matching and familiarization seem prominent as recognition mechanisms used by A. herbicolus adults. The effect of learning on kin recognition through prior contact in A. herbicolus requires further investigation. Studies on other adaptive functions of kin recognition of A. herbicolus, such as cooperation and parental care, may provide meaningful insights.
The broad impact of functional lumen imaging probe panometry in addition to high-resolution manometry in an esophageal clinical practice
Authors: Ellison Ashton , Nguyen Anh D , Zhang Jesse , Mendoza Roseann , Davis Daniel , Podgaetz Eitan , Ward Marc , Reddy Chanakyaram , Souza Rhonda , Spechler Stuart J , Konda Vani J A 
Published: September 2022

SummaryHigh-resolution manometry (HRM) with the Chicago Classification (CC) is the standard paradigm to define esophageal motility disorders. Functional lumen imaging probe (FLIP) panometry utilizes impedance planimetry to characterize esophageal compliance and secondary peristalsis. The aim of this study was to explore the clinical impact of FLIP panometry in addition to HRM. A retrospective chart review was performed on FLIP panometry cases utilizing the 322N catheter. Cases with prior foregut surgeries or botulinum injection within 6 months of FLIP panometry were excluded. EGJ-diameter and distensibility index (DI) and secondary contraction patterns at increasing balloon volumes were recorded. An EGJ-DI of ≥2.8 mm2/mm Hg at 60 mL was considered as a normal EGJ distensibility. CC diagnosis, Eckhardt score, Brief Esophageal Dysphagia Questionnaire, and clinical outcomes were obtained for each FLIP case. A total of 186 cases were included. Absent contractility and achalasia types 1 and 2 showed predominantly absent secondary contraction patterns, while type 3 had a variety of secondary contractile patterns on FLIP panometry. Among 77 cases with EGJ outflow obstruction (EGJOO), 60% had a low EGJ-DI. Among those with no motility disorder or ineffective esophageal motility on HRM, 27% had a low DI and 47% had sustained contractions on FLIP, raising concern for an esophageal dysmotility process along the achalasia and/or spastic spectrum. FLIP panometry often confirmed findings on HRM in achalasia and absent contractility. FLIP panometry is useful in characterizing EGJOO cases. Spastic features on FLIP panometry may raise concern for a motility disorder on the spastic spectrum not captured by HRM. Further studies are needed on FLIP panometry to determine how to proceed with discrepancy with HRM and explore diagnoses beyond the CC.
Randomized trial of cardiovascular prevention in Norway combining an in-hospital lifestyle course with primary care follow-up: the Hjerteløftet study
Authors: Bergum Hilde , Sandven Irene , Abdelnoor Michael , Anderssen Sigmund Alfred , Grimsmo Jostein , Rivrud Dag Elle , Myhr Nils Erling , Vold Mona Bekken , Stenbakken Cesilie , Lidfors Bengt , Dufseth Laila , Klemsdal Tor Ole 
Published: September 2022

Abstract

Aims
Cardiovascular risk factor control is suboptimal in Europe, including Norway. The present study examined the efficacy of a multimodal primary prevention intervention programme based on the existing Norwegian health care system.

Methods and results
In this open-label randomized controlled trial, adult patients with elevated cardiovascular risk were randomly assigned to an intervention programme including a hospital-based lifestyle course and primary care follow-up or to a control group (CG). The participants were recruited between 2011 and 2015. Primary outcome was change in validated cardiovascular risk scores, national and international (NORRISK, NORRISK 2, Framingham, PROCAM) between baseline and follow-up. Secondary outcomes included major cardiovascular risk factors. After 36 months the NORRISK score was significantly improved in patients assigned to the intervention group (IG) compared to patients assigned to the CG; absolute difference in mean delta score in the IG (n = 305) compared to mean delta score in the CG (n = 296): −0.92, 95% CI: −1.48 to −0.36, P = 0.001. The results for NORRISK 2, Framingham and PROCAM showed similar significant effects. The secondary endpoints including total cholesterol and blood pressure were only minimally, and non-significantly, reduced in the IG, but the proportion of smokers (P = 0.0028) and with metabolic syndrome (P &lt; 0.0001) were significantly reduced. A limited number of cardiovascular events were observed, IG (n = 9), CG (n = 16).

Conclusion
In subjects with elevated cardiovascular risk, a newly developed prevention programme, combining a hospital-based lifestyle course and primary care follow-up, significantly reduced cardiovascular risk scores after 36 months. This benefit appeared achievable primarily through improvements in metabolic syndrome characteristics and smoking habits.
The study protocol was registered in ClinicalTrials.gov (NCT01741428).
The association between dairy intake and risk of cardiovascular disease and mortality in patients with stable angina pectoris
Authors: Van Parys Anthea , Sæle Jostein , Puaschitz Nathalie G , Anfinsen Åslaug Matre , Karlsson Therese , Olsen Thomas , Haugsgjerd Teresa R , Vinknes Kathrine J , Holven Kirsten B , Dierkes Jutta , Nygård Ottar K , Lysne Vegard 
Published: September 2022

Abstract

Aims
The association of dairy products with cardiovascular disease and mortality risk remains heavily debated. We aimed to investigate the association between intake of total dairy and dairy products and the risk of acute myocardial infarction (AMI), stroke, and cardiovascular and all-cause mortality.

Methods and results
We included 1929 patients (80% men, mean age 62 years) with stable angina pectoris from the Western Norway B-vitamin Intervention Trial. Dietary data were obtained via a 169-item food frequency questionnaire. Risk associations were estimated using Cox proportional hazard regression models adjusted for relevant covariates. Non-linear associations were explored visually. The mean (±SD) dairy intake in the study population was 169 ± 108 g/1000 kcal. Median follow-up times were 5.2, 7.8, and 14.1 years for stroke, AMI, and mortality, respectively. Higher intake of total dairy and milk were positively associated with stroke risk [HR (95% CI): 1.14 (1.02, 1.27) and 1.13 (1.02, 1.27), cardiovascular mortality 1.06 (1.00, 1.12) and 1.07 (1.01, 1.13)] and all-cause mortality [1.07 (1.03, 1.11) and 1.06 (1.03, 1.10)] per 50 g/1000 kcal. Higher cheese intake was inversely associated with AMI risk [0.92 (0.83, 1.02)] per 10 g/1000 kcal. Butter was associated with increased AMI risk [1.10 (0.97, 1.24)] and all-cause mortality [1.10 (1.00, 1.20) per 5 g/1000 kcal.

Conclusion
Higher dairy and milk consumption were associated with increased risk of mortality and stroke. Cheese was associated with decreased, and butter with increased, risk of AMI. Dairy is a heterogenous food group with divergent health effects and dairy products should therefore be investigated individually.
learnMET: an R package to apply machine learning methods for genomic prediction using multi-environment trial data
Authors: Westhues Cathy C , Simianer Henner , Beissinger Timothy M 
Published: September 2022

AbstractWe introduce the R-package learnMET, developed as a flexible framework to enable a collection of analyses on multi-environment trial breeding data with machine learning-based models. learnMET allows the combination of genomic information with environmental data such as climate and/or soil characteristics. Notably, the package offers the possibility of incorporating weather data from field weather stations, or to retrieve global meteorological datasets from a NASA database. Daily weather data can be aggregated over specific periods of time based on naive (for instance, nonoverlapping 10-day windows) or phenological approaches. Different machine learning methods for genomic prediction are implemented, including gradient-boosted decision trees, random forests, stacked ensemble models, and multilayer perceptrons. These prediction models can be evaluated via a collection of cross-validation schemes that mimic typical scenarios encountered by plant breeders working with multi-environment trial experimental data in a user-friendly way. The package is published under an MIT license and accessible on GitHub.
Seismically active structures of the Main Himalayan Thrust revealed before, during and after the 2015 Mw 7.9 Gorkha earthquake in Nepal
Authors: Adhikari L B , Laporte M , Bollinger L , Vergne J , Lambotte S , Koirala B P , Bhattarai M , Timsina C , Gupta R M , Wendling-Vazquez N , Batteux D , Lyon-Caen H , Gaudemer Y , Bernard P , Perrier F 
Published: September 2022

SUMMARY
The Mw 7.9 2015 April 25 Gorkha earthquake is the latest of a millenary-long series of large devastating Himalayan earthquakes. It is also the first time a large Himalayan earthquake and its aftershocks were recorded by a local network of seismic stations. In the 5 yr following the main shock, more than 31 000 aftershocks were located by this permanent network within the ruptured area, including 14 362 events with ML greater than 2.5, 7 events with ML &gt; 6, including one large aftershock with Mw 7.2 on 2015 May 12. In 2020, 5 yr after the main shock, the seismicity rate along the ruptured fault segments was still about 5 times higher than the background seismicity before the Gorkha earthquake. Several bursts of earthquakes, sometimes organized in clusters, have been observed from a few days to several years after the main shock. Some of these clusters were located at the same place as the clusters that happened during the decades of interseismic stress build-up that preceded the large earthquake. They also happened in the vicinity of the high frequency seismic bursts that occurred during the main shock. These heterogeneities contribute to a persistent segmentation of the seismicity along strike, possibly controlled by geological structural complexities of the Main Himalayan Thrust fault. We suggest that these pre-2015 clusters revealed the seismo-geological segmentation that influences both the coseismic rupture and the post-seismic relaxation.
Acoustic-gravity waves generated by a point source on the ground in a stratified atmosphere-Earth structure
Authors: Gao Yongxin , Li Ting , Zhou Guanqun , Chen Chieh-Hung , Sun Yang-Yi , Zhang Xuemin , Liu Jann-Yenq , Wen Jian , Yao Cheng , Bai Xiaodong 
Published: September 2022

SUMMARY
An analytically based method is proposed to simulate the acoustic-gravity waves in the horizontally stratified atmosphere-Earth structure generated by a point force on the Earth's surface. The method solves the linear momentum, continuity and adiabaticity equations in the atmosphere and elastodynamic equations in the solid Earth in the frequency–wavenumber domain. The time-domain waveforms are obtained by wavenumber integration and fast Fourier transform with respect to the frequency. Numerical simulations are conducted to investigate the properties of the acoustic-gravity waves, including both the high-frequency acoustic-mode waves and low-frequency gravity-mode waves. Simulations of the high-frequency responses show that disturbances in the atmosphere with three apparent horizontal velocities can be identified. They are, namely, the direct acoustic-mode wave generated by source travelling with the sound speed, the head wave generated by the seismic P-wave travelling with apparent horizontal speed identical to the P velocity, and the head wave generated by the Rayleigh wave with a horizontal speed same to the Rayleigh wave velocity. Simulations of the low-frequency responses show that the gravity-mode wave and Lamb wave can be identified. The gravity-mode wave travels with a speed lower than the sound seed and does not reach everywhere, especially the area directly above the source. The Lamb wave travels along the Earth surface with a speed of about 310 m s–1 and its energy decays with the altitude. We also apply our method to explaining the Doppler sounding data observed in Taiwan area during the 2011 Tohoku M 9 earthquake, and find good agreement between the predicted signals and observed data in the arrival time and wave envelope associated with the Rayleigh wave.