bluuebunny/crossref_metadata_2025 huggingface dataset:
The 27th annual Nucleic Acids Research database issue and molecular biology database collection
Authors: Rigden Daniel J , Fernández Xosé M
Published: January 2020

The 2020 Nucleic Acids Research Database Issue contains 148 papers spanning molecular biology. They include 59 papers reporting on new databases and 79 covering recent changes to resources previously published in the issue. A further ten papers are updates on databases most recently published elsewhere. This issue contains three breakthrough articles: AntiBodies Chemically Defined (ABCD) curates antibody sequences and their cognate antigens; SCOP returns with a new schema and breaks away from a purely hierarchical structure; while the new Alliance of Genome Resources brings together a number of Model Organism databases to pool knowledge and tools. Major returning nucleic acid databases include miRDB and miRTarBase. Databases for protein sequence analysis include CDD, DisProt and ELM, alongside no fewer than four newcomers covering proteins involved in liquid–liquid phase separation. In metabolism and signaling, Pathway Commons, Reactome and Metabolights all contribute papers. PATRIC and MicroScope update in microbial genomes while human and model organism genomics resources include Ensembl, Ensembl genomes and UCSC Genome Browser. Immune-related proteins are covered by updates from IPD-IMGT/HLA and AFND, as well as newcomers VDJbase and OGRDB. Drug design is catered for by updates from the IUPHAR/BPS Guide to Pharmacology and the Therapeutic Target Database. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been revised, updating 305 entries, adding 65 new resources and eliminating 125 discontinued URLs; so bringing the current total to 1637 databases. It is available at http://www.oxfordjournals.org/nar/database/c/.
Responsive Neurostimulation of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy: A Case Report
Authors: Kokkinos Vasileios , Urban Alexandra , Sisterson Nathaniel D , Li Ningfei , Corson Danielle , Richardson R Mark
Published: January 2020

BACKGROUND AND IMPORTANCE

At least 25% of patients with idiopathic generalized epilepsy do not obtain adequate seizure control with medication. This report describes the first use of responsive neurostimulation (RNS), bilaterally targeting the centromedian/ventrolateral (CM/VL) region in a patient with drug-refractory Jeavons syndrome (eyelid myoclonia with absences).

CLINICAL PRESENTATION

A patient, diagnosed with eyelid myoclonia with absences (EMA) and refractory to medication, was offered RNS treatment in the CM/VL region of the thalamus. Stimulation was triggered by thalamic neural activity having morphological, spectral, and synchronous features that corresponded to 3- to 5-Hz spike-wave discharges recorded on prior scalp electroencephalography.

CONCLUSION

RNS decreased daily absence seizures from a mean of 60 to ≤10 and maintained the patient's level of consciousness during the occurring episodes. This therapy should be evaluated further for its potential to treat patients with pharmaco-refractory generalized epilepsy.
Prices and Illicit Trade of Cigarettes in the European Union: A Cross-sectional Analysis
Authors: Filippidis Filippos T , Chang Kiara K C , Blackmore Isabelle , Laverty Anthony A
Published: January 2020

Introduction

Within the context of the World Health Organization Framework Convention on Tobacco Control Protocol to Eliminate Illicit Trade in Tobacco Products and the impending revision of the European Union (EU) directive on tobacco excise rules we assessed whether cigarettes price is linked to being offered illicit cigarettes.

Methods

We combined data being offered illicit cigarettes from the 2015 Special Eurobarometer Survey on Illicit Tobacco (N = 27,672) with area-level data on Gross Domestic Product, unemployment, perceived corruption, and sharing a border with a non-European Economic Area (non-EEA) state. We used the 2015 Weighted Average Price of cigarettes (WAP), which reflects the average price of a cigarette pack in each Member State. We assessed associations between prices and illicit trade using three-level ordered regression models.

Results

About 19.6% of respondents reported ever being offered illicit cigarettes, 6.4% repeatedly. In fully adjusted models WAP was not associated with being more likely to have been offered illicit market cigarettes more often (adjusted odds ratio = 1.02, 95% confidence interval: 0.91; 1.15). Sharing a border with a non-EEA Member State was associated with increased likelihood of reporting being offered illicit cigarettes more often (1.73, 1.26; 2.39).

Conclusion

This study found no significant association between cigarette prices and reporting being offered illicit cigarettes; sharing a border with a non-EEA Member State was linked to illicit trade. This study adds to evidence that increasing prices of cigarettes are not associated with illicit trade and that the focus should remain on securing supply chains, including through features such as independent traceability systems.

Implications

After adjusting for individual and regional factors, we did not identify an association between prices of cigarettes and likelihood of reporting being offered illicit cigarettes in the EU. Sharing a border with a non-EEA state, however, was associated with increased likelihood of reporting being offered illicit cigarettes more often. This study adds to evidence that increasing taxes and prices of cigarettes are not a driver of illicit trade and that policies should maintain their focus on securing the supply chain.
SKIN DOSE MAPPING IN INTERVENTIONAL CARDIOLOGY: A PRACTICAL SOLUTION
Authors: Krajinović M , Dobrić M , Ciraj-Bjelac O
Published: January 2020

Numerous cases of radiation-induced tissue reactions following interventional cardiology (IC) procedures have been reported, resulting in the need for an optimized and personalized dosimetry. At present, there are many fluoroscopy units without Digital Imaging and Communications in Medicine (DICOM) Radiation Dose Structured Report globally installed. Many of these have not been updated yet, and may never be, therefore, the main objectives of this paper are to develop an offline skin dose mapping application, which uses DICOM headers for the peak skin dose (PSD) assessment and to compare the PSD assessment results to XR-RV3 Gafchromic film for common IC procedures. The mean deviation between the measured and the calculated PSD was 8.7 ± 26.3%. Simulated skin dose map showed good matching with XR-RV3 Gafchromic film. The skin dose mapping application presented in this paper is an elegant solution and a suitable alternative to XR-RV3 Gafchromic film.
Channels and processes of knowledge transfer: How does knowledge move between university and industry?
Authors: Fabiano Gianluca , Marcellusi Andrea , Favato Giampiero
Published: January 2020

The role of knowledge and technology transfer between academia and the industry has received increasing attention in the analysis of innovation. This article aims to explore the scientific literature concerning knowledge transport mechanisms and describe how the topic was organized by previous studies and terminologies applied. A systematic review was conducted in which the content of recent contributions best fitting these intensions was analysed. The characteristics of knowledge, individuals, organizations, and disciplines were found to be the main determinants in the adoption of transfer mechanisms. These were classified in terms of formalization, relational involvement, direction, and time. On the revealed multi-dimensionality of knowledge transfer and complementarity between transfer activities we framed a new taxonomy distinguishing between channels and processes. Future research may deepen these factors, such as the economic aspects driving the adoption of transfer mechanisms informing decisions on the funding of innovation.
Changes in accelerometer-measured sleep during the transition to retirement: the Finnish Retirement and Aging (FIREA) study
Authors: Myllyntausta Saana , Pulakka Anna , Salo Paula , Kronholm Erkki , Pentti Jaana , Vahtera Jussi , Stenholm Sari
Published: January 2020

Study Objectives

Retirement is associated with increases in self-reported sleep duration and reductions in sleep difficulties, but these findings need to be confirmed by using more objective measurement tools. This study aimed at examining accelerometer-based sleep before and after retirement and at identifying trajectories of sleep duration around retirement.

Methods

The study population consisted of 420 participants of the Finnish Retirement and Aging study. Participants’ sleep timing, sleep duration, time in bed, and sleep efficiency were measured annually using a wrist-worn triaxial ActiGraph accelerometer on average 3.4 times around retirement. In the analyses, sleep on nights before working days and on nights before days off prior to retirement were separately examined in relation to nights after retirement.

Results

Both in bed and out bed times were delayed after retirement compared with nights before working days. Sleep duration increased on average by 41 min (95% confidence interval [CI] = 35 to 46 min) from nights before working days and decreased by 13 min (95% CI = −20 to −6 min) from nights before days off compared with nights after retirement. By using latent trajectory analysis, three trajectories of sleep duration around retirement were identified: (1) shorter mid-range sleep duration with increase at retirement, (2) longer mid-range sleep duration with increase at retirement, and (3) constantly short sleep duration.

Conclusions

Accelerometer measurements support previous findings of increased sleep duration after retirement. After retirement, especially out bed times are delayed, thus, closely resembling sleep on pre-retirement nights before non-working days.
Trustees’ investment duties and cryptoassets
Authors: Hang Wu Tang
Published: January 2020

This article considers the legal and practical concerns for trustees regarding cryptocurrencies and other related instruments, which will be referred to as “cryptoassets”. It will briefly introduce the various types of cryptoassets and explore the risks involved when trustees decide to (or not to) invest in these instruments. This article provides a framework on how trustees should approach the issue of cryptoassets.
Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure
Authors: Jaeschke Hartmut , Akakpo Jephte Y , Umbaugh David S , Ramachandran Anup
Published: January 2020

Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) overdose is a significant clinical problem in most western countries. The only clinically approved antidote is N-acetylcysteine (NAC), which promotes the recovery of hepatic GSH. If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl-p-benzoquinone imine. More recently, it was shown that NAC can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite and can support mitochondrial bioenergetics. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP is a potent c-Jun N-terminal kinase inhibitor expanding its therapeutic window. Calmangafodipir (CMFP) is a SOD mimetic, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin and methylene blue were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities, Nrf2-dependent gene induction and autophagy activation by herbal medicine components are being evaluated. However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds. Nevertheless, based on recent studies, 4-methylpyrazole and calmangafodipir have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose.
A novel method for ultrasound-guided radial artery cannulation in neonates by trainee anaesthesiologists
Authors: Ye Ping , Tan Yanzhe , Ye Mao , Li Shangyingying , Bai Lin , Liu Lifei
Published: January 2020

BACKGROUND

The modified dynamic needle tip positioning (MDNTP) technique for ultrasound-guided radial artery cannulation (MDNTP-US technique) in neonates can be technically challenging for trainee anaesthesiologists. We hypothesised that by associating the MDNTP-US technique with hypodermic 0.9% sodium chloride (Saline MDNTP-US technique), which increases the subcutaneous radial artery depth, the procedure would become easier for trainee anaesthesiologists.

OBJECTIVE

To compare the Saline MDNTP-US technique, with the MDNTP-US technique for radial artery catheterisation in neonates by trainee anaesthesiologists with limited experience.

DESIGN

Randomised controlled trial.

PATIENTS

Ninety-six neonates scheduled to undergo major abdominal surgery requiring continuous arterial pressure monitoring between May 2018 and December 2018 at the Children's Hospital of Chongqing Medical University were enrolled. Neonates with signs of skin erosions or haematomas at or near the insertion site, as well as those with low noninvasive blood pressure values, were excluded.

INTERVENTION

Neonates were randomised to the Saline MDNTP-US and MDNTP-US groups in a 1 : 1 ratio. Twelve trainees performed the cannulation procedures.

MAIN OUTCOME MEASURES

Duration of procedure, first attempt success rate, rate of success within 10 min, and the incidence of haematoma and thrombosis.

RESULTS

The median [IQR] time to perform cannulation was less for the Saline MDNTP-US technique than for the MDNTP-US technique: 203 [160 to 600] vs. 600 s [220 to 600]; P = 0.005. The rate of success within 10 min, 72.9 vs. 47.9%; P = 0.012, was higher in the Saline MDNTP-US group than in the MDNTP-US group. The incidence of haematoma on postoperative day 1 was lower in the Saline MDNTP-US group than in the MDNTP-US group: 8.3 vs. 22.9%; P = 0.049.

CONCLUSION

Trainee anaesthesiologists can achieve higher success rates by using the Saline MDNTP-US technique instead of the MDNTP-US technique for radial artery catheterisation in neonates, taking less time with a lower incidence of complications.

TRIAL REGISTRATION

ChiCTR-IOR-17014119 (Chinese Clinical Trial Registry).
The effect of ropivacaine concentration on common peroneal nerve block duration using a fixed dose
Authors: Christiansen Claus Behrend , Madsen Mikkel Herold , Mølleskov Elise , Rothe Christian , Lundstrøm Lars Hyldborg , Lange Kai H.W.
Published: January 2020

BACKGROUND

The effect of local anaesthetic concentration on peripheral nerve block duration is unclear. Recent clinical trials found nerve blocks of equivalent duration despite changing local anaesthetic concentration but with a fixed local anaesthetic dose. A criticism of these studies is that the local anaesthetic doses used were above the proposed local anaesthetic dose-duration ceiling level, masking any potential effect of different local anaesthetic concentrations on nerve block duration.

OBJECTIVE

We investigated the effect of local anaesthetic concentration on nerve block duration using a fixed local anaesthetic dose below the local anaesthetic dose-duration ceiling level. We hypothesised that changing local anaesthetic concentration would affect nerve block duration.

DESIGN

Randomised, double-blind trial.

SETTING

Single-centre, academic hospital.

PARTICIPANTS

Healthy volunteers.

INTERVENTIONS

Each participant received an ultrasound-guided common peroneal nerve block with a fixed dose of 10 mg of ropivacaine dissolved in either 2.5, 5, 10, 15 or 20 ml of 0.9% saline according to group allocation, yielding local anaesthetic concentrations of 4, 2, 1, 0.67 and 0.5 mg ml−1.

MAIN OUTCOME MEASURES

The primary outcome was duration of sensory block defined as altered or no sensitivity to a cold stimulus. The secondary outcome was duration of motor block defined as either paresis or paralysis. Intergroup differences were tested using one-way Analysis of variance .

RESULTS

All participants had sensory block, and 56 out of 60 participants had motor block. From the highest to the lowest concentration groups, mean ± SD sensory block durations were 13.1 ± 2.7, 13.4 ± 3.3, 12.6 ± 3.9, 10.4 ± 2.9 and 11.0 ± 2.1 h (P = 0.073), and mean ± SD motor block durations were 8.5 ± 2.0, 7.9 ± 3.0, 6.1 ± 3.1, 5.9 ± 3.5, 4.0 1.9 h (P = 0.002).

CONCLUSION

In contrast to our hypothesis, we found no changes in mean sensory nerve block duration. However, local anaesthetic dilution resulted in reduced motor block duration.

TRIAL REGISTRATION

ClinicalTrials.gov, NCT03326609.
Cognitive decline after carotid endarterectomy
Authors: Aceto Paola , Lai Carlo , De Crescenzo Franco , Crea Maria A. , Di Franco Valeria , Pellicano Gaia R. , Perilli Valter , Lai Silvia , Papanice Domenico , Sollazzi Liliana
Published: January 2020

BACKGROUND

Postoperative cognitive decline (pCD) occurs frequently (6 to 30%) after carotid endarterectomy (CEA), although there are no exact estimates and risk factors are still unclear.

OBJECTIVE

The objective of this study was to determine pCD incidence and risk factors in CEA patients.

DESIGN

We performed a systematic review and meta-analysis of both randomised and nonrandomised trials following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

DATA SOURCES

We searched Cochrane, PubMed/Medline and Embase databases from the date of database inception to 1 December 2018.

ELIGIBILITY CRITERIA

We selected longitudinal studies including CEA patients with both pre-operative and postoperative cognitive assessments. Primary outcome was pCD incidence, differentiating delayed neurocognitive recovery (dNCR) and postoperative neurocognitive disorder (pNCD). dNCR and pNCD incidences were expressed as proportions of cases on total CEA sample and pooled as weighted estimates from proportions. Postoperative delirium was excluded from the study design. Secondary outcomes were patient-related (i.e. age, sex, diabetes, hypertension, contralateral stenosis, pre-operative symptoms, dyslipidaemia and statin use) and procedure-related (i.e. hyperperfusion, cross-clamping duration and shunting placement) risk factors for pCD. We estimated odds ratios (ORs) and mean differences through a random effects model by using STATA 13.1 and RevMan 5.3.

RESULTS

Our search identified 5311 publications and 60 studies met inclusion criteria reporting a total of 4823 CEA patients. dNCR and pNCD incidence were 20.5% [95% confidence interval (CI), 17.1 to 24.0] and 14.1% (95% CI, 9.5 to 18.6), respectively. pCD risk was higher in patients experiencing hyperperfusion during surgery (OR, 35.68; 95% CI, 16.64 to 76.51; P < 0.00001; I
2 = 0%), whereas dNCR risk was lower in patients taking statins before surgery (OR, 0.56; 95% CI, 0.41 to 0.77; P = 0.0004; I
2 = 19%). Sensitivity analysis revealed that longer cross-clamping duration was a predictor for dNCR (mean difference, 5.25 min; 95% CI, 0.87 to 9.63; P = 0.02; I
2 = 49%).

CONCLUSION

We found high incidences of dNCR (20.5%) and pNCD (14.1%) after CEA. Hyperperfusion seems to be a risk factor for pCD, whereas the use of statins is associated with a lower risk of dNCR. An increased cross-clamping duration could be a risk factor for dNCR.

TRIAL REGISTRATION

This systematic review was registered in the International Prospective Register of Systematic Reviews (CDR42017073633).
The effects of doxapram on time to tracheal extubation and early recovery in young morbidly obese patients scheduled for bariatric surgery
Authors: Fathi Mohammad , Massoudi Nilofar , Nooraee Navid , Beheshti Monfared Reza
Published: January 2020

BACKGROUND

Bariatric surgery is a well established treatment of the obese. Postoperative respiratory failure and airway obstruction after bariatric surgery can often be attributed to the residual depressant effects of anaesthetics, sedatives and opioids. Peri-operative management of morbidly obese patients is still a concern for operating room professionals.

OBJECTIVE

The evaluation of the effects of doxapram on the outcomes of general anaesthesia following bariatric surgical procedures in the morbidly obese.

DESIGN

A single-blind randomised controlled trial with two parallel arms.

SETTING

A tertiary care teaching hospital, Tehran, Iran, from 2017 to 2018.

PARTICIPANTS

In total, 100 patients (69 women) with at least class two obesity were included in two groups of equal sizes and underwent bariatric surgery.

MAIN OUTCOME MEASURES

The primary outcome was the time from the administration of doxapram to tracheal extubation. Secondary outcomes included vital signs and variables including peak expiratory flow rate, time to return to spontaneous breathing, time to eye-opening and hand-squeezing on the commands, and time to recovery.

INTERVENTIONS

Both groups underwent general anaesthesia. The intervention group received a single dose of doxapram 1 mg kg−1 ideal body weight, immediately after reversal of neuromuscular blockade and after discontinuation of all anaesthetics.

RESULTS

Doxapram decreased time to extubation, time to eye-opening and hand-squeezing, shortened recovery time and lowered end-tidal CO2 significantly (all P < 0.001). Moreover, it increased peak expiratory flow rate, oxygen saturation, temperature, heart rate and blood pressure (all P < 0.001). The two groups were similar in the bispectral index and mean arterial pressure (both P > 0.05). None of our participants had complications attributable to doxapram.

CONCLUSION

The postoperative use of doxapram improves peak expiratory flow rate, and decreases respiratory complications of anaesthesia during recovery in the morbidly obese undergoing bariatric surgery. Doxapram is well tolerated in young ASA physical status classes 1 to 2 morbidly obese patients; however, the anaesthesiologist should cautiously evaluate the vital signs for at least half an hour following the administration of doxapram.

REGISTRATION

Iranian Registry of Clinical Trials (IRCT) http://www.irct.ir/ number IRCT2017060712203N9.
Two-handed jaw thrust decreases postoperative sore throat in patients undergoing double-lumen endobronchial intubation
Authors: Park Jeong J. , Huh Hyub , Yoon Seung Z. , Lim Hye-Ja , Go Doo Y. , Cho Jang E. , Lee Jiwon , Park Jihoon , Kim Hyun-Chang
Published: January 2020

BACKGROUND

Tracheal intubation using a double-lumen endobronchial tube (DLT) causes postoperative sore throat.

OBJECTIVE

To determine the effect of two-handed jaw thrust on postoperative sore throat in patients requiring insertion of a DLT.

DESIGN

A randomised study.

SETTING

A tertiary teaching hospital from December 2017 to May 2018.

PATIENTS

One-hundred and six patients undergoing one-lung anaesthesia.

INTERVENTIONS

Patients were allocated to one of two groups (n=53 each). In the jaw thrust group, the two-handed jaw thrust manoeuvre was applied at intubation and advancement of the DLT. In the control group, conventional intubation with a sham jaw thrust was performed.

MAIN OUTCOME MEASURES

Incidence of sore throat at 1, 6 and 24 h postoperatively.

RESULTS

The incidence of sore throat at 6 h postoperatively was higher in the control group than in the jaw thrust group [31 (59%) vs. 14 (26%), risk ratio (95% confidence interval) 0.45 (0.27 to 0.75), P < 0.01]. The overall incidence of sore throat was higher in the control group than in the jaw thrust group [35 (66%) vs. 18 (34%), risk ratio (95% confidence interval) 0.51 (0.34 to 0.78), P < 0.01].

CONCLUSION

The jaw thrust manoeuvre can reduce the incidence of sore throat in patients undergoing DLT insertion for one-lung ventilation.

TRIAL REGISTRATION

ClinicalTrials.gov identifier: NCT03331809.
Skermanella pratensis sp. nov., isolated from meadow soil, and emended description of the genus Skermanella
Authors: Guo Qiannan , Zhou Zhengfu , Zhang Lijuan , Zhang Chen , Chen Ming , Wang Bo , Lin Min , Wang Wei , Zhang Wei , Li Xufeng
Published: January 2020

A novel Gram-stain-negative, light pink-coloured, short rod-shaped, designated strain W17T, was isolated from a meadow soil sample collected from Xinjiang, PR China. The 16S rRNA gene sequence analysis indicated that strain W17T was related most closely to

Skermanella rosea

M1T (98.72 %) and

Skermanella mucosa

8-14-6T (98.44 %). However, strain W17T showed a low level of DNA–DNA relatedness to

S. rosea

M1T (32.4±2.6 %) and

S. mucosa

8-14-6T (33.5±0.1 %). The genome size of the novel strain was 5.87 Mb and the genomic DNA G+C content was 67.27 mol%. The only respiratory quinone of strain W17T was Q-10. Diphosphatidylglycerol, phosphatidylglycerol. phosphatidylethanolamine and phosphatidylcholine were the major polar lipids. The predominant cellular fatty acids were C18 : 1ω6c and/or C18 : 1ω7c (48.53 %), C16 : 0 (20.88 %) and C18 : 0 (14.92 %). The phylogenetic, phenotypic and chemotaxonomic data showed that strain W17T represents a novel species of the genus

Skermanella

, for which the name Skermanella pratensis sp. nov. is proposed. The type strain is W17T (=GDMCC 1.1392T=KCTC 62434T).
Comparison of first trimester dating methods for gestational age estimation and their implication on preterm birth classification in a North Indian cohort
Authors: Vijayram Ramya , Damaraju Nikhita , Xavier Ashley , Desiraju Bapu Koundinya , Thiruvengadam Ramachandran , Misra Sumit , Chopra Shilpa , Khurana Ashok , Wadhwa Nitya ,   GARBH-Ini Study Group, Rengaswamy Raghunathan , Sinha Himanshu , Bhatnagar Shinjini
Published: January 2020

Background

Different formulae have been developed globally to estimate gestational age (GA) by ultrasonography in the first trimester of pregnancy. In this study, we develop an Indian population-specific dating formula and compare its performance with published formulae. Finally, we evaluate the implications of the choice of dating method on preterm birth (PTB) rate. This study’s data was from GARBH-Ini, an ongoing pregnancy cohort of North Indian women to study PTB.

Methods

Comparisons between ultrasonography-Hadlock and last menstrual period (LMP) based dating methods were made by studying the distribution of their differences by Bland-Altman analysis. Using data-driven approaches, we removed data outliers more efficiently than by applying clinical parameters. We applied advanced machine learning algorithms to identify relevant features for GA estimation and developed an Indian population-specific formula (Garbhini-GA1) for the first trimester. PTB rates of Garbhini-GA1 and other formulae were compared by estimating sensitivity and accuracy.

Results

Performance of Garbhini-GA1 formula, a non-linear function of crown-rump length (CRL), was equivalent to published formulae for estimation of first trimester GA (LoA, - 0.46,0.96 weeks). We found that CRL was the most crucial parameter in estimating GA and no other clinical or socioeconomic covariates contributed to GA estimation. The estimated PTB rate across all the formulae including LMP ranged 11.27 – 16.50% with Garbhini-GA1 estimating the least rate with highest sensitivity and accuracy. While the LMP-based method overestimated GA by three days compared to USG-Hadlock formula; at an individual level, these methods had less than 50% agreement in the classification of PTB.

Conclusions

An accurate estimation of GA is crucial for the management of PTB. Garbhini-GA1, the first such formula developed in an Indian setting, estimates PTB rates with higher accuracy, especially when compared to commonly used Hadlock formula. Our results reinforce the need to develop population-specific gestational age formulae.
Serum metabolite profiles are associated with the presence of advanced liver fibrosis in Chinese patients with chronic hepatitis B viral infection
Authors: Xie Guoxiang , Wang Xiaoning , Wei Runmin , Wang Jingye , Zhao Aihua , Chen Tianlu , Wang Yixing , Zhang Hua , Xiao Zhun , Liu Xinzhu , Deng Youping , Wong Linda , Panee Jun , Rajani Cynthia , Ni Yan , Kwee Sandi , Bian Hua , Gao Xin , Liu Ping , Jia Wei
Published: January 2020

Background & Aims

Accurate and noninvasive diagnosis and staging of liver fibrosis is essential for effective clinical management of chronic liver disease (CLD). We aimed to identify serum metabolite markers that reliably predict the stage of fibrosis in CLD patients.

Methods

We quantitatively profiled serum metabolites of participants in 2 independent cohorts. Based on the metabolomics data from Cohort 1 (504 HBV associated liver fibrosis patients and 502 normal controls, NC), we selected a panel of 4 predictive metabolite markers. Consequently, we constructed 3 machine learning models with the 4 metabolite markers using random forest (RF), to differentiate CLD patients from normal controls (NC), to differentiate cirrhosis patients from fibrosis patients, and to differentiate advanced fibrosis from early fibrosis, respectively.

Results

The panel of 4 metabolite markers consisted of taurocholate, tyrosine, valine, and linoelaidic acid. The RF models of the metabolite panel demonstrated the strongest stratification ability in Cohort 1 to diagnose CLD patients from NC (area under the receiver operating characteristic curve (AUROC) = 0.997 and the precision-recall curve (AUPR) = 0.994), to differentiate fibrosis from cirrhosis (0.941, 0.870), and to stage liver fibrosis (0.918, 0.892). The diagnostic accuracy of the models was further validated in an independent Cohort 2 consisting of 300 CLD patients with chronic HBV infection and 90 NC. The AUCs of the models were consistently higher than APRI, FIB-4 and AST/ALT ratio, with both greater sensitivity and specificity.

Conclusion

Our study showed that this 4-metabolite panel has potential usefulness in clinical assessments of CLD progression.
The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases
Authors: Mazzarotto Francesco , Hawley Megan H. , Beltrami Matteo , Beekman Leander , de Marvao Antonio , McGurk Kathryn A. , Statton Ben , Boschi Beatrice , Girolami Francesca , Roberts Angharad M. , Lodder Elisabeth M. , Allouba Mona , Romeih Soha , Aguib Yasmine , Baksi A. John , Pantazis Antonis , Prasad Sanjay K. , Cerbai Elisabetta , Yacoub Magdi H. , O’Regan Declan P. , Cook Stuart A. , Ware James S. , Funke Birgit , Olivotto Iacopo , Bezzina Connie R. , Barton Paul J.R. , Walsh Roddy
Published: January 2020

Background

Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. We sought to investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies.

Methods

We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases.

Results

We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants inMYH7, ACTN2andPRDM16may represent a distinct LVNC aetiology.MYH7truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Individuals withMYH7truncating variants identified in the UK Biobank and cohorts of healthy volunteers also displayed significantly greater non-compaction compared to matched controls, with 50% meeting the diagnostic criteria for LVNC. Additionally, structural variants (exon deletions) inRYR2and missense variants in the transmembrane region ofHCN4were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes.

Conclusions

We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVNC/arrhythmia phenotypes. These results underline the complex genetic landscape of LVNC and inform how genetic testing in LVNC cases should be pursued and interpreted.
Crystal and cryo-EM structures of the cytosolic G protein alpha chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1
Authors: McClelland Levi J. , Zhang Kaiming , Mou Tung-Chung , Johnston Jake , Yates-Hansen Cindee , Li Shanshan , Thomas Celestine J. , Doukov Tzanko I. , Triest Sarah , Wohlkonig Alexandre , Tall Gregory G. , Steyaert Jan , Chiu Wah , Sprang Stephen R.
Published: January 2020

Ric-8A is a cytosolic Guanine Nucleotide exchange Factor (GEF) that activates heterotrimeric G protein alpha subunits (Gα)1. Ric-8A is essential to life in multicellular eukaryotes by virtue of its chaperone activity that is required for Gα biogenesis and membrane localization2, 3. Ric-8A adopts an armadillo (ARM)/HEAT repeat domain architecture and is structurally unrelated to G Protein-Coupled Receptors (GPCR)4. Both GEF and chaperone activities are stimulated by Casein Kinase II phosphorylation5. The mechanisms by which Ric-8A catalyzes GDP release and GTP binding to Gα, or exerts chaperone activity are unknown. Here, we report the structure of the nanobody-stabilized complex of nucleotide-free Gαi1 (isoform 1 of Gα family i) and phosphorylated Ric-8A at near atomic resolution by cryo-electron microscopy and X-ray crystallography. We find that Ric-8A envelops the GTPase domain of Gα, disrupting all three switch regions that convey Gα nucleotide-binding and signaling activity, and displaces the C-terminal helix and helical domain of Gα. These cooperative interactions dismantle the GDP binding site and promote GDP release, while protecting structural elements of Gα that are dynamic in the nucleotide-free state. The structures also show howin vivophosphorylation stabilizes Gα-binding elements of Ric-8A, thereby enhancing its GEF and chaperone activities.
Biophysical basis of cellular multi-specificity encoded in a model molecular switch
Authors: Perica Tina , Mathy Christopher J. P. , Xu Jiewei , Jang Gwendolyn M. , Zhang Yang , Kaake Robyn , Ollikainen Noah , Braberg Hannes , Swaney Danielle L. , Lambright David G. , Kelly Mark J. S. , Krogan Nevan J. , Kortemme Tanja
Published: January 2020

Molecular switches are central to signal transduction in protein interaction networks. One switch protein can independently regulate distinct cellular processes, but the molecular mechanisms enabling this functional multi-specificity remain unclear. Here we integrate system-scale cellular and biophysical measurements to study how a paradigm switch, the small GTPase Ran/Gsp1, achieves its functional multi-specificity. We make 55 targeted point mutations to individual interactions of Ran/Gsp1 and show through quantitative, systematic genetic and physical interaction mapping that Ran/Gsp1 interface perturbations have widespread cellular consequences that cluster by biological processes but, unexpectedly, not by the targeted interactions. Instead, the cellular consequences of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle, and cycle kinetics are allosterically tuned by distal interface mutations. We propose that the functional multi-specificity of Ran/Gsp1 is encoded by a differential sensitivity of biological processes to different kinetic parameters of the Gsp1 switch cycle, and that Gsp1 partners binding to the sites of distal mutations act as allosteric regulators of the switch. Similar mechanisms may underlie biological regulation by other GTPases and biological switches. Finally, our integrative platform to determine the quantitative consequences of cellular perturbations may help explain the effects of disease mutations targeting central switches.
Optimizing immunization protocols to elicit broadly neutralizing antibodies
Authors: Sprenger Kayla G. , Louveau Joy E. , Chakraborty Arup K.
Published: January 2020

Natural infections and vaccination with a pathogen typically stimulates the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus – known as broadly neutralizing antibodies (bnAbs) – could protect against highly mutable pathogens. Despite much work, the mechanisms by which bnAbs emerge remain uncertain. Using a computational model of affinity maturation, we studied a wide variety of vaccination strategies. Our results suggest that an effective strategy to maximize bnAb evolution is through a sequential immunization protocol, wherein each new immunization optimally increases the pressure on the immune system to target conserved antigenic sites, thus conferring breadth. We describe the mechanisms underlying why sequentially driving the immune system increasingly further from equilibrium, in an optimal fashion, is effective. The optimal protocol allows many evolving B cells to become bnAbs via diverse evolutionary paths.

Significance Statement

The global health burden could be substantially alleviated by the creation of universal vaccines against highly mutable pathogens like HIV and influenza. Broadly-neutralizing antibodies (bnAbs) are encouraging targets for such vaccines, because they can bind to diverse strains of highly mutable pathogens. BnAbs typically develop only rarely upon natural infection, after the immune system has been exposed to many mutated versions of a pathogen. Thus, sequentially administering multiple different pathogen-like proteins (antigens) is a promising strategy to elicit bnAbs through vaccination. However, it remains unclear how best to design and administer these antigens. We explore this matter using physics-based simulations, and provide new mechanistic insights into antibody evolution that could guide the creation of universal vaccines against highly mutable pathogens.
Executable Simulation Model of the Liver
Authors: König Matthias
Published: January 2020

To address the issue of reproducibility in computational modeling we developed the concept of an executable simulation model (EXSIMO). An EXSIMO combines model, data and code with the execution environment to run the computational analysis in an automated manner using tools from software engineering. Key components are i) models, data and code for the computational analysis; ii) tests for models, data and code; and iii) an automation layer to run tests and execute the analysis. An EXSIMO combines version control, model, data, units, annotations, analysis, reports, execution environment, testing, continuous integration and release. We applied the concept to perform a replication study of a computational analysis of hepatic glucose metabolism in the liver. The corresponding EXSIMO is available fromhttps://github.com/matthiaskoenig/exsimo.
Genome-wide Functional Characterization of Escherichia coli Promoters and Sequence Elements Encoding Their Regulation
Authors: Urtecho Guillaume , Insigne Kimberly D. , Tripp Arielle D. , Brinck Marcia S. , Lubock Nathan B. , Acree Christopher , Kim Hwangbeom , Chan Tracey , Kosuri Sriram
Published: January 2020

Despite decades of intense genetic, biochemical, and evolutionary characterizations of bacterial promoters, we lack the ability to identify or predict transcriptional activities of promoters using primary sequence. Even in simple, well-characterized organisms such asE. colithere is little agreement on the number, location, and strength of promoters. We use a genomically-encoded massively parallel reporter assay to perform the first full characterization of autonomous promoter activity across theE. coligenome. We measure promoter activity of >300,000 sequences spanning the entire genome and map 2,228 promoters active in rich media. Surprisingly, 944 of these promoters were found within intragenic sequences and are associated with conciliatory sequence adaptations by both the protein-coding regions and overlapping RNAP binding sites. Furthermore, we perform a scanning mutagenesis of 2,057 promoters to uncover sequence elements regulating promoter activity, revealing 3,317 novel regulatory elements. Finally, we show that despite these large datasets and modern machine learning algorithms, predicting endogenous promoter activity from primary sequence is still challenging.
CRISPR-based bioengineering of the Transferrin Receptor revealed a role for Rab7 in the biosynthetic secretory pathway
Authors: Deffieu Maika S. , Cesonyte Ieva , Delalande François , Boncompain Gaelle , Dorobantu Cristina , Song Eli , Lucansky Vincent , Hirschler Aurélie , Cianferani Sarah , Xu Tao , Perez Franck , Carapito Christine , Gaudin Raphael
Published: January 2020

The regulated secretory trafficking of neosynthesized transmembrane receptors is particularly challenging to investigate as it is under-represented at steady state compared to the abundance of the other trafficking routes. Here, we combined the retention using selective hook (RUSH) system to a CRISPR/Cas9 gene editing approach (eRUSH) to identify molecular players involved in the trafficking of neosynthesized Transferrin Receptor (TfR)en routeto the plasma membrane (PM). TfR-eRUSH monoclonal cells expressing endogenous, ER-retainable and fluorescent TfR were engineered and characterized. Spatiotemporal quantitative proteomics of TfR-eRUSH cells allowed the identification of molecular partners associated with TfR-containing membranes and provided a comprehensive list of potential regulators, co-trafficking cargos, and enriched pathways. Furthermore, we chose to focus our attention on the Rab GTPase family members for their function as vesicle trafficking regulators and performed a Rab-targeted siRNA screen that we correlated to our proteomics data. Unexpectedly, we identified Rab7-harboring vesicles as an intermediate compartment of the Golgi-to-PM transport of the neosynthetic TfR. These vesicles did not exhibit degradative properties and were not associated to Rab6A-harboring vesicles, also involved in Golgi-to-PM transport. However, Rab6A-TfR vesicles delivered TfR directly to the PM, while in contrast, Rab7A was transiently associated to neosynthetic TfR-containing post-Golgi vesicles but dissociated before PM vesicle fusion. Together, our study proposes the eRUSH as a powerful tool to further study the secretory pathway and reveals an unforeseen role for Rab7 in the neosynthetic transport of the TfR, highlighting the diversity of the secretory vesicles’ nature for a given cargo.
Dense cellular segmentation for EM using 2D-3D neural network ensembles
Authors: Guay Matthew D. , Emam Zeyad A.S. , Anderson Adam B. , Aronova Maria A. , Storrie Brian , Pokrovskaya Irina D. , Leapman Richard D.
Published: January 2020

Cell biologists can now build 3D models from segmentations of electron microscopy (EM) images, but accurate manual segmentation of densely-packed organelles across gigavoxel image volumes is infeasible. Here, we introduce 2D-3D neural network ensembles that produce dense cellular segmentations at scale, with accuracy levels that outperform baseline methods and approach those of human annotators.
Alignment of single-cell RNA-seq samples without over-correction using kernel density matching
Authors: Chen Mengjie , Zhan Qi , Mu Zepeng , Wang Lili , Zheng Zhaohui , Miao Jinlin , Zhu Ping , Li Yang I
Published: January 2020

Single-cell RNA sequencing (scRNA-seq) technology is poised to replace bulk cell RNA sequencing for most biological and medical applications as it allows users to measure gene expression levels in a cell-type-specific manner. However, data produced by scRNA-seq often exhibit batch effects that can be specific to a cell-type, to a sample, or to an experiment, which prevent integration or comparisons across multiple experiments. Here, we presentDmatch, a method that leverages an external expression atlas of human primary cells and kernel density matching to align multiple scRNA-seq experiments for downstream biological analysis.Dmatchfacilitates alignment of scRNA-seq datasets with cell-types that may overlap only partially, and thus allows integration of multiple distinct scRNA-seq experiments to extract biological insights. In simulation,Dmatchcompares favorably to other alignment methods, both in terms of reducing sample-specific clustering, and in terms of avoiding over-correction. When applied to scRNA-seq data collected from clinical samples in a healthy individual and five autoimmune disease patients,Dmatchenabled cell-type-specific differential gene expression comparisons across biopsy sites and disease conditions, and uncovered a shared population of pro-inflammatory monocytes across biopsy sites in RA patients. We further show thatDmatchincreases the number of eQTLs mapped from population scRNA-seq data.Dmatchis fast, scalable, and improves the utility of scRNA-seq for several important applications.Dmatchis freely available online (https://qzhan321.github.io/dmatch/).
Low-Dimensional Spatio-Temporal Dynamics Underlie Cortex-Wide Neural Activity
Authors: MacDowell Camden J. , Buschman Timothy J.
Published: January 2020

Cognition arises from the dynamic flow of neural activity through the brain. To capture these dynamics, we used mesoscale calcium imaging to record neural activity across the dorsal cortex of awake mice. We found that the large majority of variance in cortex-wide activity (∼75%) could be explained by a limited set of ∼14 ‘motifs’ of neural activity. Each motif captured a unique spatio-temporal pattern of neural activity across the cortex. These motifs generalized across animals and were seen in multiple behavioral environments. Motif expression differed across behavioral states and specific motifs were engaged by sensory processing, suggesting the motifs reflect core cortical computations. Together, our results show that cortex-wide neural activity is highly dynamic, but that these dynamics are restricted to a low-dimensional set of motifs, potentially to allow for efficient control of behavior.