bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of median effective concentration of ropivacaine in multiparas or primiparas during epidural labor analgesia
Authors: Peng Qinghua , Yang Zeyong , Zhang Wangping , Wu Xiaomin
Published: January 2020

The documents on the median effective concentration of local analgesic were many in primiparas during labor analgesia. However, the studies were fewer in multiparas. To explore the analgesic requirements in multiparas during epidural labor analgesia, we investigated the median effective concentration of ropivacaine with 2 μg/mL fentanyl for epidural labor analgesia in multiparas.

Sixty-two women were recruited and assigned to the primipara group and multipara group in this prospective study. All the parturients received ropivacaine combined with 2 μg/mL fentanyl for epidural labor analgesia. The concentration of ropivacaine was determined by the up and down method and an initial concentration was set as 0.1% with a 0.01% interval. Effective analgesia was defined as the visual analog scale (VAS) ≤3 within 30 minutes after epidural administration when cervical dilatation is about 2 cm. The median effective concentration of ropivacaine was calculated by the up and down sequential method. The pain intensity was assessed using VAS. Hemodynamic parameters, the labor stages, and neonatal Apgar scores were recorded. Umbilical artery blood was drawn to analyze. The side effects, if any, were also recorded.

The median effective concentration of ropivacaine was 0.057% (95% confidence interval [CI], 0.051–0.064%) in primiparas during epidural labor analgesia, and 0.068% (95% CI, 0.063–0.072%) in multiparas during epidural labor analgesia, there was significant difference between the groups (P = .02).

This study indicated that the median effective concentration of ropivacaine with fentanyl for epidural labor analgesia was 0.068% (95% CI, 0.063–0.072%) and increased in multiparas compared with the primiparas (www.chictr.org.cn, registration number: ChiCTR-1800016486)
Antiviral therapy and hepatocellular carcinoma risk in hepatitis B patients with cirrhosis
Authors: Gao Xuesong , Yang Hwai-I , Trinh Huy , Jeong Donghak , Li Jiayi , Zhang Jian , Le An , Hoang Joseph , Nguyen Pauline , Henry Linda , Nguyen Mindie H.
Published: January 2020

Objectives:

Our goal was to evaluate the effect of antiviral therapy on hepatocellular carcinoma incidence for cirrhotic patients with lower hepatitis B virus DNA levels.

Methods:

Consecutive cirrhosis patients from a US cohort (n = 381) and 408 patients from a Taiwan cohort were enrolled. Patients were classified into a low (<20 IU/ml) and high hepatitis B virus DNA group (≥20 IU/ml), and each was further stratified into treated and untreated subgroups.

Results:

Except for hepatitis B e antigen, baseline characteristics were similar for both hepatitis B virus DNA groups. Antiviral therapy significantly reduced hepatocellular carcinoma incidence in cirrhotic patients with hepatitis B virus DNA ≥20 IU/ml at 5-years (12.2% vs. 22.8%) and 10-years (23.3% vs. 37.2%) (P = 0.0018). For cirrhotic patients with hepatitis B virus DNA <20 IU/ml, there was no statistically significant difference in cumulative hepatocellular carcinoma incidence between the treated and untreated groups. After adjusting for age, sex, and hepatitis B e antigen status, antiviral therapy was an independent predictor (hazard ratio 0.43, P < 0.0001) for reduced hepatocellular carcinoma risk in patients with hepatitis B virus DNA ≥20 IU/ml.

Conclusion:

Antiviral therapy was associated with a 57% reduction in hepatocellular carcinoma incidence in chronic hepatitis B patients with cirrhosis and hepatitis B virus DNA as low as 20 IU/ml (but no lower). However, hepatocellular carcinoma incidence remained substantial, regardless of hepatitis B virus DNA levels and treatment status, highlighting the need for ongoing hepatocellular carcinoma surveillance for all cirrhotic hepatitis B virus patients.
Biological response under treatment and prognostic value of protein induced by vitamin K absence or antagonist-II in a French cohort of patients with hepatocellular carcinoma
Authors: Payancé Audrey , Dioguardi Burgio Marco , Peoc’h Katell , Achahboun Mohamed , Albuquerque Miguel , Devictor Julie , Chor Hélène , Manceau Hana , Soubrane Olivier , Durand François , Castera Laurent , Bouattour Mohamed , Paradis Valérie
Published: January 2020

Objectives

We have confirmed the diagnostic value of protein induced by vitamin K absence or antagonist-II (PIVKA-II) in a French cohort of patients with hepatocellular carcinoma (HCC). Herein, we aim to study the biological response under treatment and the prognostic value of PIVKA-II serum level in patients treated for HCC.

Methods

Patients with primary HCC developed chronic liver disease with serum PIVKA-II, and alpha-fetoprotein (AFP) levels available at baseline and after first HCC treatment [within 3 months (M1–M3) and/or within 6–9 months (M6–M9)] were included.

Results

A total of 94 patients were included. Median follow-up was 23 months (range 11–31 months). PIVKA-II levels significantly decreased from baseline to M1–M3 (P = 0.002) and to M6–M9 (P = 0.035). By multivariate analysis, biological response (M1–M3/baseline PIVKA-II ratio) independently and significantly predicted overall survival (OS). A ratio below 0.73 was able to identify patients with the better prognosis in the total population [OS: 27 months (range 17–31) vs. 17 (range 9–25); P = 0.008] and in patients who had transarterial chemoembolization or selective internal radiation therapy as first treatment approach [OS: 26 months (range 14–31) vs. 16 (range 9–25); P = 0.002 and 2-year OS of 73% vs. 30%; P = 0.009]. PIVKA-II serum levels at baseline and PIVKA-II biological response were significantly associated with radiological response.

Conclusion

PIVKA-II serum level seems to be a good prognostic and promising biomarker for early monitoring treatment outcomes for patients with HCC.
Low-free triiodothyronine is associated with poor prognosis of portal hypertension in cirrhosis
Authors: Huang Xiaoquan , Jiang Siyu , Fan Xiaowen , Jiang Yingyi , Wu Ling , Li Feng , Wang Jian , Chen Shiyao
Published: January 2020

Background and aims

The role of thyroid function in the portal hypertension development and prognosis remains unclear. This study aimed to investigate the correlation between serum-free triiodothyronine (fT3) levels and the outcomes of cirrhotic portal hypertension.

Methods

A total of 385 cirrhotic patients with confirmed portal hypertension underwent computed tomography angiography and thyroid function test at a tertiary care referral center from January 2009 to December 2017. The patients were assigned to the low-fT3 (n = 98) and normal-fT3 groups (n = 287).

Results

Child-Pugh (8.88 ± 0.22 vs. 7.09 ± 0.12, P < 0.001) and model for end-stage liver disease (MELD) scores (14.75 ± 0.57 vs. 10.59 ± 0.23, P < 0.001) significantly increased in the low-fT3 group. The hemoglobin level correlated with fT3 (R = 0.299, P < 0.0001) and fT4 (R = 0.310, P < 0.0001), while only fT3 significantly correlated with the albumin level (R = 0.537, P < 0.001). The Kaplan–Meier analysis indicated that the two-year survival rate was 74.51% in the low-fT3 group vs. 94.25% in the normal-fT3 group (P < 0.0001). The Cox regression analysis demonstrated that the serum level of fT3 [hazard ratio: 0.478; 95% confidence interval (CI) 0.391–0.758; P = 0.002] and prothrombin time (hazard ratio: 2.247; 95% CI: 1.316–3.838; P = 0.003) were independent prognostic factors in cirrhotic patients.

Conclusion

The low fT3 level was associated with poor prognosis and the progression of cirrhotic portal hypertension.
Cost effectiveness of treatment models of care for hepatitis C: the South Australian state-wide experience
Authors: Ramachandran Jeyamani , Kaambwa Billingsley , Muller Kate , Haridy James , Tse Edmund , Tilley Emma , Altus Rosalie , Waddell Victoria , Gordon David , Shaw David , Huynh Dep , Stewart Jeffrey , Nelson Renjy , Warner Morgyn , Boyd Mark A. , Chinnaratha Mohamed A. , Harding Damian , Ralton Lucy , Colman Anton , Woodman Richard , Wigg Alan J.
Published: January 2020

Aim

The objective was to study the long-term (lifetime) cost effectiveness of four different hepatitis C virus (HCV) treatment models of care (MOC) with directly acting antiviral drugs.

Methods

A cohort Markov model-based probabilistic cost-effectiveness analysis (CEA) was undertaken extrapolating to up to 30 years from cost and outcome data collected from a primary study involving a real-life Australian cohort. In this study, noncirrhotic patients treated for HCV from 1 March 2016 to 28 February 2017 at four major public hospitals and liaising sites in South Australia were studied retrospectively. The MOC were classified depending on the person providing patient workup, treatment and monitoring into MOC1 (specialist), MOC2 (mixed specialist and hepatitis nurse), MOC3 (hepatitis nurse) and MOC4 (general practitioner, GP). Incremental costs were estimated from the Medicare perspective. Incremental outcomes were estimated based on the quality-adjusted life years (QALY) gained by achieving a sustained virological response. A cost-effectiveness threshold of Australian dollar 50 000 per QALY gained, the implicit criterion used for assessing the cost-effectiveness of new pharmaceuticals and medical services in Australia was assumed. Net monetary benefit (NMB) estimates based on this threshold were calculated.

Results

A total of 1373 patients, 64% males, mean age 50 (SD ±11) years, were studied. In the CEA, MOC4 and MOC2 clearly dominated MOC1 over 30 years with lower costs and higher QALYs. Similarly, NMB was the highest in MOC4, followed by MOC2.

Conclusion

Decentralized care using GP and mixed consultant nurse models were cost-effective ways of promoting HCV treatment uptake in the setting of unrestricted access to new antivirals.
A ‘real-world’ analysis of risk factors for post liver transplant delirium and the effect on length of stay
Authors: Tavabie Oliver D. , Colwill Michael , Adamson Robbie , McPhail Mark J.W. , Bernal William , Jassem Wayel , Prachialias Andreas , Heneghan Michael , Aluvihare Varuna R. , Agarwal Kosh
Published: January 2020

Background

The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS).

Methods

All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records.

Results

Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure.

Conclusion

Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.
The safety and efficacy of tenofovir disoproxil fumarate used throughout pregnancy for mothers with chronic hepatitis B
Authors: Gao Xuesong , Duan Xuefei , Cai Haodong , Hu Yuhong , Liu Min , Kang Kai , Zhou Mingfang , Fu Dong , Yi Wei
Published: January 2020

Background

Antiviral therapy throughout pregnancy in women with chronic hepatitis B (CHB) during pregnancy has been suggested; however, the data of tenofovir disoproxil fumarate (TDF) are limited. The aim of this study was to evaluate the safety and efficiency in women with CHB.

Methods

It was a single-center, retrospectively study. Eighty-one women received TDF 300 mg/day before pregnancy. Sixty-three women did not receive antiviral treatment. All infants in both groups received immunoprophylaxis. Mothers and infants were followed at least postpartum 7 months. The primary endpoint was the safety of mothers and infants. The secondary endpoints were mother-to-child transmission (MTCT) rate and hepatitis B virus (HBV) DNA suppression.

Results

TDF was well tolerated in the mothers. The rates of neonatal congenital abnormalities were similar between the two groups (3.7% or 3/81 versus 3.3% or 2/63, P = 1.000). There were also no significant differences in infant length and weight, Apgar score (1 minute), rate of low birth weight, gestational age, or rate of cesarean section between the two groups. TDF significantly reduced the viral load (3.4 ± 0.5 log IU/mL versus 6.3 ± 1.5 log IU/mL, P < 0.001) and the ALT levels (19.9 ± 10.2 versus 46.8 ± 44.8 U/L, P < 0.001) before delivery. At 7-month postpartum, the MTCT rate was 0% in the TDF-treated group when compared with 6.3% (4/63) in the untreated group (P = 0.035).

Conclusion

TDF used throughout pregnancy can safely reduce the rate of MTCT.
Predictors of Depressive Symptoms in Heart Failure Caregivers
Authors: Grant Joan S. , Graven Lucinda J. , Abbott Laurie , Schluck Glenna
Published: January 2020

Heart failure is a serious and complex chronic illness and family caregivers often assist these individuals in performing self-care. Unsurprisingly, caregivers often are overwhelmed by daily activities associated with heart failure management and frequently have depressive symptoms. This study examined predictors (i.e., sociodemographic and clinical characteristics, social support, social problem-solving, family functioning, and objective and subjective burden) of depressive symptoms in 530 informal caregivers of individuals with heart failure in a large cross-sectional, descriptive study in the community. Younger caregivers who provided care for longer periods of time, lived in rural areas, and had less social support and lower problem-solving skills were more likely to have depressive symptoms. These findings emphasize the need for further studies to develop dynamic and innovative approaches that incorporate multiple components to lessen caregiving challenges. Social support and problem-solving skills training may be useful components to lessen depressive symptoms in these younger, rural caregivers.
Application of Computer-Aided Navigation Technology in the Extraction of Foreign Body From the Face
Authors: Lan Lin , He Yang , An Jingang , Zhang Yi
Published: January 2020

In the oral and maxillofacial foreign body (FB) extraction surgery, computer-aided navigation technical surgery is minimally invasive and safe, and can improve the accuracy, especially for areas with relatively complex and dangerous anatomical structures. A total of 11 patients, including 8 males and 3 females, who underwent the extraction surgery of FB from oral and maxillofacial regions using computer-aided navigation technical surgery were reviewed. According to the positional relationship between the maxillofacial region and the bone tissue, the FBs were divided into 3 categories: FB in the bone; FB aside the bone; and soft-tissue FB. During the operation, the BrainLab Navigation system was used to observe and guide the operation in real-time to evaluate the effectiveness and accuracy of computer-aided navigation technical surgery in the extraction of FBs from the maxillofacial regions. The FBs were successfully located and removed in 11 patients. No adjacent nerves, blood vessels, and other important anatomical structures were injured during the operation. The postoperative function and shape were not significantly affected.
Risk Factors of Acute Gastrointestinal Failure in Critically Ill Patients With Traumatic Brain Injury
Authors: Fu Weijun , Shi Nengxian , Wan Yahui , Mei Fen , Qiu Binghui , Bao Yun , Zhang Yu , Hao Jingwen , He Jing , Peng Xiaojie
Published: January 2020

Objective:

To assess the risk factors associated with acute gastrointestinal failure (AGF) in critically ill patients with traumatic brain injury (TBI).

Methods:

Prospective, observational study was conducted in NanFang Hospital, Southern Medical University. All patients admitted to the Department of Critical Care Medicine and Department of Neurosurgery from June 1, 2017 to December 1, 2018 with TBI were enrolled.

Results:

Overall, 199 patients were enrolled. About 62 episodes (31%) of AGF were diagnosed. In the multivariate analysis, women, severe Glasgow Coma Scale (GCS) classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are significantly associated with developing AGF, independent of other prognostic factors.

Conclusion:

The AGF occurs frequently in intensive care unit patients who are suffering from TBI. In critically ill patients with TBI, women, severe GCS classification, frontal lobe injury, abnormal serum sodium, pulmonary infection, and intracranial infection are independent risk factors for AGF.
A Rare Instance of Chordoid Glioma With Large Calcification Mimicking Craniopharyngioma
Authors: Cui Zhenwen , Mu Cuiping , Yang Fengyu , Li Huanting , Liu Wei , Feng Yugong
Published: January 2020

Chordoid glioma (CG) is a world health organization classified grade II tumor whose typical localization is in the anterior part of the third ventricle. It's clinical, neuroimaging, and pathologic features may vary and furthermore mimic other types of benign lesions usually associated with a better outcome, thus representing a potential radiological and diagnostic pitfall. In this article, the authors present a novel case of a 51-year-old male who underwent gross total removal of the tumor of the third ventricle with high calcification. The imaging studies and the intraoperative examination led at first to a hypothesis of craniopharyngioma. In this case, the patient underwent successful operative management and has remained well throughout follow-up.
Endovascular Treatment of Carotid Pseudoaneurysm Bleeding Due to Parapharyngeal Abscess
Authors: Çiçek Mehmet Turan , Yildirim Ismail Okan , Gündüz Emrah
Published: January 2020

Carotid artery pseudoaneurysm are a rare complication of deep neck infections, especially in the antibiotic era. Although it is rare, it may result in life-threatening conditions. Here, the authors present a case of pseudoaneurysm of the carotid artery caused by parapharyngeal abscess and causing massive oropharyngeal bleeding and treat with endovascular approach in a 40-year-old woman presenting with neck swelling and fever.
Suberoylanilide Hydroxamic Acid Alleviates Acute Lung Injury Induced by Severe Hemorrhagic Shock and Resuscitation in Rats
Authors: Li Wei , Gao Xiaohua , Liu Weifeng , Liang Jinwei , Zhou Yingying , Chen Weican , He Hefan
Published: January 2020

Background:

This study aimed to assess the severity of acute lung injury after mild or severe hemorrhagic shock and resuscitation, and to examine the therapeutic effects of suberoylanilide hydroxamic acid (SAHA) on lung injury.

Methods:

Mild and severe hemorrhagic shock were induced by total blood volume loss of 20% or 40%, respectively, which was maintained for 60 min. Then, resuscitation was performed by autologous blood and SAHA or a vehicle solution accordingly. Mean arterial pressure, heart rate, and arterial blood gas were measured during the experiment. Histological assays, wet/dry weight ratio, inflammatory cytokines, and the extent of histone acetylation were evaluated at 3 h post-resuscitation.

Results:

There were no significant differences of the most indicators measured between the mild hemorrhagic shock and Sham groups. Although in severe hemorrhagic shock group, mean arterial pressure was markedly reduced, lactic acid was significantly increased after hemorrhage. Moreover, the lung injury score was increased, the wet/dry weight ratio was elevated, inflammatory factor expression levels were upregulated, the expression of phosphorylated NF-κB/p65 was enhanced, and the extent of histone acetylation was decreased at 3 h post-resuscitation. Remarkably, adjuvant treatment with SAHA decreased the lactic acid, the pathological injury score, the wet/dry weight ratio, the content of inflammatory factor, as well as the level of activated NF-κB/p65, but promoted the expression of acetylated H4.

Conclusions:

Total blood volume loss of 40% results in acute lung injury, whereas loss of 20% does not. Treatment with SAHA alleviates lung injury induced by severe hemorrhagic shock and resuscitation and the underlying mechanism involves a reversal of decreased histone acetylation and inhibition of the NF-κB pathway.
Isoflurane attenuates carbogen-induced blood–brain barrier disruption independent of body temperature in mice and rats
Authors: Poon Kin-Shing , Pan Yu-Ling , Liao Kate Hsiurong , Wang Hwai-Lee , Chen Kuen-Bao , Chen Hsiao-Yun , Liu Yu-Cheng , Lai Ted Weita
Published: January 2020

Isoflurane protects the blood–brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20–30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.
Gender impact on transcranial magnetic stimulation-based cortical excitability and cognition relationship in healthy individuals
Authors: Akilan Kosalan , Kumar Sanjeev , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Rajji Tarek K.
Published: January 2020

Objective

We sought to determine whether cortical excitability, measured via transcranial magnetic stimulation (TMS), is associated with cognition in healthy individuals and whether gender and education have an impact on this relationship.

Methods

Fifty-four healthy individuals (31 males, mean age = 41.94, SD = 21.98; 23 females, mean age 48.57; SD = 22.84) underwent TMS to assess their resting motor threshold (RMT) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. Multiple regression analyses were conducted to assess the association between RMT, education, gender and cognition.

Results

The multiple regression model revealed a significant association between RBANS Total Index Score and RMT in the female group (B = 0.624, β = 0.602, P = 0.001) and not the male group (B = 0.048, β = 0.034, P = 0.858).

Conclusion

This study demonstrated that lower cortical excitability is associated with better global cognition in healthy female and not male individuals. RMT could be further studied as a tool to better personalize brain stimulation protocols that aim at enhancing cognition.
Effects of voluntary and forced exercises on motor function recovery in intracerebral hemorrhage rats
Authors: Sato Chihiro , Tanji Kunikazu , Shimoyama Shuji , Chiba Mitsuru , Mikami Misaki , Koeda Shuhei , Sumigawa Koshi , Akahira Kazuki , Yamada Junko
Published: January 2020

Motor paralysis is a severe consequence of intracerebral hemorrhage (ICH) that reduces patient quality of life. Rehabilitation is beneficial for stroke patients. However, functional recovery depends on the exercise type, and which factors are effective during rehabilitation are unknown. We aimed to clarify the effect of voluntary and forced exercises for functional recovery in ICH rats. Male Sprague–Dawley rats were divided into three groups: forced treadmill running (F-Ex.), voluntary wheel cage running (V-Ex.) and no exercise (Non-Ex.). The effects of the two exercises on motor recovery were analyzed by determining the motor deficit score and using the beam walking test. Stress and motivation status after rehabilitation were determined by corticosterone concentrations (ELISA) and immunoreactivity of ΔFosB (immunohistochemistry) in the nucleus accumbens, respectively. Significantly enhanced motor functional recovery was observed in the two trained groups compared with that in the Non-Ex. group. Of note, recovery in the V-Ex. group was greater than that in the F-Ex. group. To investigate the motivation and stress related to the exercises, the expression of ΔFosB in the nucleus accumbens and corticosterone concentration were compared after rehabilitation. In the V-Ex. group, there was a significant increase of ΔFosB, and in the F-Ex. Group, there was a high concentration of corticosterone. These data suggest that the effect of training for motor recovery was enhanced by motivation and reduced by stress.
Twelve Platinum-Standard Reference Genomes Sequences (PSRefSeq) that complete the full range of genetic diversity of Asian rice
Authors: Zhou Yong , Chebotarov Dmytro , Kudrna Dave , Llaca Victor , Lee Seunghee , Rajasekar Shanmugam , Mohammed Nahed , Al-Bader Noor , Sobel-Sorenson Chandler , Parakkal Praveena , Arbelaez Lady Johanna , Franco Natalia , Alexandrov Nickolai , Hamilton N. Ruaraidh Sackville , Leung Hei , Mauleon Ramil , Lorieux Mathias , Zuccolo Andrea , McNally Kenneth , Zhang Jianwei , Wing Rod A.
Published: January 2020

As the human population grows from 7.8 billion to 10 billion over the next 30 years, breeders must do everything possible to create crops that are highly productive and nutritious, while simultaneously having less of an environmental footprint. Rice will play a critical role in meeting this demand and thus, knowledge of the full repertoire of genetic diversity that exists in germplasm banks across the globe is required. To meet this demand, we describe the generation, validation and preliminary analyses of transposable element and long-range structural variation content of 12 near-gap-free reference genome sequences (RefSeqs) from representatives of 12 of 15 subpopulations of cultivated rice. When combined with 4 existing RefSeqs, that represent the 3 remaining rice subpopulations and the largest admixed population, this collection of 16 Platinum Standard RefSeqs (PSRefSeq) can be used as a pan-genome template to map resequencing data to detect virtually all standing natural variation that exists in the pan-cultivated rice genome.
An optimality principle for locomotor central pattern generators
Authors: Ryu Hansol X. , Kuo Arthur D.
Published: January 2020

Two types of neural circuits contribute to legged locomotion:central pattern generators(CPGs) that produce rhythmic motor commands (even in the absence of feedback, termed “fictive locomotion”), andreflex circuitsdriven by sensory feedback. Each circuit alone serves a clear purpose, and the two together are understood to cooperate during normal locomotion. The difficulty is in explaining their relative balance objectively within a control model, as there are infinite combinations that could produce the same nominal motor pattern. Here we propose that optimization in the presence of uncertainty can explain how the circuits should best be combined for locomotion. The key is to re- interpret the CPG in the context of state estimator-based control: an internal model of the limbs that predicts their state, using sensory feedback to optimally balance competing effects of environmental and sensory uncertainties. We demonstrate use of optimally predicted state to drive a simple model of bipedal, dynamic walking, which thus yields minimal energetic cost of transport and best stability. The internal model may be implemented with classic neural half-center circuitry, except with neural parameters determined by optimal estimation principles. Fictive locomotion also emerges, but as a side effect of estimator dynamics rather than an explicit internal rhythm. Uncertainty could be key to shaping CPG behavior and governing optimal use of feedback.

New and Noteworthy

Sensory feedback modulates the central pattern generator (CPG) rhythm in locomotion, but there lacks an explanation for how much feedback is appropriate. We propose destabilizing noise as a determinant, where an uncertain environment demands more feedback, but noisy sensors demand less. We reinterpret the CPG as an internal model for predicting body state despite noise. Optimizing its feedback yields robust and economical gait in a walking model, and explains the advantages of feedback-driven CPG control.
Engineering indel and substitution variants of diverse and ancient enzymes using Graphical Representation of Ancestral Sequence Predictions (GRASP)
Authors: Foley Gabriel , Mora Ariane , Ross Connie M. , Bottoms Scott , Sützl Leander , Lamprecht Marnie L. , Zaugg Julian , Essebier Alexandra , Balderson Brad , Newell Rhys , Thomson Raine E. S. , Kobe Bostjan , Barnard Ross T. , Guddat Luke , Schenk Gerhard , Carsten Jörg , Gumulya Yosephine , Rost Burkhard , Haltrich Dietmar , Sieber Volker , Gillam Elizabeth M. J. , Bodén Mikael
Published: January 2020

Ancestral sequence reconstruction is a technique that is gaining widespread use in molecular evolution studies and protein engineering. Accurate reconstruction requires the ability to handle appropriately large numbers of sequences, as well as insertion and deletion (“indel”) events, but available approaches exhibit limitations. To address these limitations, we developed Graphical Representation of Ancestral Sequence Predictions (GRASP), which efficiently implements maximum likelihood methods to enable the inference of ancestors of families with more than 10,000 members. GRASP implements partial order graphs (POGs) to represent and infer insertion and deletion events across ancestors, enabling the identification of building blocks for protein engineering.

To validate the capacity to engineer novel proteins from realistic data, we predicted ancestor sequences across three distinct enzyme families: glucose-methanol-choline (GMC) oxidoreductases, cytochromes P450, and dihydroxy/sugar acid dehydratases (DHAD). All tested ancestors demonstrated enzymatic activity. Our study demonstrates the ability of GRASP (1) to support large data sets over 10,000 sequences and (2) to employ insertions and deletions to identify building blocks for engineering biologically active ancestors, by exploring variation over evolutionary time.

Author summary

Massive sequencing projects expose the extent of natural, genetic diversity. Here, we describe a method with capacity to perform ancestor sequence reconstruction from data sets in excess of 10,000 sequences, poised to recoverancestraldiversity, including the evolutionary events that determine present-time biological function and structure.

We introduce a novel strategy for suggesting “indel variants” that are distinct from, but can be explored alongside, substitution variants for creating ancestral libraries. We demonstrate how indels can be used as building blocks to form “hybrid ancestors”; based on this strategy, we synthesise ancestor variants, with varying enzymatic activities, for wide-ranging applications in the biotechnology sector.
Effect of high-frequency low-intensity pulsed electric field on protecting SH-SY5Y cells against hydrogen peroxide and β-amyloid-induced cell injury via ERK pathway
Authors: Chen Wei-Ting , Lin Guan-Bo , Kuo Yu-Yi , Hsieh Chih-Hsiung , Lu Chueh-Hsuan , Sun Yi-Kun , Chao Chih-Yu
Published: January 2020

As the most common type of neurodegenerative diseases (NDDs), Alzheimer’s disease (AD) is thought to be caused mainly by the excessive aggregation of β-amyloid protein (Aβ). However, a growing number of studies have found that reactive oxygen species (ROS) play a key role in the onset and progression of AD. The present study aimed to probe the neuroprotective effect of high-frequency low-intensity pulsed electric field (H-LIPEF) for SH-SY5Y cells against hydrogen peroxide (H2O2) and Aβ-induced cytotoxicity. By looking in a systematic way into the frequency- and amplitude-dependent neuroprotective effect of pulsed electric field (PEF), the study finds that H-LIPEF at 200 Hz produces the optimal protective effect for SH-SY5Y cells. The underlying mechanisms were confirmed to be due to the activation of extracellular signal-regulated kinase (ERK) pathway and the downstream prosurvival and antioxidant proteins. Because the electric field can be modified to focus on specific area in a non-contact manner, the study suggests that H-LIPEF holds great potential for treating NDDs, whose effect can be further augmented with the administering of drugs or natural compounds at the same time.
Stock mislabelling and its impact on phylogenomic analysis in theDrosophila nasutasubgroup/species complex
Authors: Waddell Peter J. , Wang Jeremy , Jones Corbin D.
Published: January 2020

In the course of our 28 de novo genome study of thenasuta-subgroup of theimmigransspecies group, we have come to suspect that several stocks acquired from the major stock centers may have either been mislabeled or mixed up in other ways. This is a short note to indicate which stocks these are, how they were diagnosed, and how an alignment and assembly free (AFAF) phylogenomic analysis sheds further light on what probably occurred.
Single molecule tracking reveals the role of transitory dynamics of nucleoid-associated protein HU in organizing the bacterial chromosome
Authors: Bettridge Kelsey , Verma Subhash , Weng Xiaoli , Adhya Sankar , Xiao Jie
Published: January 2020

HU is the most conserved nucleoid-associated protein in eubacteria and has been implicated as a key player in global chromosome organization. The mechanism of HU-mediated nucleoid organization, however, remains poorly understood. Using single molecule tracking coupled with genetic manipulations, we characterized the dynamics of HU in liveEscherichia colicells. We found that native HU dimers bind and unbind chromosomal DNAs weakly and transitorily across the entire nucleoid volume but remain nucleoid-localized, reminiscent of random diffusion in a liquid phase-separated, membrane-less “macro-compartment” distinct from the remaining cytosol. Mutating three key surface lysine residues of HU nearly entirely abolished the weak and transitory interactions of HU with DNA and led to severe cell growth and DNA segregation defects, suggesting the importance of HU’s interactions with chromosomal DNA mediated by the positively charged surface. A conserved proline residue important for recognizing bent and cruciform DNAs such as that in recombination intermediates, similarly abolished HU’s rapid and transitory DNA interaction dynamics but had little impact on its apparent binding stability with nonspecific chromosomal DNAs. Interestingly, the proline residue appeared to be important for HUαβ dimer formation as mutating this residue makes HUαβ behave similarly to HUα2dimers. Finally, we find that while prior evidence has found HU capable of depositing nucleoid-associated noncoding RNAs onto cruciform DNA structures, deletion of these specific naRNAs or inhibition of global transcription had a relatively minor effect on HU dynamics irrespective altered nucleoid compaction. Our results suggest a model of chromosome organization mediated by weak, transient interactions of HU, a substantial deviation from nucleoid-like proteins such as histones. Such collective sum of the numerous weak, transitory binding events of HU with nonspecific chromosome DNAs could generates a “force” to maintain a dynamic, fluid nucleoid with enough flexibility to rapidly facilitate global topological processes such as replication or nucleoid segregation.
What influences treatment response in animal models of non-alcoholic fatty liver disease? A meta-analysis with meta-regression
Authors: Hunter Harriet , de Gracia Hahn Dana , Duret Amedine , Im Yu Ri , Cheah Qinrong , Dong Jiawen , Fairey Madison , Hjalmarsson Clarissa , Li Alice , Lim Hong Kai , McKeown Lorcán , Mitrofan Claudia-Gabriela , Rao Raunak , Utukuri Mrudula , Rowe Ian A. , Mann Jake P.
Published: January 2020

The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however, there is a comparatively low conversion rate from success in animals to in humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any licensed therapies and hence a major field of animal research. We performed a meta-analysis of 414 interventional rodent studies (6,575 animals) in NAFLD to assess the mean difference in hepatic triglyceride content. 20 of 21 studied drug classes had similar efficacy with a mean difference of −30% hepatic triglyceride. However, when publication bias was accounted for, this reduced to −16% difference. Study characteristics were only able to account for a minority of variability on meta-regression, and we replicated previous findings of high risk of bias across 82% of cohorts. These findings build on previous work in preclinical neuroscience and help to explain the challenge of reproducibility and translation within the field of metabolism.
RaptRanker:in silicoRNA aptamer selection from HT-SELEX experiment based on local sequence and structure information
Authors: Ishida Ryoga , Adachi Tatsuo , Yokota Aya , Yoshihara Hidehito , Aoki Kazuteru , Nakamura Yoshikazu , Hamada Michiaki
Published: January 2020

Aptamers are short single-stranded RNA/DNA molecules that bind to specific target molecules. Aptamers with high binding-affinity and target specificity are identified using anin vitroprocedure called high throughput systematic evolution of ligands by exponential enrichment (HT-SELEX). However, the development of aptamer affinity reagents takes a considerable amount of time and is costly because HT-SELEX produces a large dataset of candidate sequences, some of which have insufficient binding-affinity. Here, we present RNA aptamer Ranker (RaptRanker), a novel insilicomethod for identifying high binding-affinity aptamers from HT-SELEX data by scoring and ranking. RaptRanker analyzes HT-SELEX data by evaluating the nucleotide sequence and secondary structure simultaneously, and by ranking according to scores reflecting local structure and sequence frequencies. To evaluate the performance of RaptRanker, we performed two new HT-SELEX experiments, and evaluated binding affinities of a part of sequences that include aptamers with low binding-affinity. In both datasets, the performance of RaptRanker was superior to Frequency, Enrichment and MPBind. We also confirmed that the consideration of secondary structures is effective in HT-SELEX data analysis, and that RaptRanker successfully predicted the essential subsequence motifs in each identified sequence.
Movement-assisted localization from acoustic telemetry data
Authors: Hostetter Nathan J. , Royle J. Andrew
Published: January 2020

Background

Acoustic telemetry technologies are being rapidly deployed to study a variety of aquatic taxa including fishes, reptiles, and marine mammals. Large cooperative telemetry networks produce vast quantities of data useful in the study of movement, resource selection and species distribution. Efficient use of acoustic telemetry data requires estimation of acoustic source locations from detections at sensors (i.e. localization). Multiple processes provide information for localization estimation including detection/non-detection data at sensors, information on signal rate, and an underlying movement model describing how individuals move and utilize space. Frequently, however, localization methods only integrate a subset of these processes and do not utilize the full spatial encounter history information available from sensor arrays.

Methods

In this paper we draw analogies between the challenges of acoustic telemetry localization and newly developed methods of spatial capture-recapture (SCR). We develop a framework for localization that integrates explicit sub-models for movement, signal (or cue) rate, and detection probability, based on acoustic telemetry spatial encounter history data. This method, which we call movement-assisted localization, makes efficient use of the full encounter history data available from acoustic sensor arrays, provides localizations with fewer than three detections, and even allows for predictions to be made of the position of an individual when it wasnotdetected at all. We demonstrate these concepts by developing generalizable Bayesian formulations of the SCR movement-assisted localization model to address study-specific challenges common in acoustic telemetry studies.

Results

Simulation studies show that movement-assisted localization models improve point-wise RMSE of localization estimates by > 50% and greatly increased the precision of estimated trajectories compared to localization using only the detection history of a given signal. Additionally, integrating a signal rate sub-model reduced biases in the estimation of movement, signal rate, and detection parameters observed in independent localization models.

Conclusions

Movement-assisted localization provides a flexible framework to maximize the use of acoustic telemetry data. Conceptualizing localization within an SCR framework allows extensions to a variety of data collection protocols, improves the efficiency of studies interested in movement, resource selection, and space-use, and provides a unifying framework for modeling acoustic data.
A Splice Site-Sensing Conformational Switch in U2AF2 is Modulated by U2AF1 and its Recurrent Myelodysplasia-Associated Mutation
Authors: Warnasooriya Chandani , Glasser Eliezra , Feeney Callen F. , Laird Kholiswa M. , Jenkins Jermaine L. , Ermolenko Dmitri N. , Kielkopf Clara L.
Published: January 2020

An essential heterodimer of the U2AF1 and U2AF2 pre-mRNA splicing factors nucleates spliceosome assembly at polypyrimidine (Py) signals preceding the major class of 3ʹ splice sites. Among myelodysplastic syndromes (MDS), U2AF1 frequently acquires an S34F-encoding mutation. The influence of the U2AF1 subunit and its S34F mutation on the U2AF2 conformations remains unknown. Here, we employ single molecule Förster resonance energy transfer (FRET) to determine the influence of wild-type or S34F-substituted U2AF1 on the conformational dynamics of U2AF2 and its splice site RNA complexes. In the absence of RNA, the U2AF1 subunit stabilizes a high FRET value, which by structure-guided mutagenesis corresponds to a closed conformation of the tandem U2AF2 RNA recognition motifs (RRMs). When the U2AF heterodimer is bound to a strong, uridine-rich splice site, U2AF2 switches to a lower FRET value characteristic of an open, side-by-side arrangement of the RRMs. Remarkably, the U2AF heterodimer binds weak, uridine-poor Py tracts as a mixture of closed and open U2AF2 conformations, which are modulated by the S34F mutation. Shifts between open and closed U2AF2 may underlie U2AF1-dependent splicing of degenerate Py tracts and contribute to a subset of S34F-dysregulated splicing events in MDS patients.
Auxin-dependent alleviation of oxidative stress and growth promotion ofScenedesmus obliquusC1S byAzospirillum brasilense
Authors: Pagnussat L.A. , Maroniche G. , Curatti L. , Creus C.
Published: January 2020

There is currently an increasing interest in the use of microalgae for wastewater treatment and the use of its biomass as a feedstock for biofuels. Both of these applications are often performed more efficiently by microalgal-bacteria consortia. However, the mechanisms that account for the stability and robustness of this kind of interactions are poorly understood. In this study, we confirmed the growth promotion activity of the plant growth-promoting bacteriumAzospirillum brasilenseSp245 on the microalgaeScenedesmus obliquusC1S. We show that this activity is critically dependent on bacterial indole-3 acetic acid (IAA) production, which results in a decrease in algal reactive oxygen species (ROS) levels, higher cell densities and ameliorates algal cells bleaching after nitrogen deprivation. We also show a close inter-species interaction between both partners and an active expression of the bacterialipdCgene involved in production of IAA when co-cultivated.

This study extends the current knowledge of the mechanisms underlying bacteria-microalgae consortia to improve their technological applications and to better understand ecological relationships in the environment.
Deep evolutionary analysis reveals the design principles of fold A glycosyltransferases
Authors: Taujale Rahil , Venkat Aarya , Huang Liang-Chin , Yeung Wayland , Rasheed Khaled , Edison Arthur S. , Moremen Kelley W. , Kannan Natarajan
Published: January 2020

Glycosyltransferases (GTs) are prevalent across the tree of life and regulate nearly all aspects of cellular functions by catalyzing synthesis of glycosidic linkages between diverse donor and acceptor substrates. Despite the availability of GT sequences from diverse organisms, the evolutionary basis for their complex and diverse modes of catalytic and regulatory functions remain enigmatic. Here, based on deep mining of over half a million GT-A fold sequences from diverse organisms, we define a minimal core component shared among functionally diverse enzymes. We find that variations in the common core and the emergence of hypervariable loops extending from the core contributed to the evolution of catalytic and functional diversity. We provide a phylogenetic framework relating diverse GT-A fold families for the first time and show that inverting and retaining mechanisms emerged multiple times independently during the course of evolution. We identify conserved modes of donor and acceptor recognition in evolutionarily divergent families and pinpoint the sequence and structural features for functional specialization. Using the evolutionary information encoded in primary sequences, we trained a machine learning classifier to predict donor specificity with nearly 88% accuracy and deployed it for the annotation of understudied GTs in five model organisms. Our studies provide an evolutionary framework for investigating the complex relationships connecting GT-A fold sequence, structure, function and regulation.