bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural Selection on the Phase-Separation Properties of FUS during 160 My of Mammalian Evolution
Authors: Dasmeh Pouria , Wagner Andreas 
Published: October 2020

Abstract
Protein phase separation can help explain the formation of many nonmembranous organelles. However, we know little about its ability to change in evolution. Here we studied the evolution of the mammalian RNA-binding protein Fused in Sarcoma (FUS), a protein whose prion-like domain (PLD) contributes to the formation of stress granules through liquid–liquid phase separation. Although the PLD evolves three times as rapidly as the remainder of FUS, it harbors absolutely conserved tyrosine residues that are crucial for phase separation. Ancestral reconstruction shows that the phosphorylation sites within the PLD are subject to stabilizing selection. They toggle among a small number of amino acid states. One exception to this pattern is primates, where the number of such phosphosites has increased through positive selection. In addition, we find frequent glutamine to proline changes that help maintain the unstructured state of FUS that is necessary for phase separation. Our work provides evidence that natural selection has stabilized the liquid forming potential of FUS and minimized the propensity of cytotoxic liquid-to-solid phase transitions during 160 My of mammalian evolution.
A mouse model reveals the events and underlying regulatory signals during the gonadotrophin-dependent phase of follicle development
Authors: Chen Yingjun , Wang Xiaodong , Yang Chan , Liu Qinghua , Ran Zaohong , Li Xiang , He Changjiu 
Published: October 2020

ABSTRACTDuring folliculogenesis, the gonadotrophin (GTH)-dependent phase begins at the small antral follicle stage and ends with Graafian follicles. In this study, pregnant mare’s serum GTH was used to induce GTH-dependent folliculogenesis in mice, following which the developmental events that follicles undergo, as well as the underlying regulatory signals, were investigated at both the morphological and transcriptomic level. GTH-dependent folliculogenesis consisted of three phases: preparation, rapid growth and decelerated growth. In the preparation phase, comprising the first 12 h, granulosa cells completed the preparations for proliferation and differentiation, shifted energy metabolism to glycolysis, and reduced protein synthesis and processing. The rapid growth phase lasted from 12 to 24 h; in this phase, granulosa cells completed their proliferation, and follicles acquired the capacity for estradiol secretion and ovulation. Meanwhile, the decelerating growth phase occurred between 24 and 48 h of GTH-dependent folliculogenesis. In this phase, the proliferation and expansion of the follicular antrum were reduced, energy metabolism was shifted to oxidative phosphorylation, and cell migration and lipid metabolism were enhanced in preparation for luteinization. We also revealed the key signaling pathways that regulate GTH-dependent folliculogenesis and elucidated the activation sequence of these pathways. A comparison of our RNA-sequencing data with that reported for humans suggested that the mechanisms involved in mouse and human folliculogenesis are evolutionarily conserved. In this study, we draw a detailed atlas of GTH-dependent folliculogenesis, thereby laying the foundation for further investigation of the regulatory mechanisms underlying this process.
Structural basis of Mfd-dependent transcription termination
Authors: Shi Jing , Wen Aijia , Zhao Minxing , Jin Sha , You Linlin , Shi Yue , Dong Shuling , Hua Xiaoting , Zhang Yu , Feng Yu 
Published: October 2020

Abstract
Mfd-dependent transcription termination plays an important role in transcription-coupled DNA repair, transcription-replication conflict resolution, and antimicrobial resistance development. Despite extensive studies, the molecular mechanism of Mfd-dependent transcription termination in bacteria remains unclear, with several long-standing puzzles. How Mfd is activated by stalled RNA polymerase (RNAP) and how activated Mfd translocates along the DNA are unknown. Here, we report the single-particle cryo-electron microscopy structures of T. thermophilus Mfd-RNAP complex with and without ATPγS. The structures reveal that Mfd undergoes profound conformational changes upon activation, contacts the RNAP β1 domain and its clamp, and pries open the RNAP clamp. These structures provide a foundation for future studies aimed at dissecting the precise mechanism of Mfd-dependent transcription termination and pave the way for rational drug design targeting Mfd for the purpose of tackling the antimicrobial resistance crisis.
Prediction of Worse Functional Status After Surgery for Degenerative Cervical Myelopathy: A Machine Learning Approach
Authors: Khan Omar , Badhiwala Jetan H , Akbar Muhammad A , Fehlings Michael G 
Published: October 2020

Abstract

BACKGROUND
Surgical decompression for degenerative cervical myelopathy (DCM) is one of the mainstays of treatment, with generally positive outcomes. However, some patients who undergo surgery for DCM continue to show functional decline.

OBJECTIVE
To use machine learning (ML) algorithms to determine predictors of worsening functional status after surgical intervention for DCM.

METHODS
This is a retrospective analysis of prospectively collected data. A total of 757 patients enrolled in 2 prospective AO Spine clinical studies, who underwent surgical decompression for DCM, were analyzed. The modified Japanese Orthopedic Association (mJOA) score, a marker of functional status, was obtained before and 1 yr postsurgery. The primary outcome measure was the dichotomized change in mJOA at 1 yr according to whether it was negative (worse functional status) or non-negative. After applying an 80:20 training-testing split of the dataset, we trained, optimized, and tested multiple ML algorithms to evaluate algorithm performance and determine predictors of worse mJOA at 1 yr.

RESULTS
The highest-performing ML algorithm was a polynomial support vector machine. This model showed good calibration and discrimination on the testing data, with an area under the receiver operating characteristic curve of 0.834 (accuracy: 74.3%, sensitivity: 88.2%, specificity: 72.4%). Important predictors of functional decline at 1 yr included initial mJOA, male gender, duration of myelopathy, and the presence of comorbidities.

CONCLUSION
The reasons for worse mJOA are frequently multifactorial (eg, adjacent segment degeneration, tandem lumbar stenosis, ongoing neuroinflammatory processes in the cord). This study successfully used ML to predict worse functional status after surgery for DCM and to determine associated predictors.
Suppression of Metacaspase- and Autophagy-Dependent Cell Death Improves Stress-Induced Microspore Embryogenesis in Brassica napus
Authors: Berenguer Eduardo , Minina Elena A , Carneros Elena , B�r�ny Ivett , Bozhkov Peter V , Testillano Pilar S 
Published: October 2020

Abstract
Microspore embryogenesis is a biotechnological process that allows us to rapidly obtain doubled-haploid plants for breeding programs. The process is initiated by the application of stress treatment, which reprograms microspores to embark on embryonic development. Typically, a part of the microspores undergoes cell death that reduces the efficiency of the process. Metacaspases (MCAs), a phylogenetically broad group of cysteine proteases, and autophagy, the major catabolic process in eukaryotes, are critical regulators of the balance between cell death and survival in various organisms. In this study, we analyzed the role of MCAs and autophagy in cell death during stress-induced microspore embryogenesis in Brassica napus. We demonstrate that this cell death is accompanied by the transcriptional upregulation of three BnMCA genes (BnMCA-Ia, BnMCA-IIa and BnMCA-IIi), an increase in MCA proteolytic activity and the activation of autophagy. Accordingly, inhibition of autophagy and MCA activity, either individually or in combination, suppressed cell death and increased the number of proembryos, indicating that both components play a pro-cell death role and account for decreased efficiency of early embryonic development. Therefore, MCAs and/or autophagy can be used as new biotechnological targets to improve in vitro embryogenesis in Brassica species and doubled-haploid plant production in crop breeding and propagation programs.
Additive Analgesic Effect of Transcranial Direct Current Stimulation Together with Mirror Therapy for the Treatment of Phantom Pain
Authors: Segal Nitza , Pud Dorit , Amir Hagai , Ratmansky Motti , Kuperman Pora , Honigman, Liat , Treister, Roi 
Published: October 2020

Abstract

Objective
Current analgesic treatments for phantom pain are not optimal. One well-accepted yet limited nonpharmacological option is mirror therapy, which is thought to counterbalance abnormal plasticity. Transcranial direct current stimulation (tDCS) is an emerging approach believed to affect the membrane potential and activity threshold of cortical neurons. tDCS analgesic effectiveness, however, is mild and short, rendering it a noneffective stand-alone treatment. This study aimed to assess if a combination of mirror therapy with tDCS results in a superior analgesic effect as compared with mirror therapy alone in patients suffering from phantom pain due to recent amputation.

Design
Following ethical approval, eligible patients provided informed consent and were randomly assigned to a study treatment group that continued for 2 weeks (once daily): 1) mirror therapy; 2) mirror therapy and sham tDCS; or 3) mirror therapy and tDCS. Assessments were done before treatment; at the end of treatment weeks 1 and 2; and at 1 week, 1 month, and 3 months following treatment. The primary outcome measure was pain intensity. Secondary measures were derived from the Short Form McGill Pain Questionnaire and the Brief Pain Inventory.

Results
Thirty patients were recruited, and 29 patients completed the study. Three months following treatment, pain intensity was significantly (P&lt;0.001) reduced in the combined treatment group (reduction of 5.4±3.3 points) compared with the other study arms (mirror therapy, 1.2±1.1; mirror therapy and sham tDCS, 2.7±3.2). All secondary outcome results were in line with these findings.

Conclusions
Combining tDCS with mirror therapy results in a robust long-lasting analgesic effect. These encouraging findings may contribute to the understanding of the underlying mechanisms of phantom pain.
Technology transfer models for knowledge-based regional development: New R&D institutes in Guangdong, China
Authors: Conlé Marcus , Zhao Wei , ten Brink Tobias 
Published: October 2020

AbstractChina has long struggled to make science and technology useful for industry. One essential element in overcoming this problem is vigorous knowledge infrastructure development. This article focuses on the most salient outcomes of recent organization-building initiatives in Guangdong: the ‘New R&D Institutes’ (NRDIs). We employ a process tracing approach including a mix of methods to systematically study NRDIs, and we examine the ways in which these institutes extend, and improve upon, previous Chinese approaches to technology transfer. We observe a flexible approach that engages a wide range of intra-regional and extra-regional knowledge actors and allows for the emergence of a variety of technology transfer models—including models that are better adapted to the local setting than those discussed in the literature. The article contributes to fragmentary knowledge on the role of technology transfer in China and to the literature on innovation policy in peripheral manufacturing regions.
Antimicrobial Prescribing during Infant Hospital Admissions in a Birth Cohort in Dhaka, Bangladesh
Authors: Boone Katherine , Morris Shaun K , Doshi Sejal , Black Jason , Mohsin Minhazul , Ahmed Tahmeed , Al Mahmud Abdullah , Roth Daniel E 
Published: October 2020

AbstractEmpirical antimicrobial use is common in hospitalized infants and may contribute to antimicrobial resistance in low- and middle-income countries. In this observational birth cohort study nested in a randomized controlled trial in Dhaka, Bangladesh, inpatient antimicrobial prescription data were extracted from serious adverse event forms completed for hospitalizations of infants (0–12 months of age). The primary outcome was the proportion of inpatient admissions where systemic antimicrobials were prescribed. Infant and hospitalization-related factors associated with antimicrobial prescriptions were determined. Among 1254 infants, there were 448 admissions to 32 facilities from 2014 to 2016. Antimicrobials were prescribed in 73% of admissions with a mean antimicrobial exposure rate of 0.25 antimicrobials per day of admission [95% confidence intervals (95% CIs): 0.24–0.27]. The most common antibiotics were aminoglycosides (29%), penicillins (26%) and third-generation cephalosporins (25%). In all, 58% of antibiotics were classified as ‘access’, 38% ‘watch’ and 1% ‘reserve’ using the World Health Organization (WHO) Essential Medicines List classification. WHO-recommended antimicrobial regimens were used in 68% of neonatal sepsis and 9% of lower respiratory tract infection (LRTI) admissions. ‘Watch’ antimicrobials were used in 26% of neonatal sepsis and 76% of LRTI admissions. Compared with private facilities, antimicrobial prescription rates were lower at government [rate ratio (RR) 0.71; 95% CI: 0.61–0.83] and charitable facilities (RR 0.39; 95% CI: 0.28–0.53), after adjustment for household wealth index and parental education. Younger infant age, older maternal age and longer admission were associated with higher prescription rates. These findings highlight the need for paediatric antimicrobial stewardship programs in Bangladesh.
Tolerance mechanisms in allergen immunotherapy
Authors: Celebi Sözener Zeynep , Mungan Dilsad , Cevhertas Lacin , Ogulur Ismail , Akdis Mübeccel , Akdis Cezmi 
Published: October 2020

Purpose of reviewAllergen immunotherapy is the only treatment modality which alters the natural course of allergic diseases by restoring immune tolerance against allergens. Deeper understanding of tolerance mechanisms will lead to the development of new vaccines, which target immune responses and promote tolerance.Recent findingsSuccessful allergen immunotherapy (AIT) induces allergen-specific peripheral tolerance, characterized mainly by the generation of allergen-specific Treg cells and reduction of Th2 cells. At the early phase, AIT leads to a decrease in the activity and degranulation of mast cells and basophils and a decrease in inflammatory responses of eosinophils in inflamed tissues. Treg cells show their effects by secreting inhibitory cytokines including interleukin (IL)-10, transforming growth factor-β, interfering with cellular metabolisms, suppressing antigen presenting cells and innate lymphoid cells (ILCs) and by cytolysis. AIT induces the development of regulatory B cells producing IL-10 and B cells expressing allergen-specific IgG4. Recent investigations have demonstrated that AIT is also associated with the formation of ILC2reg and DCreg cells which contribute to tolerance induction.SummaryResearch done so far, has shown that multiple molecular and cellular factors are dysregulated in allergic diseases and modified by AIT. Studies should now focus on finding the best target and ideal biomarkers to identify ideal candidates for AIT.
Acid-sensing Ion Channel 3 Overexpression in Incisions Regulated by Nerve Growth Factor Participates in Postoperative Nociception in Rats
Authors: Li Hao , Li Huiping , Cheng Jing , Liu Xicheng , Zhang Zhongjun , Wu Chaoran 
Published: October 2020

Background
Acid-sensing ion channel 3 (ASIC3) upregulation has been reported in dorsal root ganglion neurons after incision and contributes to postoperative nociception. This study hypothesized that upregulation of ASIC3 in incised tissues is induced by nerve growth factor through the phosphoinositide 3–kinase/protein kinase B signaling pathway.

Methods
A plantar incision model was established in adult male and female Sprague–Dawley rats. ASIC3 was inhibited by APETx2 treatment, small interfering RNA treatment, or ASIC3 knockout. Sciatic nerve ligation was performed to analyze ASIC3 transport. A nerve growth factor antibody and a phosphoinositide 3–kinase inhibitor were used to investigate the mechanism by which nerve growth factor regulates ASIC3 expression.

Results
Acid-sensing ion channel 3 inhibition decreased incisional guarding and mechanical nociception. ASIC3 protein levels were increased in skin and muscle 4 h after incision (mean ± SD: 5.4 ± 3.2-fold in skin, n = 6, P = 0.001; 4.3 ± 2.2-fold in muscle, n = 6, P = 0.001). Sciatic nerve ligation revealed bidirectional ASIC3 transport. Nerve growth factor antibody treatment inhibited the expression of ASIC3 (mean ± SD: antibody 2.3 ± 0.8-fold vs. vehicle 4.9 ± 2.4-fold, n = 6, P = 0.036) and phosphorylated protein kinase B (mean ± SD: antibody 0.8 ± 0.3-fold vs. vehicle 1.8 ± 0.8-fold, n = 6, P = 0.010) in incised tissues. Intraplantar injection of nerve growth factor increased the expression of ASIC3 and phosphorylated protein kinase B. ASIC3 expression and incisional pain–related behaviors were inhibited by pretreatment with the phosphoinositide 3–kinase inhibitor LY294002.

Conclusions
Acid-sensing ion channel 3 overexpression in incisions contributes to postoperative guarding and mechanical nociception. Bidirectional transport of ASIC3 between incised tissues and dorsal root ganglion neurons occurs through the sciatic nerve. Nerve growth factor regulates ASIC3 expression after plantar incision through the phosphoinositide 3–kinase/protein kinase B signaling pathway.

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Slower Speaking Rate Reduces Listening Effort Among Listeners With Cochlear Implants
Authors: Winn Matthew B. , Teece Katherine H. 
Published: October 2020

Objectives:
Slowed speaking rate was examined for its effects on speech intelligibility, its interaction with the benefit of contextual cues, and the impact of these factors on listening effort in adults with cochlear implants.

Design:
Participants (n = 21 cochlear implant users) heard high- and low-context sentences that were played at the original speaking rate, as well as a slowed (1.4× duration) speaking rate, using uniform pitch-synchronous time warping. In addition to intelligibility measures, changes in pupil dilation were measured as a time-varying index of processing load or listening effort. Slope of pupil size recovery to baseline after the sentence was used as an index of resolution of perceptual ambiguity.

Results:
Speech intelligibility was better for high-context compared to low-context sentences and slightly better for slower compared to original-rate speech. Speech rate did not affect magnitude and latency of peak pupil dilation relative to sentence offset. However, baseline pupil size recovered more substantially for slower-rate sentences, suggesting easier processing in the moment after the sentence was over. The effect of slowing speech rate was comparable to changing a sentence from low context to high context. The effect of context on pupil dilation was not observed until after the sentence was over, and one of two analyses suggested that context had greater beneficial effects on listening effort when the speaking rate was slower. These patterns maintained even at perfect sentence intelligibility, suggesting that correct speech repetition does not guarantee efficient or effortless processing. With slower speaking rates, there was less variability in pupil dilation slopes following the sentence, implying mitigation of some of the difficulties shown by individual listeners who would otherwise demonstrate prolonged effort after a sentence is heard.

Conclusions:
Slowed speaking rate provides release from listening effort when hearing an utterance, particularly relieving effort that would have lingered after a sentence is over. Context arguably provides even more release from listening effort when speaking rate is slower. The pattern of prolonged pupil dilation for faster speech is consistent with increased need to mentally correct errors, although that exact interpretation cannot be verified with intelligibility data alone or with pupil data alone. A pattern of needing to dwell on a sentence to disambiguate misperceptions likely contributes to difficulty in running conversation where there are few opportunities to pause and resolve recently heard utterances.
The Association of Preoperative Duration of Symptoms With Clinical Outcomes and Minimal Clinically Important Difference Following Anterior Cervical Discectomy and Fusion
Authors: Jenkins Nathaniel W. , Parrish James M. , Lynch Conor P. , Cha Elliot D.K. , Mohan Shruthi , Geoghegan Cara E. , Jadczak Caroline N. , Singh Kern 
Published: October 2020

Study Design:
This was a retrospective cohort study.

Objective:
The purpose of this study is to examine whether the time duration from symptom onset to operative treatment is associated with postoperative clinical improvement after anterior cervical discectomy and fusion (ACDF).

Summary of Background Data:
There is a paucity of literature regarding the influence of preoperative symptom duration on patient-reported outcomes (PROs) following ACDF.

Methods:
Patients who underwent primary, single-level ACDF were retrospectively reviewed and stratified according to preoperative symptom duration (<12 and ≥12 mo). Demographic and perioperative characteristics were compared using χ2 analysis and linear regression. Subgroup mean scores were compared and achievement of minimal clinically important difference (MCID) was assessed for the Neck Disability Index (NDI), Visual Analogue Scale (VAS) neck pain, VAS arm pain, and 12-Item Short-Form Physical Component Score.

Results:
A total of 109 patients underwent primary, single-level ACDF: 68 had duration of symptoms (DOS) <12 months and 41 had a DOS ≥12 months. When comparing DOS subgroup preoperative PROs, there was no preoperative difference in NDI, VAS arm or neck pain, and 12-Item Short-Form Physical Component Score. In the postoperative period, there were no significant differences in the improvement of PROs throughout the 12-month timepoint. A significantly larger proportion of the <12 months DOS cohort achieved NDI MCID at the 3-month (66.1% vs. 43.8%, P=0.039) and 6-month (76.8% vs. 53.6%, P=0.030) postoperative period.

Conclusions:
Among the patient subgroups with <12 and ≥12 months DOS, there were no statistically significant differences observed in any of the measured PRO means at any timepoint. When assessing MCID, however, patients with shorter DOS (<12 mo) were observed to attain NDI MCID at the 3- and 6-month timepoints more often than patients with DOS ≥12 months. Our findings suggest that delayed surgical intervention may impair functional recovery to MCID in patients with degenerative cervical disease.