bluuebunny/crossref_metadata_2025_split huggingface dataset:
siRNAs containing 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides: in vitro and in vivo RNAi activity and inability of mitochondrial polymerases to incorporate 2′-F-NMC NTPs
Authors: Akabane-Nakata Masaaki , Erande Namrata D , Kumar Pawan , Degaonkar Rohan , Gilbert Jason A , Qin June , Mendez Martha , Woods Lauren Blair , Jiang Yongfeng , Janas Maja M , O’Flaherty Derek K , Zlatev Ivan , Schlegel Mark K , Matsuda Shigeo , Egli Martin , Manoharan Muthiah 
Published: February 2021

Abstract
We recently reported the synthesis of 2′-fluorinated Northern-methanocarbacyclic (2′-F-NMC) nucleotides, which are based on a bicyclo[3.1.0]hexane scaffold. Here, we analyzed RNAi-mediated gene silencing activity in cell culture and demonstrated that a single incorporation of 2′-F-NMC within the guide or passenger strand of the tri-N-acetylgalactosamine-conjugated siRNA targeting mouse Ttr was generally well tolerated. Exceptions were incorporation of 2′-F-NMC into the guide strand at positions 1 and 2, which resulted in a loss of the in vitro activity. Activity at position 1 was recovered when the guide strand was modified with a 5′ phosphate, suggesting that the 2′-F-NMC is a poor substrate for 5′ kinases. In mice, the 2′-F-NMC-modified siRNAs had comparable RNAi potencies to the parent siRNA. 2′-F-NMC residues in the guide seed region position 7 and at positions 10, 11 and 12 were well tolerated. Surprisingly, when the 5′-phosphate mimic 5′-(E)-vinylphosphonate was attached to the 2′-F-NMC at the position 1 of the guide strand, activity was considerably reduced. The steric constraints of the bicyclic 2′-F-NMC may impair formation of hydrogen-bonding interactions between the vinylphosphonate and the MID domain of Ago2. Molecular modeling studies explain the position- and conformation-dependent RNAi-mediated gene silencing activity of 2′-F-NMC. Finally, the 5′-triphosphate of 2′-F-NMC is not a substrate for mitochondrial RNA and DNA polymerases, indicating that metabolites should not be toxic.
Single bacterial resolvases first exploit, then constrain intrinsic dynamics of the Holliday junction to direct recombination
Authors: Ray Sujay , Pal Nibedita , Walter Nils G 
Published: February 2021

Abstract
Homologous recombination forms and resolves an entangled DNA Holliday Junction (HJ) crucial for achieving genetic reshuffling and genome repair. To maintain genomic integrity, specialized resolvase enzymes cleave the entangled DNA into two discrete DNA molecules. However, it is unclear how two similar stacking isomers are distinguished, and how a cognate sequence is found and recognized to achieve accurate recombination. We here use single-molecule fluorescence observation and cluster analysis to examine how prototypic bacterial resolvase RuvC singles out two of the four HJ strands and achieves sequence-specific cleavage. We find that RuvC first exploits, then constrains the dynamics of intrinsic HJ isomer exchange at a sampled branch position to direct cleavage toward the catalytically competent HJ conformation and sequence, thus controlling recombination output at minimal energetic cost. Our model of rapid DNA scanning followed by ‘snap-locking’ of a cognate sequence is strikingly consistent with the conformational proofreading of other DNA-modifying enzymes.
Neurocognitive functioning and radiologic changes in primary CNS lymphoma patients: results from the HOVON 105/ALLG NHL 24 randomized controlled trial
Authors: van der Meulen Matthijs , Dirven Linda , Habets Esther J J , Bakunina Katerina , Smits Marion , Achterberg Hakim C , Seute Tatjana , Cull Gavin , Schouten Harry , Zijlstra Josée M , Brandsma Dieta , Enting Roelien H , Beijert Max , Taphoorn Martin J B , van den Bent Martin J , Issa Samar , Doorduijn Jeanette K , Bromberg Jacoline E C 
Published: February 2021

Abstract

Background
To analyze the effect of treatment on neurocognitive functioning and the association of neurocognition with radiological abnormalities in primary central nervous system lymphoma (PCNSL).

Methods
One hundred and ninety-nine patients from a phase III trial (HOVON 105/ALLG NHL 24), randomized to standard chemotherapy with or without rituximab, followed in patients ≤60 years old by 30-Gy whole-brain radiotherapy (WBRT), were asked to participate in a neuropsychological evaluation before and during treatment, and up to 2 years posttreatment. Scores were transformed into a standardized z-score; clinically relevant changes were defined as a change in z-score of ≥1 SD. The effect of WBRT was analyzed in irradiated patients. All MRIs were centrally assessed for white matter abnormalities and cerebral atrophy, and their relation with neurocognitive scores over time in each domain was calculated.

Results
125/199 patients consented to neurocognitive evaluation. Statistically significant improvements in neurocognition were seen in all domains. A clinically relevant improvement was seen only in the motor speed domain, without differences between the arms. In the follow-up of irradiated patients (n = 43), no change was observed in any domain score, compared to after WBRT. Small but significant inverse correlations were found between neurocognitive scores over time and changes in white matter abnormalities (regression coefficients: −0.048 to −0.347) and cerebral atrophy (−0.212 to −1.774).

Conclusions
Addition of rituximab to standard treatment in PCNSL patients did not impact neurocognitive functioning up to 2 years posttreatment, nor did treatment with 30-Gy WBRT in patients ≤60 years old. Increased white matter abnormalities and brain atrophy showed weak associations with neurocognition.
Diazotrophic Bacteria and Their Mechanisms to Interact and Benefit Cereals
Authors: Pankievicz Vânia Carla Silva , do Amaral Fernanda Plucani , Ané Jean-Michel , Stacey Gary 
Published: February 2021

Plant-growth-promoting bacteria (PGPB) stimulate plant growth through diverse mechanisms. In addition to biological nitrogen fixation, diazotrophic PGPB can improve nutrient uptake efficiency from the soil, produce and release phytohormones to the host, and confer resistance against pathogens. The genetic determinants that drive the success of biological nitrogen fixation in nonlegume plants are understudied. These determinants include recognition and signaling pathways, bacterial colonization, and genotype specificity between host and bacteria. This review presents recent discoveries of how nitrogen-fixing PGPB interact with cereals and promote plant growth. We suggest adopting an experimental model system, such as the Setaria–diazotrophic bacteria association, as a reliable way to better understand the associated mechanisms and, ultimately, increase the use of PGPB inoculants for sustainable agriculture.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Satisfaction with prophylactic risk-reducing salpingo-oophorectomy in BRCA mutation carriers is very high and little dependent on the participants’ characteristics at surgery: a prospective study
Authors: Grandi Giovanni , Sammarini Margaret , Cortesi Laura , Toss Angela , Botticelli Laura , Varliero Federico , Sighinolfi Giovanna , Barbieri Elena , Facchinetti Fabio 
Published: February 2021

Abstract

Objective:

BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO.

Methods:
A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019.

Results:
Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ± 7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new “RRSO-caused” vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ± 8.6 points (range 62-100). To the question “Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)” the answer was 99.4 ± 3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, “RRSO-caused” symptoms versus not RRSO-caused (P > 0.05).

Conclusions:
Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants’ characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.

Video Summary:

http://links.lww.com/MENO/A712.
Patient-reported sexual function of breast cancer survivors with genitourinary syndrome of menopause after fractional CO2 laser therapy
Authors: Quick Allison M. , Zvinovski Filadelfiya , Hudson Catherine , Hundley Andrew , Evans Cynthia , Stephens Julie A. , Arthur Elizabeth , Ramaswamy Bhuvaneswari , Reinbolt Raquel E. , Noonan Anne M. , VanDeusen Jeffrey Bryan , Wesolowski Robert , Stover Daniel G. , Williams Nicole Olivia , Sardesai Sagar D. , Faubion Stephanie S. , Loprinzi Charles L. , Lustberg Maryam B. 
Published: February 2021

Abstract

Objective:
The objective of this pilot study was to evaluate the change in sexual function following treatment with fractional CO2 laser therapy in breast cancer (BC) survivors with genitourinary syndrome of menopause (GSM).

Methods:
A single-arm feasibility study of BC survivors with symptoms of GSM, including dyspareunia and/or vaginal dryness, was conducted. Participants who received three treatments with fractional CO2 laser and 4-week follow-up were contacted for patient-reported outcomes and adverse events at 12 months. Sexual function was measured using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale Revised (FSDS-R). Descriptive statistics were calculated for patient demographics and disease characteristics for the set of participants who agreed to long-term follow-up and those who were lost to follow-up. FSFI and FSDS-R scores were summarized at baseline, 4 weeks and 12 months, as well as the change from baseline, and were compared using a Wilcoxon signed rank test.

Results:
A total of 67 BC survivors enrolled, 59 completed treatments and 4-week follow-up; 39 participated in the 12 month follow-up. The overall FSFI score improved from baseline to 4-week follow-up (median Δ 8.8 [Q1, Q3] (QS) (2.2, 16.7)], P < 0.001). There were improvements at 4 weeks in all domains of the FSFI (P < 0.001 for each) including desire (median Δ 1.2; QS [0.6, 1.8]), arousal (median Δ 1.2; QS [0.3, 2.7]), lubrication (median Δ 1.8 (0, 3.3), orgasm (median Δ 1.2; QS [0, 3.6]), satisfaction (median Δ 1.6 (0.4, 3.2)), and pain (median Δ 1.6 (0, 3.6). The FSDS-R score also improved from baseline to 4-week follow-up (median Δ −10.0; QS [−16, −5] P < 0.001) indicating less sexually related distress. The scores of the FSFI and FSDS-R remained improved at 12 months and there were no serious adverse events reported.

Conclusions:
In BC survivors with GSM, the total and individual domain scores of the FSFI and the FSDS-R improved after fractional CO2 laser therapy.

Video Summary:

http://links.lww.com/MENO/A711.
Is there a beneficial effect of gamma-linolenic acid supplementation on body fat in postmenopausal hypertensive women? A prospective randomized double-blind placebo-controlled trial
Authors: da Costa Hime Lúcia de Fátima Cahino , Carvalho Lopes Ceci Mendes , Roa Cristiane Lima , Zuchelo Lea Tami Suzuki , Baracat Edmund C. , de Andrade Januário , Soares José Maria 
Published: February 2021

Abstract

Objective:
Systemic arterial hypertension and obesity are major public health problems that increase risks of serious cardiovascular diseases and kidney failure as well as increase mortality. Substances that can alleviate these problems are desirable. We evaluated the beneficial effects of nutritional supplementation with gamma-linolenic acid in postmenopausal hypertensive women.

Methods:
This was a prospective, double-blind, placebo-controlled, randomized study involving 96 postmenopausal women. Participants were divided into two groups either receiving 1,000 mg of borage oil rich in gamma-linolenic acid + vitamin E (drug) or only vitamin E (placebo) capsules for 6 months. They were followed up monthly to assess the impact on systemic blood pressure and body composition. To verify group homogeneity, Fisher's exact and Student t tests were performed. To evaluate differences in various parameters between the two groups and at various times, repeated measures analysis of variance was performed, with Bonferroni correction.

Results:
The power of the test was calculated based on the difference in the mean systolic blood pressure between baseline and after 6 months of treatment in the placebo group and in the drug group. A 92.9% test power was found with a 95% confidence interval. There was a significant reduction in the systolic and diastolic pressure as well as a significant change in waist-hip ratio (P < 0.01) in the drug group as compared with the placebo group.

Conclusions:
Supplementation with borage oil rich in gamma-linolenic acid had significant beneficial short-term effects without showing any adverse effect. There remains a need for further studies to evaluate long-term benefits.
Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune, Western India
Authors: Dravid Ameet , Kashiva Reema , Khan Zafer , Memon Danish , Kodre Aparna , Potdar Prashant , Mane Milind , Borse Rakesh , Pawar Vishal , Patil Dattatraya , Banerjee Debashis , Bhoite Kailas , Pharande Reshma , Kalyani Suraj , Raut Prathamesh , Bapte Madhura , Mehta Anshul , Reddy M Sateesh , Bhayani Krushnadas , Laxmi S S , Vishnu P D , Srivastava Shipra , Khandelwal Shubham , More Sailee , Shinde Rohit , Pawar Mohit , Harshe Amol , Kadam Sagar , Mahajan Uma , Joshi Gaurav , Mane Dilip 
Published: February 2021

AbstractBackgroundCytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednisolone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for the treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroids in COVID-19 associated CRS.MethodsThis retrospective cohort study was conducted at a tertiary level private hospital in Pune, India between 2nd April and 2nd November 2020. All patients administered TCZ and steroids for treatment of CRS were included. The primary endpoint was incidence of all-cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of infectious complications. Baseline and time-dependent risk factors significantly associated with death were identified by Relative risk estimation.ResultsOut of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. Median age of the cohort was 57 (IQR: 46.5, 66) years. Almost 72 % patients had preexisting co-morbidities. Median time to TCZ administration since onset of symptoms was 9 days (IQR: 7, 11). 63% patients needed intensive care unit (ICU) admission. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Infectious complications like hospital acquired pneumonia, bloodstream bacterial and fungal infections were observed in 2.13 %, 2.13 % and 0.06 % patients respectively. Age ≥ 60 years (p=0.014), presence of co-morbidities like hypertension (p = 0.011), IL-6 ≥ 100 pg/ml (p = 0.002), D-dimer ≥ 1000 ng/ml (p < 0.0001), CT severity index ≥ 18 (p < 0.0001) and systemic complications like lung fibrosis (p = 0.019), cardiac arrhythmia (p < 0.0001), hypotension (p < 0.0001) and encephalopathy (p < 0.0001) were associated with increased risk of death.ConclusionsCombination therapy of TCZ and Steroids is likely to be safe and effective in the management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled clinical trials.
Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons
Authors: Edwards Caitlyn M. , Dolezel Tyla , Rinaman Linda 
Published: February 2021

AbstractCompeting motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fedad libitumprior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. Overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.
Improving RNA branching predictions: advances and limitations
Authors: Poznanovíc Svetlana , Wood Carson , Cloer Michael , Heitsch Christine 
Published: February 2021

AbstractMinimum free energy prediction of RNA secondary structures is based on the Nearest Neighbor Thermodynamics Model. While such predictions are typically good, the accuracy can vary widely even for short sequences, and the branching thermodynamics are an important factor in this variance. Recently, the simplest model for multiloop energetics — a linear function of the number of branches and unpaired nucleotides — was found to be the best. Subsequently, a parametric analysis demonstrated that per family accuracy can be improved by changing the weightings in this linear function. However, the extent of improvement was not known due to the ad hoc method used to find the new parameters. Here we develop a branch-and-bound algorithm that finds the set of optimal parameters with the highest average accuracy for a given set of sequences. Our analysis shows that the previous ad hoc parameters are nearly optimal for tRNA and 5S rRNA sequences on both training and testing sets. Moreover, cross-family improvement is possible but more difficult because competing parameter regions favor different families. The results also indicate that restricting the unpaired nucleotide penalty to small values is warranted. This reduction makes analyzing longer sequences using the present techniques more feasible.
Engineering Threshold-Based Selection Systems
Authors: Pedone Katherine H. , González-Pérez Vanessa , Leopold Luciana E. , Der Channing J. , Cox Adrienne D. , Ahmed Shawn , Reiner David J. 
Published: February 2021

AbstractUsing model organisms to identify novel therapeutic targets is frequently constrained by pre-existing genetic toolkits. To expedite positive selection for identification of novel downstream effectors, we engineered conditional expression of activated CED-10/Rac to disruptC. elegansembryonic morphogenesis, titrated to 100% lethality. The strategy of engineering thresholds for positive selection using experimental animals was validated with pharmacological and genetic suppression and is generalizable to diverse molecular processes and experimental systems.
Expectation-Based Gist Facilitation: Rapid Scene Understanding and the Role of Top-Down Information
Authors: McLean Dominic , Renoult Louis , Malcolm George L. 
Published: February 2021

AbstractScene meaning is processed rapidly, with ‘gist’ extracted even when presentation duration spans a few dozen milliseconds. This has led some to suggest a primacy of bottom-up information. However, gist research has typically relied on showing successions of unrelated scene images, contrary to our everyday experience in which the world unfolds around us in a predictable manner. Thus, we investigated whether top-down information – in the form of observers’ predictions of an upcoming scene – facilitates gist processing. Within each trial, participants (N=336) experienced a series of images, organised to represent an approach to a destination (e.g., walking down a sidewalk), followed by a final target scene either congruous or incongruous with the expected destination (e.g., a store interior or a bedroom). Over a series of behavioural experiments, we found that: appropriate expectations facilitated gist processing; inappropriate expectations interfered with gist processing; the effect of congruency was driven by provision of contextual information rather than the thematic coherence of approach images, and; expectation-based facilitation was most apparent when destination duration was most curtailed. We then investigated the neural correlates of predictability on scene processing using ERP (N=26). Congruency-related differences were found in a putative scene-selective ERP component, related to integrating visual properties (P2), and in later components related to contextual integration including semantic and syntactic coherence (N400 and P600, respectively). Taken together, these results suggest that in real-world situations, top-down predictions of an upcoming scene influence even the earliest stages of its processing, affecting both the integration of visual properties and meaning.