bluuebunny/crossref_metadata_2025 huggingface dataset:
Cucumis melopectin as potential candidate to control herpes simplex virus infection
Authors: Agostinho Karoline Fontana , Rechenchoski Daniele Zendrini , Faccin-Galhardi Ligia Carla , de Sousa André Luiz Nascimento , Cunha Arcelina Pacheco , Ricardo Nágila Maria Pontes Silva , Linhares Rosa Elisa Carvalho , Nozawa Carlos
Published: February 2021

The herpes simplex virus, also known as HSV, is an important human pathogen. Acyclovir (ACV) is the first-line antiviral for the treatment of HSV infections; nevertheless HSV resistance to ACV has been increasingly reported and, therefore, search for alternative drugs have been encouraged. Herein, the effect of Cucumis melo sulfated pectin (SPCm) was evaluated in the HSV-1 infection. Pectin cytotoxicity and its antiherpetic action were determined by assays of MTT and plaque reduction, respectively. The SPCm concentration that reduced the cell viability by 50% (CC50) was 1440 μg/mL, while the concentration that reduced PFU in 50% (IC50) was 6 μg/mL against ACV-sensitive (KOS) strain and 12 μg/mL for ACV-resistant (AR-29) strain. The pectin showed high selectivity index (SI) for both viral strains. Therefore, we suggest that SPCm has been effective for HSV-1, strenghten by viral protein and DNA syntheses inhibition. In conclusion, we have found that SPCm is a promising alternative compound to control HSV infection.
Obtaining Evidence in Patent Litigation and Trade Secret Protection – A Tale of Two Poles
Authors: Schröder Vilhelm , Widera Philipp
Published: February 2021

In this article, the authors compare how the courts in two different jurisdictions handle trade secrets in patent litigation. Even though the two countries observed, Finland and Germany, are both continental European civil law systems with similar legal traditions, the approach to trade secret protection in litigation is quite different in many aspects. While Finland already has comparatively sophisticated legislation and jurisprudence when it comes to the protection of trade secrets, the German approach is rather different, and could be compared to a patchwork carpet. In this article, the authors review the international and European legal framework before delving into the details of the two national legal systems. Finally, they give guidelines on how to harmonize trade secret protection in litigation in order to strike a fair balance between the different interests at stake.
Evaluation of a U.S. National Cohort to Determine Utilization in Colectomy Rates for Ulcerative Colitis Among Ethnicities
Authors: Bhurwal Abhishek , Minacapelli Carlos D , Patel Anish , Mutneja Hemant , Goel Akshay , Shah Ishani , Bansal Vikas , Brahmbhatt Bhaumik , Das Kiron M
Published: February 2021

Background

Colectomy is the curative management for ulcerative colitis (UC). Multiple studies have reported racial disparities for colectomy before the advent of anti-TNF alpha agents. The aim of this study was to describe racial and geographic differences in colectomy rates among hospitalized patients with UC after anti-TNF therapy was introduced.

Methods

We examined all patients discharged from the hospital between 2010 and 2014 with a primary diagnosis of UC or of complications of UC. The data were evaluated for race and colectomy rates among the hospitalized patients with UC.

Results

The unadjusted national colectomy rate among hospitalized patients with UC between 2010 and 2014 was 3.90 per 1000 hospitalization days (95% confidence interval, 3.72-4.08). The undajusted colectomy rates in African American (2.33 vs 4.35; P < 0.001) and Hispanic patients (3.99 vs 4.35; P ≤ 0.009) were considerably lower than those for White patients. After adjustment for confounders, the incidence rate ratio for African American as compared to White patients was 0.43 (95% confidence interval, 0.32-0.58; P < 0.001). Geographic region of the United States also showed significant variation in colectomy rates, with western regions having the highest rate (4.76 vs 3.20; P < 0.001).

Conclusions

Racial and geographical disparities persist for the rate of colectomy among hospitalized patients with UC. The national database analysis reveals that colectomy rates for hospitalized African American and Hispanic patients were lower than those for White patients. Further studies are important to determine the social and biologic foundations of these disparities.
Counterintuitive active directional swimming behaviour by Atlantic salmon during seaward migration in the coastal zone
Authors: Newton Matthew , Barry James , Lothian Angus , Main Robert , Honkanen Hannele , Mckelvey Simon , Thompson Paul , Davies Ian , Brockie Nick , Stephen Alastair , Murray Rory O’Hara , Gardiner Ross , Campbell Louise , Stainer Paul , Adams Colin
Published: February 2021

Acoustic telemetry was used to track salmon smolts during river migration and into the open marine coastal zone. We compared migration direction and speed with particle tracking simulations to test the hypothesis that marine migration pathways are defined by active swimming current following behaviour. Habitat-specific survival rates, movement speeds, depths and directions in riverine, estuarine, and coastal habitats were also quantified. Salmon post-smolts did not disperse at random as they entered the unrestricted, coastal zone of the North sea; rather they chose a common migration pathway. This was not the most direct route to marine feeding grounds (ca. 44° N); north in the direction of the prevailing currents. Particle modelling showed that the actual post-smolt migration route was best predicted by active swimming at 1.2 body length.sec.−1 at a bearing of 70° from north but not by current following behaviour. Fish migrating in larger groups and earlier in the migration period had increased migration success. We conclude that: post-smolts have preferred migration routes that are not predicted by the shortest direction to their ultimate destination; they do not simply use the current advantage to migrate; and that they actively swim, occasionally directly against the current prevailing at the time.
The Distribution of Spacings Between the Fractional Parts of ndα
Authors: Fassina Martino , Kim Sun , Zaharescu Alexandru
Published: February 2021

We study the distribution of spacings between the fractional parts of $n^d\alpha $. For $\alpha $ of high enough Diophantine type we prove a necessary and sufficient condition for $n^d\alpha \mod 1, 1\leq n\leq N,$ to be Poissonian as $N\to \infty $ along a suitable subsequence.
Advancements in sensor technology and decision support intelligent tools to assist smart livestock farming
Authors: Tedeschi Luis O , Greenwood Paul L , Halachmi Ilan
Published: February 2021

Remote monitoring, modern data collection through sensors, rapid data transfer, and vast data storage through the Internet of Things (IoT) have advanced precision livestock farming (PLF) in the last 20 yr. PLF is relevant to many fields of livestock production, including aerial- and satellite-based measurement of pasture’s forage quantity and quality; body weight and composition and physiological assessments; on-animal devices to monitor location, activity, and behaviors in grazing and foraging environments; early detection of lameness and other diseases; milk yield and composition; reproductive measurements and calving diseases; and feed intake and greenhouse gas emissions, to name just a few. There are many possibilities to improve animal production through PLF, but the combination of PLF and computer modeling is necessary to facilitate on-farm applicability. Concept- or knowledge-driven (mechanistic) models are established on scientific knowledge, and they are based on the conceptualization of hypotheses about variable interrelationships. Artificial intelligence (AI), on the other hand, is a data-driven approach that can manipulate and represent the big data accumulated by sensors and IoT. Still, it cannot explicitly explain the underlying assumptions of the intrinsic relationships in the data core because it lacks the wisdom that confers understanding and principles. The lack of wisdom in AI is because everything revolves around numbers. The associations among the numbers are obtained through the “automatized” learning process of mathematical correlations and covariances, not through “human causation” and abstract conceptualization of physiological or production principles. AI starts with comparative analogies to establish concepts and provides memory for future comparisons. Then, the learning process evolves from seeking wisdom through the systematic use of reasoning. AI is a relatively novel concept in many science fields. It may well be “the missing link” to expedite the transition of the traditional maximizing output mentality to a more mindful purpose of optimizing production efficiency while alleviating resource allocation for production. The integration between concept- and data-driven modeling through parallel hybridization of mechanistic and AI models will yield a hybrid intelligent mechanistic model that, along with data collection through PLF, is paramount to transcend the current status of livestock production in achieving sustainability.
A chlorophyll a oxygenase 1 gene ZmCAO1 contributes to grain yield and waterlogging tolerance in maize
Authors: Li Qin , Zhou Shuangzhen , Liu Wenyu , Zhai Zhensheng , Pan Yitian , Liu Changchang , Chern Mawsheng , Wang Hongwei , Huang Min , Zhang Zuxin , Tang Jihua , Du Hewei
Published: February 2021

Chlorophylls function in photosynthesis, and are critical to plant developmental processes and responses to environmental stimuli. Chlorophyll b is synthesized from chlorophyll a by chlorophyll a oxygenase (CAO). Here, we characterize a yellow-green leaf (ygl) mutant and identify the causal gene which encodes a chlorophyll a oxygenase in maize (ZmCAO1). A 51 bp Popin transposon insertion in ZmCAO1 strongly disrupts its transcription. Low enzyme activity of ZmCAO1 leads to reduced concentrations of chlorophyll a and chlorophyll b, resulting in the yellow-green leaf phenotype of the ygl mutant. The net photosynthetic rate, stomatal conductance, and transpiration rate are decreased in the ygl mutant, while concentrations of δ-aminolevulinic acid (ALA), porphobilinogen (PBG) and protochlorophyllide (Pchlide) are increased. In addition, a ZmCAO1 mutation results in down-regulation of key photosynthetic genes, limits photosynthetic assimilation, and reduces plant height, ear size, kernel weight, and grain yield. Furthermore, the zmcao1 mutant shows enhanced reactive oxygen species production leading to sensitivity to waterlogging. These results demonstrate the pleiotropy of ZmCAO1 function in photosynthesis, grain yield, and waterlogging tolerance in maize.
A tidally tilted sectoral dipole pulsation mode in the eclipsing binary TIC 63328020
Authors: Rappaport S A , Kurtz D W , Handler G , Jones D , Nelson L A , Saio H , Fuller J , Holdsworth D L , Vanderburg A , Žák J , Skarka M , Aiken J , Maxted P F L , Stevens D J , Feliz D L , Aliçavuş F Kahraman
Published: February 2021

We report the discovery of the third tidally tilted pulsator, TIC 63328020. Observations with the TESS satellite reveal binary eclipses with an orbital period of 1.1057 d, and δ Scuti-type pulsations with a mode frequency of 21.09533 d−1. This pulsation exhibits a septuplet of orbital sidelobes as well as a harmonic quintuplet. Using the oblique pulsator model, the primary oscillation is identified as a sectoral dipole mode with l = 1, |m| = 1. We find the pulsating star to have M1 ≃ 2.5 M⊙, R1 ≃ 3 R⊙, and Teff, 1 ≃ 8000 K, while the secondary has M2 ≃ 1.1 M⊙, R2 ≃ 2 R⊙, and Teff, 2 ≃ 5600 K. Both stars appear to be close to filling their respective Roche lobes. The properties of this binary as well as the tidally tilted pulsations differ from the previous two tidally tilted pulsators, HD74423 and CO Cam, in important ways. We also study the prior history of this system with binary evolution models and conclude that extensive mass transfer has occurred from the current secondary to the primary.
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

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

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

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

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

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

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

Background

Cytokine 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.

Methods

This 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.

Results

Out 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.

Conclusions

Combination 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

Competing 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

Minimum 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

Using 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

Scene 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.
Mental imagery can generate and regulate acquired differential fear conditioned reactivity
Authors: Greening Steven G. , Lee Tae-Ho , Burleigh Lauryn , Grégoire Laurent , Robinson Tyler , Jiang Xinrui , Mather Mara , Kaplan Jonas
Published: February 2021

Mental imagery is an important tool in the cognitive control of emotion. The present study tests the prediction that visual imagery can generate and regulate differential fear conditioning via the activation and prioritization of stimulus representations in early visual cortices. We combined differential fear conditioning with manipulations of viewing and imagining basic visual stimuli in humans. We discovered that mental imagery of a fear-conditioned stimulus compared to imagery of a safe conditioned stimulus generated a significantly greater conditioned response as measured by self-reported fear, the skin conductance response, and right anterior insula activity (experiment 1). Moreover, mental imagery effectively down- and up-regulated the fear conditioned responses (experiment 2). Multivariate classification using the functional magnetic resonance imaging data from retinotopically defined early visual regions revealed significant decoding of the imagined stimuli in V2 and V3 (experiment 1) but significantly reduced decoding in these regions during imagery-based regulation (experiment 2). Together, the present findings indicate that mental imagery can generate and regulate a differential fear conditioned response via mechanisms of the depictive theory of imagery and the biased-competition theory of attention. These findings also highlight the potential importance of mental imagery in the manifestation and treatment of psychological illnesses.
Landscape composition mediates suppression of major pests by natural enemies in conventional cruciferous vegetables
Authors: Zhang Jie , You Shijun , Niu Dongsheng , Guaman Karla Giovana Gavilanez , Wang Ao , Saqib Hafiz Sohaib Ahmed , He Weiyi , Yu Yuan , Yang Guang , Pozsgai Gabor , You Minsheng
Published: February 2021

Background

Conservation biological control provides an environment-friendly approach to improve the efficacy of natural enemies. Although numerous studies have demonstrated the potential of semi-natural habitats in promoting biological control in organic or unsprayed agroecosystems, few studies were conducted in conventional agricultural fields. In this study, we investigated the effects of landscape composition on the major pests of cruciferous vegetables and on the assemblages of their natural enemies in southeastern China.

Results

Habitat diversity, particularly increasing grassland proportion in the landscape, had a positive impact in controlling both small-sized pests (aphids, leaf miners, thrips and flea beetles) andPlutella xylostella. This increasing proportion also promoted greater abundance and diversity of canopy-dwelling predators, more forests supported a higher diversity of airborne enemies (parasitoids and canopy-dwelling predators) as well as a higher abundance of ground-dwelling predators. A general increase in habitat diversity was beneficial to parasitoids and ground-dwelling predators. Additionally, the proportion of forest, grassland, and non-cruciferous vegetable area, as well as habitat diversity, affected the compositions of natural enemy communities. Moreover, inconsistent effects of non-cruciferous and grassland habitats were found between sampling regions for small-sized pests and canopy-dwelling predators. Moreover, the scale at which pests and natural enemies’ abundance and richness responded most to landscape composition varied with their feeding range and dispersal ability.

Conclusion

Our study provides evidence that increasing the amount of semi-natural habitats and habitat diversity can result in lower pest and higher natural enemy abundance in conventional cruciferous agroecosystems. Regional conditions and spatial scales also should be considered in designing the agricultural landscape mosaic.
Cancer relevance of human genes
Authors: Qing Tao , Mohsen Hussein , Cannataro Vincent L. , Marczyk Michal , Rozenblit Mariya , Foldi Julia , Murray Michael F. , Townsend Jeffrey P. , Kluger Yuval , Gerstein Mark , Pusztai Lajos
Published: February 2021

Background

It is unclear how many of genes contribute to the biology of cancer. We hypothesize that genes that interact with core cancer gene (CCG) in a protein-protein interaction network (PPI) may have functional importance.

Methods

We categorized genes into 1- (n=6791), 2- (n=7724), 3- (n=1587), and >3-steps (n=362) removed from the nearest CCG in the STRING PPI and demonstrate that the cancer-biology related functional contribution of the genes in these different neighborhood categories decreases as their distance from the CCGs increases.

Results

Genes closer to cancer genes manifest greater connectedness in the network, show greater importance in maintaining cell viability in a broad range of cancer cells in vitro, are also under greater negative germline selection pressure in the healthy populations, and have higher somatic mutation frequency and cancer effect.

Conclusions

Approximately 70% of human genes are 1 or 2 steps removed from cancer genes in protein network and show functional importance in cancer-biology. These results suggest that the universe of cancer-relevant genes extends to thousands of genes that can contribute functional effects when dysregulated.
LAMP3 is critical for surfactant homeostasis in mice
Authors: Lunding Lars P. , Krause Daniel , Stichtenoth Guido , Stamme Cordula , Lauterbach Niklas , Hegermann Jan , Ochs Matthias , Schuster Björn , Sedlacek Radislav , Saftig Paul , Schwudke Dominik , Wegmann Michael , Damme Markus
Published: February 2021

Lysosome-associated membrane glycoprotein 3 (LAMP3) is a type I transmembrane protein of the LAMP protein family with a cell-type-specific expression in alveolar type II cells in mice and hitherto unknown function. In type II pneumocytes, LAMP3 is localized in lamellar bodies, secretory organelles releasing pulmonary surfactant into the extracellular space to lower surface tension at the air/liquid interface. The physiological function of LAMP3, however, remains enigmatic. We generatedLamp3knockout mice by CRISPR/Cas9. LAMP3 deficient mice are viable with an average life span and display regular lung function under basal conditions. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung ofLamp3knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. In ovalbumin-induced experimental allergic asthma, the changes in lipid composition are aggravated, and LAMP3-deficient mice exert an increased airway resistance. Our data suggest a critical role of LAMP3 in the regulation of pulmonary surfactant homeostasis and normal lung function.
waveRAPID® - a robust assay for high-throughput kinetic screens with the Creoptix® WAVEsystem
Authors: Kartal Önder , Andres Fabio , Lai May Poh , Nehme Rony , Cottier Kaspar
Published: February 2021

Surface-based biophysical methods for measuring binding kinetics of molecular interactions, such as Surface Plasmon Resonance (SPR) or Grating-Coupled Interferometry (GCI), are now well established and widely used in drug discovery. Increasing throughput is an often-cited need in the drug discovery process, and this has been achieved with new instrument generations where multiple interactions are measured in parallel, shortening the total measurement times and enabling new application areas within the field. Here, we present the development of a novel technology called waveRAPID for a further - up to ten-fold - increase in throughput, consisting of an injection method using a single sample. Instead of sequentially injecting increasing analyte concentrations for constant durations, the analyte is injected at a single concentration in short pulses of increasing durations. A major advantage of the new method is its ability to determine kinetics from a single well of a micro-titer plate, making it uniquely suitable for kinetic screening. We present the fundamentals of this approach using a small molecule model system for experimental validation and comparing kinetic parameters to traditional methods. By varying experimental conditions, we furthermore assess the robustness of this new technique.

Finally, we discuss its potential for improving hit quality and shortening cycle times in the areas of fragment screening, low molecule weight compound screening, and hit-to-lead optimization.
Sex pheromone signal and stability covary with fitness
Authors: Blankers Thomas , Lievers Rik , Plata Camila , van Wijk Michiel , van Veldhuizen Dennis , Groot Astrid T.
Published: February 2021

If sexual signals are costly to produce or maintain, covariance between signal expression and fitness is expected. This signal-fitness covariance is important evolutionarily, because it can contribute to the maintenance of genetic variation in signal traits, despite selection from mate preferences. Chemical signals, such as moth sex pheromones, have traditionally been assumed to be stereotypical species-recognition signals, but their relationship with fitness is unclear. Here we test the hypothesis that for chemical signals that are primarily used for conspecific mate finding, there is covariation between signal properties and fitness in the noctuid mothHeliothis subflexa. Additionally, as moth signals are synthesizedde novoevery night throughout the female’s reproductive life, the maintenance of the signal can be costly. Therefore, we also hypothesized that fitness covaries with signal stability (i.e. the lack of intra-individual variation over time). We measured among- and within-individual variation in pheromone amount and composition as well as fecundity, fertility, and fitness in two independent groups of females that differed in the time in between two consecutive pheromone samples. In both groups, we found reproductive success and longevity to be correlated with pheromone amount, composition, and stability, supporting both our hypotheses. This study is the first to report a correlation between fitness and sex pheromone composition in moths, solidifying previous indications of condition-dependent moth pheromones and highlighting how signal-fitness covariance may contribute to heritable variation in chemical signals both among and within individuals.
A novel class of sulfur-containing aminolipids widespread in marine roseobacters
Authors: Smith Alastair F. , Silvano Eleonora , Päuker Orsola , Guillonneau Richard , Quareshy Mussa , Murphy Andrew , Mausz Michaela A , Stirrup Rachel , Rihtman Branko , Ferretjans Maria Aguilo , Brandsma Joost , Petersen Jörn , Scanlan David J , Chen Yin
Published: February 2021

Marine roseobacter group bacteria are numerically abundant and ecologically important players in ocean ecosystems. These bacteria are capable of modifying their membrane lipid composition in response to environmental change. Remarkably, a variety of lipids are produced in these bacteria, including phosphorus-containing glycerophospholipids and several amino acid-containing aminolipids such as ornithine lipids and glutamine lipids. Here, we present the identification and characterization of a novelsulfur-containingaminolipid (SAL) in roseobacters. Using high resolution accurate mass spectrometry, a SAL was found in the lipid extract ofRuegeria pomeroyiDSS-3 andPhaeobacter inhibensDSM 17395. Using comparative genomics, transposon mutagenesis and targeted gene knockout, we identified a gene encoding a putative lyso-lipid acyltransferase, designatedSalA, which is essential for the biosynthesis of this SAL. Multiple sequence analysis and structural modelling suggest that SalA is a novel member of the lysophosphatidic acid acyltransferase (LPAAT) family, the prototype of which is the PlsC acyltransferase responsible for the biosynthesis of the phospholipid phosphatidic acid. SAL appears to play a key role in biofilm formation in roseobacters.SalAis widely distributed inTaraOceans metagenomes and actively expressed inTaraOceans metatranscriptomes. Our results raise the importance of sulfur-containing membrane aminolipids in marine bacteria.