bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecological landscapes guide the assembly of optimal microbial communities
Authors: George Ashish B. , Korolev Kirill S.
Published: December 2021

Assembling optimal microbial communities is key for various applications in biofuel production, agriculture, and human health. Finding the optimal community is challenging because the number of possible communities grows exponentially with the number of species, and so an exhaustive search cannot be performed even for a dozen species. A heuristic search that improves community function by adding or removing one species at a time is more practical, but it is unknown whether this strategy can discover an optimal or nearly optimal community. Using consumer-resource models with and without cross-feeding, we investigate how the efficacy of search depends on the distribution of resources, niche overlap, cross-feeding, and other aspects of community ecology. We show that search efficacy is determined by the ruggedness of the appropriately-defined ecological landscape. We identify specific ruggedness measures that are both predictive of search performance and robust to noise and low sampling density. The feasibility of our approach is demonstrated using experimental data from a soil microbial community. Overall, our results establish the conditions necessary for the success of the heuristic search and provide concrete design principles for building high-performing microbial consortia.

Author summary

Research shows that microbial communities comprised of specific species combinations can cure disease, improve agricultural output, or synthesize valuable chemicals. But finding the species combinations that generate high-performing communities is challenging because there are too many species combinations to test exhaustively. So, scientists use heuristic strategies that test only a few species combinations to search for high-performing communities. However, these heuristic strategies often fail to find the best species combinations, and we still do not understand when they fail. Here, we develop a framework to analyze these heuristic strategies, building on the concept of fitness landscapes studied in evolution and computer science. We apply this framework to data from simulated microbial community models to identify biological properties that affect the success of heuristic search strategies, such as the extent to which microbes compete for the same metabolites. Further, we establish statistical measures of the landscape structure that can help estimate search success from preliminary data. We validate our findings using experimental data from communities of soil microbes. Together, our results develop a conceptual framework to analyze and develop heuristic search strategies and identify guiding principles to help scientists choose species and environmental conditions that make finding high-performing microbial communities easier.
Animal soil food web complexity triggers shifts in microbial communities, including PAH degraders, but without clear effects on phenanthrene phytoremediation
Authors: Correa-Garcia Sara , Corelli Vincenzo , Tremblay Julien , Dozois Jessica Ann , Mukula Eugenie , Séguin Armand , Yergeau Etienne
Published: December 2021

The aim of this study was to determine whether the complexity of the animal soil food web (SFWC) is a significant factor influencing the soil microbial communities, the productivity of the willow, and the degradation rates of 100 mg kg-1 phenanthrene contamination. The SFWC treatment had eight levels: just the microbial community (BF), or the BF with nematodes (N), springtails (C), earthworms (E), CE, CN, EN, CEN. After eight weeks of growth, the height and biomass of willows were significantly affected by the SFWC, whereas the amount of phenanthrene degraded was not affected, reaching over 95% in all pots. SFWC affected the structure and the composition of the bacterial, archaeal and fungal communities, with significant effects of SFWC on the relative abundance of fungal genera such as Sphaerosporella, a known willow symbiont during phytoremediation, and bacterial phyla such as Actinobacteriota, containing many PAH degraders. These SFWC effects on microbial communities were not clearly reflected in the community structure and abundance of PAH degraders, even though some degraders related to the Actinobacteriota and the diversity of Gram-negative degraders were affected by the SFWC treatments. Overall, our results suggest that, under our experimental conditions, SFWC does not affect significantly willow phytoremediation outcomes.

Importance

Polycyclic aromatic hydrocarbons (PAH) pose a threat to soil ecosystems. Phytoremediation is a green technology that can help restore ecosystems’ health affected by PAH contamination. Past research on phytoremediation of PAH has focused on the roles of plant and microbes in contaminant fates. However, soil environments usually harbor large faunal communities that interact with both the plant and the microbial communities, potentially altering the phytoremediation process. We hypothesized that soil food web complexity (SFWC), represented by increasing levels of soil fauna, influences PAH degradation through interactions with the plant and the microbes. In this study, we demonstrated that SFWC increases the plant biomass and changes the composition of the microbial community, especially the fungal structure. In our pot experiment, more complex levels of SFWC did not contribute to higher degradation rates, but the increased plant biomass and the higher relative abundance of fungal genera associated with lower plant stress could indirectly contribute to better phytoremediation outcomes. Our results highlight the importance of considering the contributions of soil fauna to the success of phytoremediation.
Integrated Analyses of Growth Differentiation Factor-15 Concentration and Cardiometabolic Diseases in Humans
Authors: Lemmelä Susanna , Wigmore Eleanor M. , Benner Christian , Havulinna Aki , Ong Rachel M. Y. , Kempf Tibor , Wollert Kai C. , Blankenberg Stefan , Zeller Tanja , Peters James E. , Salomaa Veikko , Fritsch Maria , March Ruth , Palotie Aarno , Daly Mark , Butterworth Adam S. , Kinnunen Mervi , Paul Dirk S. , Matakidou Athena
Published: December 2021

Growth differentiation factor 15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6,610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across 3 different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant rs1058587 in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine-mapping identified 4 independent putative causal signals at the locus. Mendelian randomisation (MR) analysis did not find evidence of a causal relationship between GDF15 concentration and cardiometabolic traits. Using reverse MR, we identified a potential causal association of body mass index on GDF15 (IVW pFDR=0.0072). Taken together, our data do not support a role for elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.
Delivering HIV pre-exposure prophylaxis (PrEP) care online: A scoping review
Authors: Kincaid Ross , Estcourt Claudia , Frankis Jamie , Dalrymple Jenny , Gibbs Jo
Published: December 2021

Objectives

HIV pre-exposure prophylaxis (PrEP), in which people take HIV medication to prevent HIV acquisition, is a highly effective method of HIV prevention; however, global implementation of PrEP is patchy. PrEP provision will need to be upscaled significantly to achieve UNAIDS/WHO goals of elimination of HIV transmission. Online provision of PrEP care could enhance access to, and delivery of, care at scale. We explored the extent to which PrEP care has been delivered online to inform the development of a novel online PrEP clinic.

Design

Scoping review.

Data sources

Embase, MEDLINE, Web of Science, CINAHL, PsycINFO, ASSIA, PUBMED, Open Grey, and EThOS databases.

Eligibility criteria

English language articles describing a service that delivered one or more element of PrEP-related care online, published from 2009 onwards.

Data extraction and synthesis

Data were extracted using matrices and synthesised using summary statistics and thematic analysis. The Mixed Methods Appraisal Tool was used to assess study quality.

Results

Fifty-nine articles were included: eight randomised controlled trials, 12 non-randomised quantitative studies, 30 descriptive quantitative studies, 14 qualitative studies, and four reviews of online content. Seven studies detailed comprehensive PrEP care pathways that used a combination of online, face-to-face and telephone based care. Of the remaining studies, the majority focused on HIV testing outside a PrEP context. Care tended to be delivered via websites (n=41), video chat, and smartphone apps (both n=10). The acceptability and feasibility of delivering elements of care online was high.

Conclusions

Online PrEP care appears feasible and acceptable, offering convenience and a means to overcome some of the reported barriers to face-to-face care. Services tended to focus on a single element of PrEP-related care or use a combination of online, face-to-face and phone-based care. Additional formative work is needed to inform the development of complete online PrEP care pathways.

Strengths and limitations of this study

This scoping review provides a comprehensive, critical overview of existing literature related to online provision of HIV pre-exposure prophylaxis (PrEP)-related care.

We developed a comprehensive definition of PrEP care which took into consideration all essential elements of care required for safe and appropriate PrEP prescribing.

Established guidelines for conducting and reporting scoping reviews were followed throughout.

We conducted an exhaustive search of nine databases.

The heterogeneity in design and aim of the included studies limited our ability to synthesise findings.
COVID-19 and Indian population: a comparative genetic analysis
Authors: Patil Saurabh , Pemmasani Sandhya Kiran , Chitturi Neelima , Bhatnagar Ishita , Acharya Anuradha , Subash Lingareddy Venkata
Published: December 2021

Background

Major risk factors of COVID-19 include older age, male gender, and comorbidities. In addition, host genetic makeup is also known to play a major role in COVID-19 susceptibility and severity. To assess the genetic predisposition of the Indian population to COVID-19, a comparative analysis of the frequencies of polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and fatal outcomes was done between the Indian population and other major populations (European, African, East Asian, South Asian, and American).

Materials and methods

Polymorphisms directly or potentially associated with COVID-19 susceptibility, severity, immune response, and mortality were mined from genetic association studies, comparative genetic studies, expression quantitative trait loci studies among others. Genotype data of these polymorphisms were either sourced from the GenomegaDB™ database of Mapmygenome India Ltd. (sample size = 3054; Indian origin) or were imputed. Polymorphisms with minor allele frequency >= 0.05 and that are in Hardy-Weinberg equilibrium in the Indian population were considered for allele frequency comparison between the Indian population and 1000 Genome population groups.

Results

Allele frequencies of 421 polymorphisms were found to be significantly different in the Indian population compared to European, African, East Asian, South Asian, and American populations. 128 polymorphisms were shortlisted based on linkage disequilibrium and were analyzed in detail. Apart from well-studied genes, like ACE2, TMPRSS2, ADAM17, and FURIN, variants from AHSG, IFITM3, PTPN2, CD209, CCL5, HEATR9, SELENBP9, AGO1, HLA-G, MX1, ICAM3, MUC5B, CRP, C1GALT1, and other genes were also found to be significantly different in Indian population. These variants might be implicated in COVID-19 susceptibility and progression.

Conclusion

Our comparative study unraveled multiple genetic variants whose allele frequencies were significantly different in the Indian population and might have a potential role in COVID-19 susceptibility, its severity, and fatal outcomes. This study can be very useful for selecting candidate genes/variants for future COVID-19 related genetic association studies.
Comparison of the Immunogenicity of five COVID-19 vaccines in Sri Lanka
Authors: Jeewandara Chandima , Aberathna Inoka Sepali , Danasekara Saubhagya , Gomes Laksiri , Fernando Suranga , Guruge Dinuka , Ranasinghe Thushali , Gunasekera Banuri , Kamaladasa Achala , Kuruppu Heshan , Somathilake Gayasha , Jayamali Jeewantha , Jayathilaka Deshni , Wijayatilake Helanka Dinesh Kumara , Pushpakumara Pradeep Darshana , Harvie Michael , Nimasha Thashmi , de Silva Shiromi Devika Grace , Wijayamuni Ruwan , Schimanski Lisa , Rijal Pramila , Tan Jack , Townsend Alain , Ogg Graham S. , Malavige Gathsaurie Neelika
Published: December 2021

We assessed antibody responses 3 months post-vaccination in those who received mRNA-1273 (n=225), Sputnik V (n=128) or the first dose of Gam-COVID-Vac (n=184) and compared the results with previously reported data of Sinopharm and AZD1222 vaccinees. 99.5% of Moderna >94% of AZD1222 or Sputnik V, 72% to 76% of Gam-COVID-Vac (first dose) and 38.1% to 68.3% of Sinopharm vaccinees had ACE2 blocking antibodies above the positive threshold. The ACE2 blocking antibody levels were highest to lowest was Moderna > Sputnik V/ AZD1222 (had equal levels)> first dose of Gam-COVID-Vac > Sinopharm. All Moderna recipients had antibodies above the positive threshold to the ancestral (WT), B.1.1.7, B.1.351.1 and 80% positivity rate for B.1.617.2. Positivity rates of Sputnik V vaccinees for WT and variants, were higher than AZD1222 vaccinees, while Sinopharm vaccinees had the lowest positivity rates (<16.7%). These findings highlight the need for further studies to understand the effects on clinical outcomes.
A combined transcriptional and dynamic roadmap of single human pancreatic endocrine progenitors reveals proliferative capacity and differentiation continuum
Authors: Beydag-Tasöz Belin Selcen , D’Costa Joyson Verner , Hersemann Lena , Luppino Federica , Kim Yung Hae , Zechner Christoph , Grapin-Botton Anne
Published: December 2021

Basic helix-loop-helix genes, particularly proneural genes, are well-described triggers of cell differentiation, yet limited information exists on their dynamics, notably in human development. Here, we focus on Neurogenin 3 (NEUROG3), which is crucial for pancreatic endocrine lineage initiation. Using a double reporter to monitor endogenous NEUROG3 transcription and protein expression in single cells in 2D and 3D models of human pancreas development, we show peaks of expression for the RNA and protein at 22 and 11 hours respectively, approximately two-fold slower than in mice, and remarkable heterogeneity in peak expression levels all triggering differentiation. We also reveal that some human endocrine progenitors proliferate once, mainly at the onset of differentiation, rather than forming a subpopulation with sustained proliferation. Using reporter index-sorted single-cell RNA-seq data, we statistically map transcriptome to dynamic behaviors of cells in live imaging and uncover transcriptional states associated with variations in motility as NEUROG3 levels change, a method applicable to other contexts.
Can associative learning be the general process for intelligent behavior in non-human animals?
Authors: Lind Johan , Vinken Vera
Published: December 2021

The general process- and adaptive specialization hypotheses represent two contrasting explanations for understanding intelligence in non-human animals. The general process hypothesis proposes that associative learning underlies all learning, whereas the adaptive specialization hypothesis suggests additional distinct learning processes required for intelligent behavior. Here, we use a selection of experimental paradigms commonly used in comparative cognition to explore these hypotheses. We tested if a novel computational model of associative learning — A-learning — could solve the problems presented in these tests. Results show that this formulation of associative learning suffices as a mechanism for general animal intelligence, without the need for adaptive specialization, as long as adequate motor- and perceptual systems are there to support learning. In one of the tests, however, the addition of a short-term trace memory was required for A-learning to solve that particular task. We further provide a case study showcasing the flexibility, and lack thereof, of associative learning, when looking into potential learning of self-control and the development of behavior sequences. From these simulations we conclude that the challenges do not so much involve the complexity of a learning mechanism, but instead lie in the development of motor- and perceptual systems, and internal factors that motivate agents to explore environments with some precision, characteristics of animals that have been fine-tuned by evolution for million of years.

Author summary

What causes animal intelligence? One hypothesis is that, among vertebrates, intelligence relies upon the same general processes for both memory and learning. A contrasting hypothesis states that important aspects of animal intelligence come from species- and problem specific cognitive adaptations. Here, we use a recently formulated model of associative learning and subject it, through computer simulations, to a battery of tests designed to probe cognitive abilities in animals. Our computer simulations show that this associative learning model can account well for how animals learn these various tasks. We conclude that a major challenge in understanding animal and machine intelligence lies in describing behavior systems. Specifically, how motor flexibility and perceptual systems together with internal factors allow animals and machines to navigate the world. As a consequence of our results, together with current progress in both animal- and machine learning, we cannot reject the idea that associative learning provides a general process for animal intelligence.
METTL3 facilitates hepatic fibrosis progression via m6A-YTHDF2 dependent silencing of GPR161
Authors: Pan Xue-yin , Bi Yi-hui , Cheng Miao , Qian Zhen-zhen , Wang Ling , You Hong-mei , Liu Lei , Zhang Zhen-hua , Meng Xiao-ming , Huang Cheng , Li Jun
Published: December 2021

Hepatic fibrosis (HF) is a very common condition seen in millions of patients with various liver diseases. N6-methyladenosine (m6A) plays critical roles in various biological and pathological processes. However, the role of m6A and its main methyltransferase METTL3 in HF remains obscure. Here, we reported that METTL3 expression was elevated in HSCs from CCl4 induced fibrotic liver. METTL3 knockdown in HSCs mediated by recombinant adeno-associated-virus serotype 9 packed short hairpin RNA against METTL3 alleviated liver injury and fibrosis compared to empty carrier group. Mechanistically, the decreased liver fibrosis in CCl4-treated HSC-specific METTL3 knockdown mice was due to the increased GPR161 that is a suppressor of Hedgehog pathway, a well-known pathway to activate in liver injury and regeneration. As expect, GPR161 transferred into HSCs alleviated liver fibrosis and HSC activation. Forced GPR161 expression inhibited Gli3 activated form nuclear accumulation and subsequently suppressed fibrosis-associate gene expression. Conclusion, HSC-specific deletion of METTL3 inhibits liver fibrosis via elevated GPR161 expression, which subsequently suppressed Hedgehog pathway activation and fibrosis-associated genes expression, providing novel therapeutic targets for HF therapy.

Synopsis

The role of RNA m6A methyltransferase METTL3 in the progression of hepatic fibrosis is unclear. Here, we reveal that suppresses m6A modification by depletion of METTL3 in Hepatic Stellate Cells (HSCs), stabilizes the GPR161 transcripts, that involved in suppressing Hedgehog signaling pathway, through YTHDF2, thereby alleviating the fibrosis feature of CCl4-induced liver injury.

Disruption of m6A methyltransferases METTL3 in HSCs alleviates liver fibrosis feature.

METTL3 depletion in liver HSCs suppresses its activation by suppressing Hedgehog signaling pathway through stabilizing GPR161 transcripts in an m6A-YTHDF2 dependent manner.

GPR161 activates PKA that mediates phosphorylation and degradation of full-length Gli3 (Gli3-FL) protein, then the short Gli3 (Gli3-R) translocated into the nucleus and suppresses the fibrosis associated gene transcription.

The elevated METTL3 expression is attribute to its promoter H3K27ac modification.
Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice
Authors: Fielder Edward , Wan Tengfei , Alimohammadiha Ghazaleh , Ishaq Abbas , Low Evon , Weigand B. Melanie , Kelly George , Parker Craig , Griffin Brigid , Jurk Diana , Korolchuk Viktor I. , von Zglinicki Thomas , Miwa Satomi
Published: December 2021

Cancer survivors suffer from progressive frailty, multimorbidity and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting.

Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year. Treatments commencing within a month after irradiation effectively reduced frailty progression (p<0.05) and improved muscle (p<0.01) and liver (p<0.05) function as well as short-term memory (p<0.05) until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty (p<0.05) and short-term memory (p<0.05). Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells.

Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.
Automated identification of chicken distress vocalisations using deep learning models
Authors: Mao Axiu , Giraudet Claire , Liu Kai , De Almeida Nolasco Inês , Xie Zhiqin , Xie Zhixun , Gao Yue , Theobald James , Bhatta Devaki , Stewart Rebecca , McElligott Alan G.
Published: December 2021

The annual global production of chickens exceeds 25 billion birds, and they are often housed in very large groups, numbering thousands. Distress calling triggered by various sources of stress has been suggested as an “iceberg indicator” of chicken welfare. However, to date, the identification of distress calls largely relies on manual annotations, which is very labour-intensive and time-consuming. Thus, a novel light-VGG11 was developed to automatically identify chicken distress calls using recordings (3,363 distress calls and 1,973 natural barn sounds) collected on intensive chicken farms. The light-VGG11 was modified from VGG11 with a significantly smaller size in parameters (9.3 million vs 128 million) and 55.88% faster detection speed while displaying comparable performance, i.e., precision (94.58%), recall (94.89%), F1-score (94.73%), and accuracy (95.07%), therefore more useful for model deployment in practice. To further improve the light-VGG11’s performance, we investigated the impacts of different data augmentation techniques (i.e., time masking, frequency masking, mixed spectrograms of the same class, and Gaussian noise) and found that they could improve distress calls detection by up to 1.52%. In terms of precision livestock farming, our research opens new opportunities for developing technologies used to monitor the output of distress calls in large, commercial chicken flocks.
mslp: a comprehensive pipeline in predicting cancer mutations specific synthetic lethal partners
Authors: Shao Chunxuan
Published: December 2021

Background

Mutation specific synthetic lethal partners (SLPs) offer significant insights in identifying novel targets and designing personalized treatments in cancer studies. Large scale genetic screens in cell lines and model organisms provide crucial resources for mining SLPs, yet those experiments are expensive and might be difficult to set up. Various computational methods have been proposed to predict the potential SLPs from different perspectives. However, those efforts are hampered by the low signal-to-noise ratio in simple correlation based approaches, or incomplete reliable training sets in supervised approaches.

Results

Here we present mslp, a comprehensive pipeline to identify potential SLPs via integrating genomic and transcriptomic datasets from both patient tumours and cancer cell lines. Leveraging cuttingedges algorithms, we identify a broad spectrum of primary SLPs for mutations presented in patient tumours. Further, for mutations detected in cell lines, we develop the idea of consensus SLPs which are also identified as screen hits, and show consistency impact on cell viability. Applied in real datasets, we successfully identified known synthetic lethal gene pairs. Remarkably, genetic screen results suggested that consensus SLPs have a significant impact on cell viability compared to common hits.

Conclusions

Mslp is a powerful and flexible pipeline to identify potential SLPs in a cancer context-specific manner, which might aid in drug developments and precise medicines in cancer treatments. The pipeline is implemented in R and freely available in github.
Reciprocity between retrograde signal and putative metalloprotease reconfigures plastidial metabolism and structure
Authors: Wang Jin-Zheng , van de Ven Wilhelmina , Xiao Yanmei , He Xiang , Ke Haiyan , Yang Panyu , Dehesh Katayoon
Published: December 2021

Reconfiguration of the plastidial proteome in response to environmental inputs is central to readjustment of its metabolic and structural states. This is necessary for the functionality of this metabolic hub, and the maintenance of organismal integrity. This report establishes the role of the plastidial retrograde signaling metabolite, MEcPP, in increasing the abundance of the putative plastidial metalloprotease (VIR3), and the ensuing decline of VIR3 target enzymes, ascorbate peroxidase and glyceraldehyde 3-phophate dehydrogenase B. The decreased abundance of these enzymes is linked to increased levels of their substrates: H2O2, an elicitor of salicylic acid production and stromule formation; and G3P the substrate for MEcPP synthesis. High-light treatment of wild type plants recapitulated the VIR3-associated reconfiguration of the plastidial metabolic and structural states. These results identify a previously unrecognized link between the stress-induced plastidial retrograde signaling metabolite and a putative zinc-binding metalloprotease. Moreover, the data reveal that the reciprocity between these two components, results in the reconfiguration of the metabolic and structural states of the plastid, deemed necessary to maintain cellular integrity and to shape adaptive responses.
Leptomeningeal Enhancement in Multiple Sclerosis and Other Neurological Diseases: A Systematic Review and Meta-Analysis
Authors: Ineichen Benjamin V. , Tsagkas Charidimos , Absinta Martina , Reich Daniel S.
Published: December 2021

Background

The lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings.

Purpose

To perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases.

Materials and Methods

In a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS.

Results

Of eligible publications, 161 investigated LME in neoplastic neurological (n=2392), 91 in neuroinfectious (n=1890), and 75 in primary neuroinflammatory diseases (n=4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37–0.57], 0.59 [95%-CI: 0.47–0.69], and 0.26 [95%-CI: 0.20–0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21–0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13–0.27]) compared to progressive MS (0.39 [95%-CI 0.30–0.49], p=0.002) and higher proportions in studies imaging at 7T (0.79 [95%-CI 0.64–0.89]) compared to lower field strengths (0.21 [95%-CI 0.15–0.29], p<0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2–4.2], p=0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2–1.0], p=0.006), higher T1 (mean difference 1.6ml [95%-CI 0.1–3.0], p=0.04) and T2 lesion load (mean difference 5.9ml [95%-CI 3.2–8.6], p<0.001), and lower cortical volume (mean difference −21.3ml [95%-CI −34.7–-7.9], p=0.002).

Conclusions

Our study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS.

PROSPERO No: CRD42021235026.

Summary statement

Our systematic review and meta-analysis synthesize leptomeningeal enhancement proportions across a comprehensive panel of neurological diseases, including multiple sclerosis, and assesses its prognostic value in multiple sclerosis.

Summary data

Leptomeningeal enhancement (LME) is a nonspecific imaging feature present across many neurological disorders, including neoplasm, infection, and primary neuroinflammation.

The presence of LME is associated with worse clinical and imaging outcomes in multiple sclerosis, justifying its ascertainment in clinical practice.

Neuroinflammatory animal models can be used to further investigate the pathophysiology of LME, including its pathological tissue signature and/or its association with cortical pathology.
Differential requirement for the EDS1 catalytic triad inA. thalianaandN. benthamiana
Authors: Zönnchen Josua , Gantner Johannes , Lapin Dmitry , Barthel Karen , Eschen-Lippold Lennart , Zantop Stefan , Kretschmer Carola , Parker Jane E. , Guerois Raphael , Stuttmann Johannes
Published: December 2021

Heterodimeric complexes incorporating the lipase-like proteins EDS1 with PAD4 or SAG101 are central hubs in plant innate immunity. EDS1 functions encompass signal relay from TIR domain-containing intracellular NLR-type immune receptors (TNLs) towards RPW8-type helper NLRs (RNLs) and, inA. thaliana, bolstering of signaling and resistance mediated by cell-surface pattern recognition receptors (PRRs). Biochemical activities underlying these mechanistic frameworks remain unknown.

We used CRISPR/Cas-generated mutant lines and agroinfiltration-based complementation assays to interrogate functions of EDS1 complexes inN. benthamiana.

We do not detect impaired PRR signaling inN. benthamianalines deficient in EDS1 complexes or RNLs. Intriguingly, mutations within the catalytic triad ofSolanaceaeEDS1 can abolish or enhance TNL immunity inN. benthamiana. Furthermore, nuclear EDS1 accumulation is sufficient forN. benthamianaTNL (Roq1) immunity.

Reinforcing PRR signaling in Arabidopsis might be a derived function of the TNL/EDS1 immune sector. Dependency ofSolanaceaebut notA. thalianaEDS1 on catalytic triad residues raises the possibility that a TNL-derived small molecule binds to theSolanaceaeEDS1 lipase-like domain, and that EDS1 lipase-like domain pocket contributions to TNL immune responses vary between lineages. Whether and how nuclear EDS1 activity connects to membrane pore-forming RNLs remains unknown.
Enabling inference for context-dependent models of mutation by bounding the propagation of dependency
Authors: Matsen Frederick A , Ralph Peter L
Published: December 2021

Although the rates at which positions in the genome mutate are known to depend not only on the nucleotide to be mutated, but also on neighboring nucleotides, it remains challenging to do phylogenetic inference using models of context-dependent mutation. In these models, the effects of one mutation may in principle propagate to faraway locations, making it difficult to compute exact likelihoods. This paper shows how to use bounds on the propagation of dependency to compute likelihoods of mutation of a given segment of genome by marginalizing over sufficiently long flanking sequence. This can be used for maximum likelihood or Bayesian inference. Protocols examining residuals and iterative model refinement are also discussed. Tools for efficiently working with these models are provided in an R package, that could be used in other applications. The method is used to examine context dependence of mutations since the common ancestor of humans and chimpanzee.
Mitotic spindle formation in the absence of Polo kinase
Authors: Kim Juyoung , Goshima Gohta
Published: December 2021

Mitosis is a fundamental process in every eukaryote, in which chromosomes are segregated into two daughter cells by the action of the microtubule (MT)-based spindle. Despite this common principle, genes essential for mitosis are variable among organisms. This indicates that the loss of essential genes or bypass-of-essentiality (BOE) occurred multiple times during evolution. While many BOE relationships have been recently revealed experimentally, the BOE of mitosis regulators (BOE-M) has been scarcely reported and how this occurs remains largely unknown. Here, by mutagenesis and subsequent evolutionary repair experiments, we isolated viable fission yeast strains that lacked the entire coding region of Polo-like kinase (Plk), a versatile essential mitotic kinase. The BOE of Plk was enabled by specific mutations in the downstream machinery, including the MT-nucleating γ-tubulin complex, and more surprisingly, through downregulation of glucose uptake, which is not readily connected to mitosis. The latter bypass was dependent on casein kinase I (CK1), which has not been considered as a major mitotic regulator. Our genetic and phenotypic data suggest that CK1 constitutes an alternative mechanism of MT nucleation, which is normally dominated by Plk. A similar relationship was observed in a human colon cancer cell line. Thus, our study shows that BOE-M can be achieved by simple genetic or environmental changes, consistent with the occurrence of BOE-M during evolution. Furthermore, the identification of BOE-M constitutes a powerful means to uncover a hitherto under-studied mechanism driving mitosis and also hints at the limitations and solutions for selecting chemotherapeutic compounds targeting mitosis.
Waning of mRNA-1273 vaccine effectiveness against SARS-CoV-2 infection in Qatar
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Ayoub Houssein H. , Yassine Hadi M. , Benslimane Fatiha M. , Al Khatib Hebah A. , Tang Patrick , Hasan Mohammad R. , Coyle Peter , Kanaani Zaina Al , Kuwari Einas Al , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul Rahim Hanan F. , Nasrallah Gheyath K. , Al Kuwari Mohamed Ghaith , Butt Adeel A. , Al Romaihi Hamad Eid , Al-Thani Mohamed H. , Khal Abdullatif Al , Bertollini Roberto
Published: December 2021

BACKGROUND

In early 2021, Qatar launched a mass immunization campaign with Moderna’s mRNA-1273 COVID-19 vaccine. We assessed persistence of real-world mRNA-1273 effectiveness against SARS-CoV-2 infection and against COVID-19 hospitalization and death.

METHODS

Effectiveness was estimated using test-negative, case-control study design, between January 1 and December 5, 2021. Effectiveness was estimated against documented infection (a PCR-positive swab, regardless symptoms), and against any severe (acute-care hospitalization), critical (ICU hospitalization), or fatal COVID-19.

RESULTS

By December 5, 2021, 2,962 breakthrough infections had been recorded among those who received two mRNA-1273 doses. Of these infections, 19 progressed to severe COVID-19 and 4 to critical, but none to fatal disease. mRNA-1273 effectiveness against infection was negligible for the first two weeks after the first dose, increased to 65.5% (95% CI: 62.7-68.0%) 14 or more days after the first dose, and reached its peak at about 90% in the first three months after the second dose. Effectiveness declined gradually starting from the fourth month after the second dose and was below 50% by the 7th month after the second dose. Effectiveness against severe, critical, or fatal COVID-19 reached its peak at essentially 100% right after the second dose, and there was no evidence for declining effectiveness over time. Effectiveness against symptomatic versus asymptomatic infection demonstrated the same pattern of waning, but effectiveness against symptomatic infection was consistently higher than that against asymptomatic infection and waned more slowly.

CONCLUSIONS

mRNA-1273-induced protection against infection appears to wane month by month after the second dose. Meanwhile, protection against hospitalization and death appears robust with no evidence for waning for several months after the second dose.
Modeling a unit cell: crystallographic refinement procedure using the biomolecular MD simulation platform Amber
Authors: Mikhailovskii Oleg , Xue Yi , Skrynnikov Nikolai R.
Published: December 2021

A procedure has been developed for the refinement of crystallographic protein structures based on the biomolecular simulation program Amber. The procedure constructs a model representing a crystal unit cell, which generally contains multiple protein molecules and is fully hydrated with TIP3P water. Periodic boundary conditions are applied to the cell in order to emulate the crystal lattice. The refinement is conducted in the form of a specially designed short molecular-dynamics run controlled by the Amber ff14SB force field and the maximum-likelihood potential that encodes the structure-factor-based restraints. The new Amber-based refinement procedure has been tested on a set of 84 protein structures. In most cases, the new procedure led to appreciably lower R
free values compared with those reported in the original PDB depositions or obtained by means of the industry-standard phenix.refine program. In particular, the new method has the edge in refining low-accuracy scrambled models. It has also been successful in refining a number of molecular-replacement models, including one with an r.m.s.d. of 2.15 Å. In addition, Amber-refined structures consistently show superior MolProbity scores. The new approach offers a highly realistic representation of protein–protein interactions in the crystal, as well as of protein–water interactions. It also offers a realistic representation of protein crystal dynamics (akin to ensemble-refinement schemes). Importantly, the method fully utilizes the information from the available diffraction data, while relying on state-of-the-art molecular-dynamics modeling to assist with those elements of the structure that do not diffract well (for example mobile loops or side chains). Finally, it should be noted that the protocol employs no tunable parameters, and the calculations can be conducted in a matter of several hours on desktop computers equipped with graphical processing units or using a designated web service.
Synthesis and crystal structures of three Schiff bases derived from 3-formylacetylacetone ando-,m- andp-aminobenzoic acid
Authors: Halz Jan Henrik , Hentsch Andreas , Wagner Christoph , Merzweiler Kurt
Published: December 2021

Treatment of 3-formylacetylacetone with the isomerico-,m- andp-aminobenzoic acids led to the formation of the corresponding Schiff bases, namely, 3-[(2-carboxyphenylamino)methylidene]pentane-2,4-dione,1, 3-[(3-carboxyphenylamino)methylidene]pentane-2,4-dione,2, and 3-[(4-carboxyphenylamino)methylidene]pentane-2,4-dione,3, all C13H13NO4, that contain a planar amino-methylene-pentane-2,4-dione core with a strong intramolecular N—H...O hydrogen bridge. The carboxyphenyl groups attached to the nitrogen atom are almost coplanar to the central molecular fragment. Depending on the position of the carboxyl unit, different supramolecular structures with hydrogen-bonding networks are formed in the three title structures.
rac-(2aS,2a1
R,3aR,3a1
S,5aS,6aR)-2a-Allyl-2,4-dichloro-2a,2a1,3a1,5a,6,6a-hexahydro-3aH-3-oxadicyclopenta[cd,gh]pentalen-3a-ol
Authors: Kotha Sambasivarao , Ansari Saima , Gupta Naveen Kumar
Published: December 2021

The title racemic triquinane, C14H14Cl2O2, is composed of four five-membered rings, one of which is a tetrahydrofuran ring to which an allyl group on one side and a hydroxyl group on the other side are attached. The core of the triquinane unit has a cis–syn–cis configuration. In the crystal, the molecules are linked by pairwise O—H...O hydrogen bonds, generating inversion dimers featuring R
2
2(8) loops.
Color, microstructure, physicochemical, textural and sensory properties with the retention of secondary metabolites in convective-, microwave- and freeze-dried carrot (Daucus carota) slices
Authors: Yildiz Gulcin
Published: December 2021

Purpose

This work was undertaken to evaluate the impact of different drying methods (convective, microwave and freeze drying) on color, selected secondary metabolites (total phenolic substances, ascorbic acid, beta-carotene and antioxidant capacity), texture (hardness), sensory properties and microstructure of carrot slices.

Design/methodology/approach

Convective drying at three different temperatures (55, 65 and 75 °C), microwave drying at two different power levels (100 and 200 W) and freeze drying were applied.

Findings

Significant differences were found among fresh and dried-carrot slices. Convective-dried carrots showed better quality characteristics in comparison with microwave-dried carrots. The convective-dried carrots at 65 °C exhibited the highest retention of bioactive compounds and best color among all convective drying conditions. The microwave-dried carrot slices at lower power (100 W) showed higher quality characteristics compared to the dried carrots at 200 W. The freeze-dried carrots exhibited the highest retention of secondary metabolites, sensory properties and best color among all drying methods.

Originality/value

The results from this study are significant for the processing of dried carrots by optimizing the conditions to obtain a high-quality product. Overall, freeze drying is a promising application as shown in the present study by its capability to better retention carrot quality underlying color, sensory, texture, microstructure and secondary metabolites.
The challenges of presenting traditional music in gastronomic establishments – the case of Slovenian Istria
Authors: Sedmak Gorazd
Published: December 2021

Purpose

Through investigation and comparisons between tourists and restaurant managers regarding their understanding of traditional music and their attitudes, expectations and assigned importance to it, this paper aims to identify the most problematic aspects of the (non)inclusion of traditional music in restaurant settings in tourist destinations.

Design/methodology/approach

Data were collected through a field survey of tourists and managers/owners of catering establishments in the four municipalities of Slovenian Istria.

Findings

The results show that tourists attach a relatively high importance to this element of cultural heritage and that it is not sufficiently included in the overall product of the destination and in the catering establishments. Differences in the understanding of traditional music between the two groups were also found.

Research limitations/implications

The research limitations are, namely, a relatively small sample of managers for the quantitative analysis, the particular nature of the chosen destination which does not allow generalization of the results and finally, the study was conducted in the high season when the structure of tourists is significantly different compared to that in the mid and low season.

Practical implications

The findings bring some useful insights into tourists’ expectations and understanding of traditional music as part of the tourism experience for catering establishments’ managers and destination management organizations. By addressing the identified gaps, they can enrich the overall tourism product of the destination, while catering operators can achieve better business results.

Social implications

The more frequent and cogent inclusion of traditional music in the hospitality sector would provide a new social function and raison d'être for this segment of cultural heritage, which is in danger of being forgotten in many tourist destinations.

Originality/value

This research addresses a widely overlooked area of two interrelated fields of research, namely, hospitality and cultural heritage. Unlike the majority of previous research on this topic, which only involves actual guests, the present research is designed as a comprehensive investigation and comparison of the attitudes of the general population of actual tourists in the destination (as potential guests of the inns/restaurants) and managers of catering businesses operating in the destination.