bluuebunny/crossref_metadata_2025 huggingface dataset:
Luigi Luca Cavalli-Sforza. 25 January 1922—31 August 2018
Authors: Edwards A. W. F.
Published: March 2021

Though it was as a bacteriologist that Luca Cavalli-Sforza first flourished scientifically, it was the subject of human population genetics that he dominated for the second half of the twentieth century. He pioneered both genetical demography and the construction of the genetical evolutionary tree of man, initially from gene-frequency data and ultimately from tracing the paths of descent of individual DNA sequences. He was among the first to apply the new computers to the problems he encountered, using his self-taught knowledge of mathematics and statistics. He conducted expeditions to the Pygmies of the African rainforest and studied the spread of agriculture in Europe, demonstrating the similarity between its wave of advance and the contours of population gene frequency. He noted the correspondence between the descent tree of languages and the human evolutionary tree.

Cavalli headed university departments in Pavia and then Stanford, surrounding himself with young colleagues and driving forward research with vigorous discussion and unceasing enthusiasm. His knowledge was spread across medicine and genetics, anthropology and linguistics, archaeology and history, and he expressed himself fluently in speech and writing in Italian, English and French. A true Renaissance man.

His published work in human population genetics and cultural evolution over more than 50 years constituted ‘one long argument’, as Darwin said ofThe origin of species. The villages of the Parma valley were his Galapagos Islands, and random genetic drift his adjunct to natural selection for the case of man. His demonstration of the importance of drift in recent human evolution informed the model for constructing evolutionary trees from gene-frequency data. On this one long argument he wrote and lectured ceaselessly, not only for other scientists but also for a wider audience, always mindful of a responsibility to promote an understanding of man's biology and evolutionary history for society's benefit. In so doing he brought an informed and rational approach to the problem of human diversity and the problems of human diversity.
Safety and Immunogenicity Evaluation of Inactivated whole-virus-SARS-COV-2 As Emerging Vaccine Development In Egypt
Authors: Saleh Amani A. , Saad Mohamed A. , Ryan Islam , Amin Magdy , Shindy Mohamed I. , Hassan Wael A. , Samir Mahmoud , Khattab Ayman A. , Abdelgayed Sherein S. , Seadawy Mohamed G. , Fahmy Hossam M. , Amer Khaled
Published: March 2021

The current worldwide pandemic COVID-19 is causing severe human health problems, with high numbers of mortality rates and huge economic burdens that require an urgent demand for safe, and effective and vaccine development. Our study was the first trail to development and evaluation of safety and immune response to inactivated whole SARS-COV-2 virus vaccine adjuvanted with aluminium hydroxide. We used characterized SARS-COV-2 strain, severe acute respiratory syndrome coronavirus 2 isolates(SARS-CoV-2/human/EGY/Egy-SERVAC/2020)with accession numbers;MT981440;MT981439; MT981441; MT974071; MT974069 and MW250352at GenBank that isolated from Egyptian patients SARS-CoV-2-positive. Development of the vaccine was carried out in a BSL - 3 facilities and the immunogenicity was determined in mice at two doses (55µg and 100µg per dose). All vaccinated mice were received a booster dose 14 days post first immunization. Our results demonstrated distinct cytopathic effect on the vero cell monolayers induced through SARS-COV-2 propagation and the viral particles were identified as Coronaviridae by transmission electron microscopy. SARS-CoV-2 was identified by RT-PCR performed on the cell culture. Immunogenicity of the developed vaccine indicated the high antigen-binding and neutralizing antibody titers, regardless the dose concentration, with excellent safety profiles.However, no deaths or clinical symptoms in mice groups. The efficacy of the inactivated vaccine formulation was tested by wild virus challenge the vaccinated mice and detection of viral replication in lung tissues. Vaccinated mice recorded complete protection from challenge infection three weeks post second dose. SARS-COV-2 replication was not observed in the lungs of mice following SARS-CoV-2 challenge, regardless of the level of serum neutralizing antibodies. This finding will support the future trials for evaluation an applicable SARS-CoV-2 vaccine candidate.
Geminiviral genomes encode additional proteins with specific subcellular localizations and virulence function
Authors: Gong Pan , Tan Huang , Zhao Siwen , Li Hao , Liu Hui , Ma Yu , Zhang Xi , Rong Junjie , Fu Xing , Lozano-Durán Rosa , Li Fangfang , Zhou Xueping
Published: March 2021

Geminiviruses are plant viruses with limited coding capacity. Geminivirus-encoded proteins were identified applying a 10-kDa arbitrary threshold; however, it is increasingly clear that small proteins play relevant roles in biological systems, which calls for the reconsideration of this criterion. Here, we show that geminiviral genomes contain additional ORFs. Using tomato yellow leaf curl virus, we demonstrate that some of these novel ORFs are expressed during the infection, and that the encoded proteins display specific subcellular localizations. We prove that the largest of these new ORFs, which we name V3, is required for full viral infection, and that the V3 protein localizes in the Golgi apparatus and functions as an RNA silencing suppressor. These results imply that the repertoire of geminiviral proteins can be expanded, and that getting a comprehensive overview of the molecular plant-geminivirus interactions will require the detailed study of small ORFs so far neglected.
Synthetic algal-bacteria consortia for space-efficient microalgal growth in a simple hydrogel system
Authors: Martin Noah , Bernat Tatum , Dinasquet Julie , Stoftko Andrea , Damon April , Deheyn Dimitri D. , Azam Farooq , Smith Jennifer E. , Davey Matthew P. , Smith Alison G. , Vignolini Silvia , Wangpraseurt Daniel
Published: March 2021

Photosynthetic microalgae are an attractive source of food, fuel or nutraceuticals, but commercial production of microalgae is limited by low spatial efficiency. In the present study, we developed a simple photosynthetic hydrogel system that cultivates the green microalga,Marinichlorella kaistiaeKAS603, together with a novel strain of the bacteriaErythrobactersp.. We tested the performance of the co-culture in the hydrogel using a combination of chlorophyll-afluorimetry, microsensing and bio-optical measurements. Our results showed that growth rates in algal-bacterial hydrogels were about 3-fold enhanced compared to hydrogels with algae alone. Chlorophyll-afluorimetry based light curves found that electron transport rates were enhanced about 20% for algal-bacterial hydrogels compared to algal hydrogels for intermediate irradiance levels. We also show that the living hydrogel is stable under different environmental conditions and when exposed to natural seawater. Our study provides a potential bio-inspired solution for problems that limit the space-efficient cultivation of microalgae for biotechnological applications.
Factors influencing maternal microchimerism throughout infancy and its impact on infant T cell immunity
Authors: Balle Christina , Armistead Blair , Kiravu Agano , Song Xiaochang , Happel Anna-Ursula , Hoffmann Angela , Kanaan Sami B. , Nelson J. Lee , Gray Clive M. , Jaspan Heather B. , Harrington Whitney E.
Published: March 2021

Determinants of the acquisition and maintenance of maternal microchimerism (MMc) during infancy and the impact of MMc on infant immune responses are unknown. We examined factors which influence MMc detection and level across infancy and the effect of MMc on T cell responses to BCG vaccination in a cohort of HIV exposed, uninfected and HIV unexposed infants in South Africa. MMc was measured in whole blood from 58 infants using a panel of quantitative PCR assays at day one and 7, 15, and 36 weeks of life. Infants received BCG at birth, and selected whole blood samples from infancy were stimulated in vitro with BCG and assessed for polyfunctional CD4+ T cell responses. MMc was present in most infants across infancy with levels ranging from 0-1,193/100,000 genomic equivalents and was positively impacted by absence of maternal HIV, maternal-infant HLA compatibility, infant female sex, and exclusive breastfeeding. Initiation of maternal antiretroviral therapy prior to pregnancy partially restored MMc level in HIV exposed, uninfected infants. Birth MMc was associated with an improved polyfunctional CD4+ T cell response to BCG. These data emphasize that both maternal and infant factors influence the level of MMc, which may subsequently impact infant T cell responses.

Abstract Figure
Altered Subgenomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections
Authors: Parker Matthew D , Lindsey Benjamin B. , Shah Dhruv R , Hsu Sharon , Keeley Alexander J , Partridge David G , Leary Shay , Cope Alison , State Amy , Johnson Katie , Ali Nasar , Raghei Rasha , Heffer Joe , Smith Nikki , Zhang Peijun , Gallis Marta , Louka Stavroula F , Hornsby Hailey R , Whiteley Max , Foulkes Benjamin H , Christou Stella , Wolverson Paige , Pohare Manoj , Hansford Samantha E , Green Luke R , Evans Cariad , Raza Mohammad , Wang Dennis , Gaudieri Silvana , Mallal Simon ,   The COVID-19 Genomics UK (COG-UK) consortium, de Silva Thushan I.
Published: March 2021

SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median expression. We hypothesise that this is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT>CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.

One Sentence Summary

The recently emerged and more transmissible SARS-CoV-2 lineage B.1.1.7 shows greater subgenomic RNA expression in clinical infections and enhanced expression of a noncanonical subgenomic RNA near ORF9b.
Uncovered genetic diversity inHemidactylus mabouia(Reptilia: Gekkonidae) from Madeira Island reveals uncertain sources of introduction
Authors: Rato Catarina , Martins Beatriz , Rocha Ricardo , Silva-Rocha Iolanda
Published: March 2021

Hemidactylus mabouiais one of the most widely distributed species within its genus. It was first reported to Madeira in 2002 and the first individuals were considered to have originated from Cape Verde. Almost 20 years later, we found thatH. mabouiahas substantially expanded its distribution and can now be found >10 km away from Funchal, where it was first reported. Based on a 12S phylogenetic analysis and using 29 individuals from Funchal and Câmara de Lobos we found that Madeira actually harbours two distinct lineages ofH. mabouia: one exclusively South American and another widespread in America and Africa. However, the lack of genetic diversity typical of this species outside its native range and the obtained phylogenetic pattern prevent us to infer possible introduction routes or sources. Our study emphasizes that authorities should remain vigilant regarding the arrival of other non-natives and act to prevent their establishment as soon as they are detected.
Olanzapine leads to nonalcoholic fatty liver disease through the apolipoprotein A5 pathway
Authors: Li Rong , Zhu Wenqiang , Huang Piaopiao , Yang Yang , Luo Fei , Dai Wen , Shen Li , Pei Wenjing , Huang Xiansheng
Published: March 2021

The antipsychotic drug olanzapine was reported to induce nonalcoholic fatty liver disease (NAFLD), whereas the underlying mechanism remains incompletely understood. This study investigated whether apolipoprotein A5 (apoA5) and sortilin, two interactive factors involved in NAFLD pathogenesis, are implicated in olanzapine-induced NAFLD. In the present study, at week 8, olanzapine treatment successfully induced hepatic steatosis in male C57 BL/6J mice, even when fed a normal chow diet, which was independent of animal body weight gain. Likewise, olanzapine effectively mediated hepatocyte steatosis in human HepG2 cellsin vitro, characterized by substantially elevated intracellular lipid droplets. Increased plasma triglyceride concentration and decreased plasma apoA5 levels were observed in mice treated for 8 weeks with olanzapine. Surprisingly, olanzapine markedly enhanced hepatic apoA5 protein levels in mice, without a significant effect on rodent hepaticApoA5mRNA expression. Ourin vitrostudy showed that olanzapine reduced apoA5 protein levels in the medium and enhanced apoA5 protein expression in hepatocytes, whereas this drug exerted no effect on hepatocyteAPOA5mRNA expression. By transfectingAPOA5siRNA into HepG2 cells, it was demonstrated thatAPOA5knockdown effectively reversed olanzapine-induced hepatocyte steatosis. In addition, olanzapine drastically increased sortilin mRNA and protein levelsin vivoandin vitro. Interestingly,SORT1knockdown reduced intracellular apoA5 protein expression and increased medium apoA5 protein levelsin vitro, without affecting intracellularAPOA5mRNA expression. Furthermore,SORT1knockdown greatly ameliorated hepatocyte steatosisin vitro. This study provides the first evidence that sortilin inhibits the hepatic apoA5 secretion that is attributable to olanzapine-induced NAFLD, which provides new insight into effective strategies against NAFLD for patients with schizophrenia administered olanzapine.
An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation
Authors: Kitao Koichi , Nakagawa So , Miyazawa Takayuki
Published: March 2021

Retroviruses utilize multiple unique RNA elements to control several aspects of RNA processing, such as splicing, subcellular export, and translation. However, it is mostly unclear whether such functional RNA elements are present in endogenous retroviruses (ERVs), many of which were inserted into the host genomes millions of years ago. Previously, in human ERV-derivedsyncytin-1gene, we found acis-acting RNA element named SPRE that enhances its protein expression. In this study, we found a 17-nt common sequence in SPRE ofsyncytin-1and another ERV-derived gene,syncytin-2, and the sequence is confirmed to be essential for the expression of the proteins. We detected the sequences of SPRE-like elements in 41 ERV families. Though the SPRE-like elements were not found in currently prevailing (i.e.exogenous) viral sequences, more than thousands of copies of the elements were found in several mammalian genomes, suggesting the ancient integration and propagation of the SPRE-harboring retroviruses in mammalian lineages. Indeed, other mammalian ERV-derived genes:mac-syncytin-3of macaque,syncytin-Ten1of tenrec, andsyncytin-Car1of Carnivora contain the SPRE-like elements, and we validated their function for efficient protein expression byin vitroassays. A reporter assay revealed that the enhancement of gene expression by SPRE depended on reporter genes. Moreover, the mutation in SPRE did not affect the gene expression in codon-optimizedsyncytin-2. However, the same mutation in SPRE impaired the gene expression in wild-typesyncytin-2, suggesting that the SPRE dependency of Syncytin-2 expression is due to the negative factors such as inefficient codon frequency or repressive elements within the coding sequence. These results provide new implications that ERVs harbor unique RNA elements involved in the regulation of ERV-derived genes.
Methylation-mediated retuning on the enhancer-to-silencer activity scale of networked regulatory elements guides driver-gene misregulation
Authors: Edrei Y. , levy R. , Marom A. , Radlwimmer B. , Hellman A.
Published: March 2021

Cancers arise when particular disease-driving genes adopt abnormal functions, but analyses of coding and regulatory sequences leave many of these abnormalities unexplained. We developed a strategy to explore alternations in the regulatory effects of silencers and enhancers in cancer tumors. Applying the method to 177 gene regulatory domains in human glioblastomas, we produced a driver-gene wide dataset of gene-associated, functional regulatory elements. Many genes were controlled by cis-regulatory networks composed of multiple regulatory elements, each of them providing a defined positive or negative input to the overall regulatory output of the network. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints within wide ranges of potential regulatory effects, varying between strong transcriptional enhancing to strong silencing. Extensive analysis of methylation-expression associations reveals the organization of domain-wide cis-regulatory networks, and highlighted key regulatory sites which provide pivotal contributions to the network outputs. Consideration of these effects through mathematical models of gene expression variations signified prime molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Of the observed gene-malfunctioning events, gene misregulation due to epigenetic retuning of networked enhancers and silencers dominated driver-genes mutagenesis, compared with other types of mutation including coding or regulatory sequence alterations. Elucidation of this gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases.
Reduced PTPRD expression differentially alters brain phosphotyrosine phosphoproteomic profiles of 2 and 12 month-old mice
Authors: Uhl George R , Henderson Ian M , Martinez Maria , Stokes Matthew P
Published: March 2021

The receptor type protein tyrosine phosphatase PTPRD is implicated in maturation of synapses of expressing neurons, vulnerability to addictions, reward from addictive substances, vulnerability to restless leg syndrome and densities of neurofibrillary pathology in Alzheimer’s disease brains by a variety of evidence. However, PTPRD’s physiological substrates and adaptations to differences in levels of PTPRD expression in brains of young and aging animals have not been explored in depth. We report phosphoproteomic studies of brains of young and aged mice with different levels of PTPRD expression, gene ontology studies of genes identified in this way and validation of several candidate PTPRD substrates within vitroassays using recombinant PTPRD phosphatase. PTPRD is well positioned to modulate the extent of phosphorylation of phosphotyrosine phosphoprotein substrates, including those involved in synaptic maturation and adaptation.
Implications of (co)evolution of agriculture and resource foraging for the maintenance of species diversity and community structure
Authors: Picot Aurore , Monnin Thibaud , Loeuille Nicolas
Published: March 2021

Agriculture is found in numerous taxa such as humans, ants, beetles, fishes and even bacteria. This type of niche construction has evolved independently from hunting, though many species remain primarily predators. When a consumer has a positive effect on its resource, we can expect an allocative cost of agriculture, as the agricultural care diverts time and energy from other activities. Defending the resource against predators may divert time from its consumption (exploitation cost). The cost may also occur on the foraging of alternative resources, for instance if the consumer spends more time nearby the farmed resource and underexploiting resources elsewhere (opportunity cost). We here investigate transitions from predation to agriculture in a simple three-species model of a farmer that consumes two resources and has a positive effect on one. We study the conditions for the (co)evolution of the investment into agriculture and specialization on the two resources, and its consequences on the ecological dynamics of the community. Eco-evolutionary dynamics generate a feedback between the evolution of agriculture and specialization on the helped resource, that can lead to varying selected intensity of agriculture, from generalist strategies with no agriculture, to specialist farmers, with possible coexistence between these two extreme strategies.
Rhythmic neuronal activities of the rat nucleus of the solitary tract are impaired by short-term high fat diet - implications for daily control of satiety by the brainstem
Authors: Chrobok Lukasz , Klich Jasmin D , Sanetra Anna M , Jeczmien-Lazur Jagoda S , Pradel Kamil , Palus-Chramiec Katarzyna , Kepczynski Mariusz , Piggins Hugh D , Lewandowski Marian H
Published: March 2021

Temporal partitioning of daily food intake is crucial for survival and involves the integration of internal circadian states and external influences such as the light-dark cycle and the composition of diet. These intrinsic and extrinsic factors are interdependent with misalignment of circadian rhythms promoting body weight gain, while consumption of a calorie dense diet elevates the risk of obesity and blunts circadian rhythms. Since cardiovascular disease, metabolic disorders, and cancer are comorbid with obesity, understanding the relationships between brain activity and diet is of pivotal importance. Recently, we defined for the first time the circadian properties of the dorsal vagal complex of the brainstem, a structure implicated in the control of food intake and autonomic tone, but if and how 24 h rhythms in this area are influenced by diet remains unresolved. Here we focused on a key structure of this complex, the nucleus of the solitary tract, and using a range of approaches, we interrogated how its neuronal and cellular rhythms are affected by high-fat diet. We report that short term consumption of this diet increases food intake during the day and blunts daily rhythms in gene expression and neuronal discharge in the nucleus of the solitary tract. These alterations in this structure occur without prominent body weight gain, suggesting that high-fat diet acts initially to reduce activity in the nucleus of the solitary tract, thereby disinhibiting mechanisms that suppress daytime feeding.

GRAPHICAL ABSTRACT
The Orsay Virus as a model for population-wide viral infection dynamics
Authors: Pirenne Laurence , Jakobs Maximilian A. H. , Jordan David , Franze Kristian , Miska Eric A.
Published: March 2021

To this day, epidemics pose a considerable threat to mankind. Experimental models that simulate the spread of infectious diseases are thus crucial to the inception of effective control policies. Current models have had great success incorporating virulence and host immune response but do rarely take host genetics, behavior and host environment into account. Here, we present a full-scale imaging setup that utilizes the infection of the nematodeC. eleganswith a positive-stranded RNA virus (Orsay Virus) to probe key epidemiological parameters and simulate the spread of infection in a whole population. We demonstrate that our system is able to quantify infection levels and host behavior at a high sampling rate and show that different host genetic backgrounds can influence viral spread, while also highlighting the influence of infection on various host behaviors. Future work will allow the isolation of key behavioral and environmental factors that affect viral spread, potentially enabling novel policies to combat the spread of viral infections.

Significance Statement

In the ongoing COVID-19 pandemic, we struggle to find effective control policies that “stop the spread”. While current animal models of virus spread in populations are highly sophisticated, they rarely explore effects of host behavior and its environment. We developed an experimental animal model system that allows us to visualize virus transmission in whole populations ofC. eleganswhile also measuring behaviors. We were able to demonstrate howC. elegansgenetics influences the progression of viral infection in a population and how animals adjust their behavior when infected. In the future, we envision that animal model systems like ours are used to test the effects of viral control policies on viral spread before they are applied in real world scenarios.
MEG Oscillatory and Aperiodic neural dynamics contribute to different cognitive aspects of short-term memory decline through lifespan
Authors: Thuwal Kusum , Banerjee Arpan , Roy Dipanjan
Published: March 2021

Neural communication or signal transmission in the brain propagates via distinct oscillatory frequency bands. With aging, the communication mediated by these frequency bands is hindered by noise, which arises from the increased stochastic variability in the baseline neural spiking. This increase in noise measured as 1/f power-law scaling reflects the global background noise and is often linked to impaired cognition in different tasks. In this study, we quantified the 1/f slope and intercept of MEG brain signal as a putative marker of neural noise and examined its effect on cognitive and metacognitive measures. We hypothesize that as neural communication becomes noisier with age, it impacts global information processing, whereas specific periodic features mediate local aspects of cognition. Using recently proposed parametric Fooof model, we first characterised the normative pattern of periodic and aperiodic features (temporal dynamics) across the lifespan, modelled via spectral peaks (Central frequency, power, bandwidth) and 1/f noise activity (slope and intercept) respectively. Secondly, how this Resting-State (RS) baseline shift in temporal dynamics of the signal is associated with various aspects of visual short-term memory (VSTM). Our results suggest that age-associated global change in noisy baseline affects global information processing and crucially impacts the oscillatory features, which relates to more local processing and selective behavioural measures in the VSTM task. Moreover, we suggest that the task-related differences observed across age groups are due to the baseline shift of periodic and aperiodic features.

Significant statement

Aging is accompanied by the decline in cognitive functions and age itself is a major risk factor for Alzheimer’s Disease and other neurological conditions. Our study provides MEG 1/f aperiodic and periodic markers across the healthy adult lifespan and shows that different frequency bands and their spectral features mediate age-related changes across different brain regions, in multiple cognitive and metacognitive domains, which not only provides us with a better understanding of the aging process but would also help in better prevention of cognitive impairments. A clear characterization of the association between baseline MEG temporal dynamics, healthy aging and cognition, is established in this study.
Blockade of SARS-CoV-2 infection in vitro by highly potent PI3K-α/mTOR/BRD4 inhibitor
Authors: Acharya Arpan , Pandey Kabita , Thurman Michellie , Challagundala Kishore B. , Vann Kendra R. , Kutateladze Tatiana G. , Morales Guillermo A , Durden Donald L. , Byrareddy Siddappa N.
Published: March 2021

Pathogenic viruses like SARS-CoV-2 and HIV hijack the host molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2/BRD4 and mTOR, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR PI3K-α/(BRD2/BRD4) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cellsin vitro, showing an IC50value of 1.5 µM, comparable to IC50value of remdesivir (1.1 µM). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2/BRD4 and mTOR signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection and hence be beneficial in preventing severe COVID-19 disease evolution.

One Sentence Summary

Evidence ofin silicodesigned chemotype (SF2523) targeting PI3K-α/mTOR/BRD4 inhibits SARS-CoV-2 infection and is highly synergistic with remdesivir.
Clonal evolution in serially passagedCryptococcus neoformansxdeneoformanshybrids reveals a heterogenous landscape of genomic change
Authors: Michelotti Lucas A. , Sun Sheng , Heitman Joseph , James Timothy Y.
Published: March 2021

Cryptococcus neoformansxdeneoformanshybrids (also known as serotype AD hybrids) are basidiomycete yeasts that are common in a clinical setting. Like many hybrids, the AD hybrids are largely locked at the F1 stage and are mostly unable to undergo normal meiotic reproduction. However, these F1 hybrids, which display a high (∼10%) sequence divergence are known to genetically diversify through mitotic recombination and aneuploidy, and this diversification may be adaptive. In this study, we evolved a single AD hybrid genotype in six diverse environments by serial passaging and then used genome resequencing of evolved clones to determine evolutionary mechanisms of adaptation. The evolved clones generally increased fitness after passaging, accompanied by an average of 3.3 point mutations, 2.9 loss of heterozygosity (LOH) events, and 0.7 trisomic chromosomes per clone. LOH occurred through nondisjunction of chromosomes, crossing over consistent with break-induced replication, and gene conversion, in that order of prevalence. The breakpoints of these recombination events were significantly associated with regions of the genome with lower sequence divergence between the parents and clustered in subtelomeric regions, notably in regions that had undergone introgression between the two parental species. Parallel evolution was observed, particularly through repeated homozygosity via nondisjunction, yet there was little evidence of environment-specific parallel change for either LOH, aneuploidy, or mutations. These data show that AD hybrids have both a remarkable genomic plasticity and yet are challenged in the ability to recombine through sequence divergence and chromosomal rearrangements, a scenario likely limiting the precision of adaptive evolution to novel environments.
Perturbation of ACE2 structural ensembles by SARS-CoV-2 spike protein binding
Authors: Uyar Arzu , Dickson Alex
Published: March 2021

The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein-protein interface. Although this interaction has been characterized by X-ray crystallography and Cryo-EM, these structures do not reveal significant differences in ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in ACE2 structure upon binding. These differences are determined with the Linear Discriminant Analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are “apo-like” vs “complex-like”, as well as to pinpoint long-range ligand-induced allosteric changes of ACE2 structure.
Recombinant protein subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1 biased, humoral and cellular immune responses in mice
Authors: Lai Chih-Yun , To Albert , Wong Teri Ann S. , Lieberman Michael M. , Clements David E. , Senda James T. , Ball Aquena H. , Pessaint Laurent , Andersen Hanne , Donini Oreola , Lehrer Axel T.
Published: March 2021

The speed at which several COVID-19 vaccines went from conception to receiving FDA and EMA approval for emergency use is an achievement unrivaled in the history of vaccine development. Mass vaccination efforts using the highly effective vaccines are currently underway to generate sufficient herd immunity and reduce transmission of the SARS-CoV-2 virus. Despite the most advanced vaccine technology, global recipient coverage, especially in resource-poor areas remains a challenge as genetic drift in naïve population pockets threatens overall vaccine efficacy. In this study, we described the production of insect-cell expressed SARS-CoV-2 spike protein ectodomain and examined its immunogenicity in mice. We demonstrated that, when formulated with CoVaccine HT™adjuvant, an oil-in-water nanoemulsion compatible with lyophilization, our vaccine candidates elicit a broad-spectrum IgG response, high neutralizing antibody titers, and a robust, antigen-specific IFN-γ secreting response from immune splenocytes in outbred mice. Our findings lay the foundation for the development of a dry-thermostabilized vaccine that is deployable without refrigeration.
FAM57B is a modulator of ceramide synthesis that regulates sphingolipid homeostasis and synaptic composition in the developing brain
Authors: Tomasello Danielle L. , Kim Jiyoon L. , Khodour Yara , McCammon Jasmine M. , Mitalipova Maya , Jaenisch Rudolf , Futerman Anthony H. , Sive Hazel
Published: March 2021

The complex 16p11.2 Deletion Syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder and intellectual disability. We demonstrate that 16pdel iPSC differentiated neurons showed augmented local field potential activity and altered ceramide-related lipid species relative to unaffected.FAM57B, a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. InFAM57Bmutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency ofFAM57Bcontributes to changes in neuronal activity and function in 16pdel Syndrome, through a crucial role for the gene in lipid metabolism.
Optimal transport analysis reveals trajectories in steady-state systems
Authors: Zhang Stephen , Afanassiev Anton , Greenstreet Laura , Matsumoto Tetsuya , Schiebinger Geoffrey
Published: March 2021

Understanding how cells change their identity and behaviour in living systems is an important question in many fields of biology. The problem of inferring cell trajectories from single-cell measurements has been a major topic in the single-cell analysis community, with different methods developed for equilibrium and non-equilibrium systems (e.g. haematopoeisis vs. embryonic development). We show that optimal transport analysis, a technique originally designed for analysing time-courses, may also be applied to infer cellular trajectories from a single snapshot of a population in equilibrium. Therefore optimal transport provides a unified approach to inferring trajectories, applicable to both stationary and non-stationary systems. Our method, StationaryOT, is mathematically motivated in a natural way from the hypothesis of a Waddington’s epigenetic landscape. We implemented StationaryOT as a software package and demonstrate its efficacy when applied to simulated data as well as single-cell data fromArabidopsis thalianaroot development.
Competitive binding of MatP and topoisomerase IV to the MukB dimerization hinge
Authors: Fisher Gemma L. M. , Bolla Jani R. , Rajasekar Karthik V. , Mäkelä Jarno , Baker Rachel , Zhou Man , Prince Josh P. , Stracy Mathew , Robinson Carol V. , Arciszewska Lidia K. , Sherratt David J.
Published: March 2021

SMC complexes have ubiquitous roles in chromosome organisation. InEscherichia coli,the interplay between the SMC complex, MukBEF, and matS-bound MatP in the replication termination region, ter, results in depletion of MukBEF from ter, thus promoting chromosome individualisation by directing replichores to separate cell halves. MukBEF also interacts with topoisomerase IV ParC2E2heterotetramers, to direct its chromosomal distribution to mirror that of MukBEF, thereby facilitating coordination between chromosome organisation and decatenation by topoisomerase IV. Here we demonstrate that the MukB dimerization hinge binds ParC and MatP with the same dimer to dimer stoichiometry. MatP and ParC have an overlapping binding interface on the MukB hinge, leading to their mutually exclusive binding. Furthermore, the MukB hinge fails to stably associate withmatS-bound MatP, while MatP mutants deficient inmatSbinding are impaired in MukB hinge binding, demonstrating thatmatscompetes with the hinge for MatP binding. Cells expressing MukBEF complexes containing a mutation in the MukB hinge interface for ParC/MatP binding are deficient in ParC bindingin vivo,despite having a Muk+topoisomerase IV+phenotype. This mutant protein is also impaired in MatP bindingin vitro,and cells expressing this variant exhibit a MukBEF cellular localisation consistent with impaired MatP binding.
The influence of surface roughness and viscosity on micropitting damage
Authors: Li Wei , Lu Liantao
Published: March 2021

Purpose

This study aims to investigate the influence of surface roughness and viscosity on micropitting and their influence sequence.

Design/methodology/approach

Specimens were made of carburized and quenched 18CrNiMo7-6, and different surface roughness was obtained by grinding and shot peening. Tests were carried out on a rolling-sliding tribometer, with different viscosity lubricants and a heavy load under a boundary lubrication condition. The laser confocal microscope was used to measure the aspects, surface roughness, profiles in the contacted region and micropitting damage percentage. A factorial experiment was designed, and the range analysis was applied to find the sequence of influence of surface roughness and viscosity.

Findings

The result shows that surface roughness has a more noticeable influence since the change of viscosity cannot generate sufficient wear loss to suppress micropitting.

Originality/value

The influence sequence of two factors on micropitting was investigated and the reason for the distribution was analyzed.
HIV supply chains in low- and middle-income countries: overview and research opportunities
Authors: Stulens Sofie , De Boeck Kim , Vandaele Nico
Published: March 2021

Purpose

Despite HIV being reported as one of the major global health issues, availability and accessibility of HIV services and supplies remain limited, especially in low- and middle-income countries. The effective and efficient operation of HIV supply chains is critical to tackle this problem. The purpose of this paper is to give an introduction to HIV supply chains in low- and middle-income countries and identify research opportunities for the operations research/operations management (OR/OM) community.

Design/methodology/approach

First, the authors review a combination of the scientific and grey literature, including both qualitative and quantitative papers, to give an overview of HIV supply chain operations in low- and middle-income countries and the challenges that are faced by organizing such supply chains. The authors then classify and discuss the relevant OR/OM literature based on seven classification criteria: decision level, methodology, type of HIV service modeled, challenges, performance measures, real-life applicability and countries covered. Because research on HIV supply chains in low- and middle-income countries is limited in the OR/OM field, this part also includes papers focusing on HIV supply chain modeling in high-income countries.

Findings

The authors conclude this study by identifying several tendencies and gaps and by proposing future research directions for OR/OM research.

Originality/value

To the best of the authors’ knowledge, this paper is the first literature review addressing this specific topic from an OR/OM perspective.
A study on factors limiting online shopping behaviour of consumers
Authors: Daroch Bindia , Nagrath Gitika , Gupta Ashutosh
Published: March 2021

Purpose

This study aims to investigate consumer behaviour towards online shopping, which further examines various factors limiting consumers for online shopping behaviour. The purpose of the research was to find out the problems that consumers face during their shopping through online stores.

Design/methodology/approach

A quantitative research method was adopted for this research in which a survey was conducted among the users of online shopping sites.

Findings

As per the results total six factors came out from the study that restrains consumers to buy from online sites – fear of bank transaction and faith, traditional shopping more convenient than online shopping, reputation and services provided, experience, insecurity and insufficient product information and lack of trust.

Research limitations/implications

This study is beneficial for e-tailers involved in e-commerce activities that may be customer-to-customer or customer-to-the business. Managerial implications are suggested for improving marketing strategies for generating consumer trust in online shopping.

Originality/value

In contrast to previous research, this study aims to focus on identifying those factors that restrict consumers from online shopping.
Recipient and donor characteristics govern the hierarchical structure of heterospecific pollen competition networks
Authors: Lanuza Jose B. , Bartomeus Ignasi , Ashman Tia‐Lynn , Bible Greg , Rader Romina
Published: March 2021

Pollinator sharing can have negative consequences for plant fitness via competition for visits as well as with the arrival of heterospecific pollen. Plant traits and relatedness of donor and recipient species have been suggested to drive the observed variation in plant fitness effects of both processes, but how they shape the structure of interspecific pollen competition networks has been overlooked at the community level.

To understand the importance of reproductive traits and relatedness to the impact of heterospecific pollen, we conducted a controlled glasshouse experiment with an artificial co‐flowering community. We performed 2,200 hand pollination crosses by experimentally transferring conspecific pollen alone or with 50% and 100% foreign pollen among 10 species belonging to three different plant families.

Relative to conspecific pollen alone, there was a significant reduction in seed set with 50% heterospecific pollen for 67% of the crosses. This effect is driven largely by recipient traits and the interaction between recipient and donor traits under specific circumstances of trait matching. In general, species with shorter styles, smaller stigmas and lower pollen:ovule ratios were more impacted by heterospecific pollen. These traits and their differences among species led to a hierarchical (or transitive) structure of pollen competition with clear winners and losers. However, phylogenetic distance among recipient and donor species did not explain the effects.

Synthesis. Our study shows that specific traits and trait combinations between donor and recipient species are important in determining seed production outcomes with heterospecific pollen receipt. Moreover, the differences in traits between species lead to a competitive structure with clear ‘winners’ or ‘losers’ species. The results of this study highlight the importance of specific traits in understanding the position of the competitive hierarchy of the species and the mechanisms underlying heterospecific pollen impacts upon plant reproductive success.
Prognostic and comparative performance of cardiovascular risk markers in patients with type 2 diabetes
Authors: Busch Nikolaj , Jensen Magnus T. , Goetze Jens P. , Schou Morten , Biering‐Sørensen Tor , Fritz‐Hansen Thomas , Andersen Henrik U. , Vilsbøll Tina , Rossing Peter , Jørgensen Peter G.
Published: March 2021

Background

Diagnostic tests including echocardiography, albuminuria, electrocardiogram (ECG), high‐sensitivity troponin I (hs‐TnI), and N‐terminal prohormone brain natriuretic peptide (NT‐proBNP) have been suggested as cardiovascular (CV) risk predictors in type 2 diabetes. We studied the separate and combined prognostic yield of these risk markers.

Methods

In all, 1030 patients with type 2 diabetes were recruited from specialized clinics in this prospective cohort study. Full echocardiographic evaluation was feasible in 886 patients in sinus rhythm with adequate image quality. ECG was performed in 998 patients. Albuminuria was measured in 1009 and NT‐proBNP/hs‐TnI in 933 patients. The end point was a composite of CV events.

Results

The median follow‐up was 4.7 years (interquartile range: 4.0‐5.3), and 174 patients experienced a CV disease event. All considered markers, except hs‐TnI, were significantly (P < .001) associated with the outcome: abnormal echocardiogram (hazard ratio 2.40 [1.70‐3.39]), albuminuria 2.01 (1.47‐2.76), abnormal ECG (2.27 [1.66‐3.08]), high NT‐proBNP (>150 pg/mL) 3.05 (2.11‐4.40), and hs‐TnI 1.12 (0.79‐1.59). After adjusting for clinical variables, all remained significantly associated with the end point. However, after adjusting for each other, only NT‐proBNP >150 pg/mL remained significantly associated with the end point (2.07 [1.28‐3.34], P < .001). Measured by C‐statistics, model performance was highest with log2 (NT‐proBNP) (0.70 [0.65‐0.75]) and similar to clinical variables alone (0.71 [0.67‐0.76]). Combining all risk markers only resulted in a very limited increase in C‐statistics (0.69 [0.64‐0.74]).

Conclusions

This study identified NT‐proBNP over echocardiography, ECG, and albuminuria in risk prediction in patients with type 2 diabetes. The diagnostic yield in considering more than one risk marker was limited in this population.