bluuebunny/crossref_metadata_2025 huggingface dataset:
Compartment syndrome following use of tissue plasminogen activator for frostbite in the setting of concomitant diaphyseal tibia fracture
Authors: Joseph Noah M. , Alfonso Nicholas , Hirschfeld Adam G.
Published: March 2021

Background:

Tissue plasminogen activator (tPA) is a thrombolytic agent increasingly being employed for the treatment of acute frostbite. Although tPA has been shown with success to increase digit salvage rates, data on potential complications, including risk of hemorrhage, is limited. As a result, acute trauma is considered a contraindication to use in many institution-based protocols. Currently, there is a paucity in the literature regarding use of tPA for frostbite in patients with concomitant extremity fractures.

Case presentation:

We report the case of a 36-year-old male treated with tPA for frostbite to digits of his bilateral hands in the setting of a concomitant diaphyseal tibia fracture. He subsequently developed acute compartment syndrome in his lower extremity. This was followed by emergent fasciotomy and staged fracture fixation with serial wound debridement and subsequent closure. Despite this complication, the patient went on to early radiographic and clinical union of his tibia fracture. His frostbite wounds healed without functional deficits.

Conclusions:

In patients with severe frostbite injury with digital perfusion defects, tPA for thrombolysis may be indicated. Use of thrombolytics for frostbite in trauma patients or those with concomitant extremity fractures requires a multidisciplinary discussion regarding potential risks. Contingency planning is essential to ensure that potential bleeding complications, including development of compartment syndrome, are diagnosed and treated early. Given the paucity in the current literature regarding use of thrombolytics in trauma patients, further study is warranted to inform the surgical community on instances in which the benefits of tPA administration may outweigh the risks.

Level of evidence:

Case report; Level V.
Orthopaedic trauma care during the early COVID-19 pandemic in the Asia-Pacific region
Authors: Kurozumi Taketo , Minehara Hiroaki , Kim Joon-Woo , Oh Chang-Wung , Miclau Elizabeth E. , Balogh Zsolt J.
Published: March 2021

The Asia-Pacific region countries, with their large and socioeconomically diverse populations and infrastructures, were amongst the earliest to have to respond to the COVID-19 pandemic. Although the disease is not one of surgical trauma, its effects on orthopaedic injuries have been significant. Medical systems had to adapt to better focus on patients with a highly communicable disease, while continuing to provide essential services. Even though many countries saw a decrease in traumatic injuries during the initial periods, orthopaedic trauma services nevertheless had to adapt accordingly to system-wide organizational changes. While each country took their individual approaches to address the pandemic, there were also consistencies in how musculoskeletal injuries and conditions were handled during these early stages of the pandemic. This article reviews those early management approaches to musculoskeletal injury care during the COVID-19 pandemic in different countries throughout the Asia-Pacific region following the initial outbreak in China: Australia, South Korea, and Japan.
Effect of a kimchi-derived combined starter on the fermentation
process of kimchi
Authors: Lee Jin ju
Published: March 2021

In this study, we compared the changes in the quality of kimchi fermented with a
complex starter and a single starter. Lactic acid bacteria strains isolated from
kimchi were used as starters, and fermention was performed at 10°C for 26
days. The rate of reduction in lactic acid bacteria was low, the initial pH was
maintained at a constant level, and the dominance rate of the starter was high
at 83% on the 15th day of fermentation with the complex starter, compared
to fermentation with the control and single starters. Regarding the
CO2 and free sugar content, which are factors affecting product
quality and are influenced by lactic acid bacteria fermentation, 1.4 and 1.5
times higher CO2 and mannitol production, respectively, were observed
during fermentation of free sugars with the complex starter than in fermentation
with the single starter. These results show that the use of a complex starter
can improve the distribution quality of kimchi as it results in an extended
shelf life and enhanced sensory quality.
Quality characteristics and antioxidant activities of macarons
supplemented with white sesame
Authors: Kim Su Jin , Kim Da Hee , Baek Seung Yeon , Park Young Mi , Kim Mee Ree
Published: March 2021

This study evaluated the physicochemical properties and antioxidant activitiy of
macarons containing white sesame powder (0%, 15%, 30%, and
45%). The moisture content and weight of macarons containing white sesame
were higher than those of the macarons not containing any (control), and these
increased with increasing white sesame content. However, the volume of macarons
containing white sesame was lower than that of the control. The soluble solid
content (°Brix) and reducing sugar content (%) of the control were
the lowest among all the experiment groups. The pH of the macarons decreased as
the amount of white sesame increased. As the amount of white sesame increased,
in the Hunter color system, L* (lightness) values of the white sesame containing
macarons decreased, whereas a* (redness) and b* (yellowness) values increased.
Analysis of textural properties by TPA showed that macaron hardness decreased
with increasing white sesame content. Flavonoid and total phenolic contents
increased with the addition of white sesame. Antioxidant activities such as DPPH
(2,2-diphenyl-1-picrylhydrazyl) radical scavenging and superoxide dismutase-like
activities, of the macarons containing white sesame increased compared with the
control. Analysis of the sensory properties revealed that the score of overall
acceptability of macarons containing 15% and 30% white sesame was
the highest among all the groups. There, our findings suggested that it was
desirable to add white sesame to macarons for enhanced quality and sensory
characteristics.
Physicochemical properties and physiological activities of Agastache rugosa extracts
Authors: Kim Ji Wan , Hong Joo-Heon
Published: March 2021

Agastache rugosa is used as a medicinal herb and contains various polyphenol compounds. Here, we investigated the physicochemical properties; and the immunomodulatory and anti-obesity effects of Agastache rugosa extracts. Agastache rugosa was extracted with hot water (HE), 70% ethanol (EE), and 70% methanol (ME). The yield of Agastache rugosa extracts varied depending on the extraction solvents, from 6.11 to −8.86%. The total sugar content was the highest in the HE -(33.98 g/100 g). In contrast, the total polyphenol content was the highest in the ME -(10.25 g/100 g), while the total protein content was similar in all extracts. The DPPH radical scavenging activity of the ME was 61.05%, and the ABTS radical scavenging activity of the EE was 47.73% at 1,000 μg/mL. Additionally, the FRAP activity and ORAC value of the EE at 1,000 μg/mL were 1.14 μM and 121.03 μM TE/g, respectively. Importantly, all extracts decreased the production of nitric oxide in RAW 264.7 cells, and the cytokine content also decreased in a concentration-dependent manner. In addition, all extracts decreased lipid accumulation in adipocytes in vitro, compared with that in the untreated adipocytes. Therefore, Agastache rugosa extracts can potentially be used as functional materials with immunomodulatory and anti-obesity effects.
The local and systemic response to SARS-CoV-2 infection in children and adults
Authors: Yoshida Masahiro , Worlock Kaylee B. , Huang Ni , Lindeboom Rik G.H. , Butler Colin R. , Kumasaka Natsuhiko , Conde Cecilia Dominguez , Mamanova Lira , Bolt Liam , Richardson Laura , Polanski Krzysztof , Madissoon Elo , Barnes Josephine L. , Allen-Hyttinen Jessica , Kilich Eliz , Jones Brendan C. , de Wilton Angus , Wilbrey-Clark Anna , Sungnak Waradon , Pett J. Patrick , Prigmore Elena , Yung Henry , Mehta Puja , Saleh Aarash , Saigal Anita , Chu Vivian , Cohen Jonathan M. , Cane Clare , Iordanidou Aikaterini , Shibuya Soichi , Reuschl Ann-Kathrin , Argento A. Christine , Wunderink Richard G. , Smith Sean B. , Poor Taylor A. , Gao Catherine A. , Dematte Jane E. ,   NU SCRIPT Study Investigators, Reynolds Gary , Haniffa Muzlifah , Bowyer Georgina S. , Coates Matthew , Clatworthy Menna R. , Calero-Nieto Fernando J. , Göttgens Berthold , O’Callaghan Christopher , Sebire Neil J. , Jolly Clare , de Coppi Paolo , Smith Claire M. , Misharin Alexander V. , Janes Sam M. , Teichmann Sarah A. , Nikolić Marko Z. , Meyer Kerstin B.
Published: March 2021

While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in paediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatricversusadult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data1as a highly granular reference for the study of immune responses in airways and blood in children.
Oligodendrocyte Precursor Cells Sculpt the Visual System by Regulating Axonal Remodeling
Authors: Xiao Yan , Hoodless Laura J , Petrucco Luigi , Portugues Ruben , Czopka Tim
Published: March 2021

Many oligodendrocyte precursor cells (OPCs) do not differentiate to form myelin, suggesting additional roles of this cell population. The zebrafish optic tectum contains OPCs in regions devoid of myelin. Elimination of these OPCs impaired precise control of retinal ganglion cell axon arbor size during formation and maturation of retinotectal connectivity, and in consequence impaired visual acuity. Therefore, OPCs fine-tune neural circuit structure and function independently of their canonical role to make myelin.
Durability of SARS-CoV-2-specific IgG responses in saliva for up to 8 months after infection
Authors: Randad Pranay R. , Pisanic Nora , Kruczynski Kate , Howard Tyrone , Rivera Magdielis Gregory , Spicer Kristoffer , Antar Annukka A.R. , Penson Tristan , Thomas David L. , Pekosz Andrew , Ndahiro Nelson , Aliyu Lateef , Betenbaugh Michael J. , Manley Hannah , Detrick Barbara , Katz Morgan , Cosgrove Sara , Rock Clare , Zyskind Israel , Silverberg Jonathan I. , Rosenberg Avi Z. , Duggal Priya , Manabe Yukari C. , Collins Matthew H. , Heaney Christopher D.
Published: March 2021

We evaluated the durability of IgG responses specific to SARS-CoV-2 nucleocapsid (N), receptor binding domain (RBD), and spike (S) antigens in saliva up to 8 months after RT-PCR-confirmed COVID-19 using a multiplex salivary assay. We estimated a half-life of 64 days (d) (95% CI: 49, 80 d) for N, 100 d for RBD (95% CI: 58, 141 d), and 148 d (95% CI: 62, 238 d) for S IgG responses in saliva, consistent with half-life estimates previously reported in blood. Saliva can serve as an alternative to blood to monitor humoral immune responses on a large scale following SARS-CoV-2 infection and vaccination for surveillance and assessment of population immunity.
Novel highly divergent SARS-CoV-2 lineage with the Spike substitutions L249S and E484K
Authors: Laiton-Donato Katherine , Usme-Ciro Jose A. , Franco-Muñoz Carlos , Álvarez-Díaz Diego A. , Ruiz-Moreno Hector Alejandro , Reales-González Jhonnatan , Andrés Prada Diego , Corchuelo Sheryll , Herrera-Sepúlveda Maria T. , Naizaque Julian , Santamaría Gerardo , Wiesner Magdalena , Walteros Diana Marcela , Martínez Martha Lucia Ospina , Mercado-Reyes Marcela
Published: March 2021

COVID-19 pandemics has led to genetic diversification of SARS-CoV-2 and the appearance of variants with potential impact in transmissibility and viral escape from acquired immunity. We report a new lineage containing ten distinctive amino acid changes across the genome. Further studies are required for monitoring its epidemiologic impact.
Predictive and Causal Analysis of No-Shows for Medical Exams During COVID-19: A Case Study of Breast Imaging in a Nationwide Israeli Health Organization
Authors: Ozery-Flato Michal , Pinchasov Ora , Dabush-Kasa Miel , Hexter Efrat , Chodick Gabriel , Guindy Michal , Rosen-Zvi Michal
Published: March 2021

“No-shows”, defined as missed appointments or late cancellations, is a central problem in healthcare systems. It has appeared to intensify during the COVID-19 pandemic and the nonpharmaceutical interventions, such as closures, taken to slow its spread. No-shows interfere with patients’ continuous care, lead to inefficient utilization of medical resources, and increase healthcare costs. We present a comprehensive analysis of no-shows for breast imaging appointments made during 2020 in a large medical network in Israel. We applied advanced machine learning methods to provide insights into novel and known predictors. Additionally, we employed causal inference methodology to infer the effect of closures on no-shows, after accounting for confounding biases, and demonstrate the superiority of adversarial balancing over inverse probability weighting in correcting these biases. Our results imply that a patient’s perceived risk of cancer and the COVID-19 time-based factors are major predictors. Further, we reveal that closures impact patients over 60, but not patients undergoing advanced diagnostic examinations.
Diffusion Kurtosis Imaging of neonatal Spinal Cord in clinical routine
Authors: Trò Rosella , Roascio Monica , Tortora Domenico , Severino Mariasavina , Rossi Andrea , Cohen-Adad Julien , Fato Marco Massimo , Arnulfo Gabriele
Published: March 2021

Diffusion Kurtosis Imaging (DKI) has undisputed advantages over more classical diffusion Magnetic Resonance Imaging (dMRI), as witnessed by a fast-increasing number of clinical applications and software packages widely adopted in brain imaging. However, in the neonatal setting, DKI is still largely underutilized in Spinal Cord (SC) imaging because of its inherently demanding technological requirements.

Due to its extreme sensitivity to non-gaussian diffusion, DKI proves particularly suitable for detecting complex, subtle, fast microstructural changes occurring in this area at this early and critical stage of development, and not identifiable with only DTI. Given the multiplicity of congenital anomalies of the spinal canal, their crucial effect on later developmental outcome, and the close interconnection between SC region and the above brain, managing to apply such a method to neonatal cohort becomes of utmost importance.

This study will (i) review the current methodological challenges associated with application of advanced dMRI methods like DKI in early infancy, (ii) illustrate the first semi-automated pipeline built on Spinal Cord Toolbox (SCT) for handling with DKI data of neonatal SC, from acquisition setting to estimation of diffusion measures, through accurate adjustment of processing algorithms customized for adult SC, and (iii) present preliminary results of its application in a pilot clinical case study.

Results of this application agree with findings achieved in a corresponding adult survey, thus confirming validity of adopted pipeline and diagnostic value of DKI in pediatrics.
Niche partitioning facilitates coexistence of closely related gut bacteria
Authors: Brochet Silvia , Quinn Andrew , Mars Ruben A.T. , Neuschwander Nicolas , Sauer Uwe , Engel Philipp
Published: March 2021

Ecological processes underlying bacterial coexistence in the gut are not well understood. Here, we disentangled the effect of the host and the diet on the coexistence of four closely relatedLactobacillusspecies colonizing the honey bee gut. We serially passaged the four species through gnotobiotic bees and in liquid cultures in the presence of either pollen (bee diet) or simple sugars. Although the four species engaged in negative interactions, they were able to stably coexist, bothin vivoandin vitro. However, coexistence was only possible in the presence of pollen, and not in simple sugars, independent of the environment. Using metatranscriptomics and metabolomics, we found that the four species utilize different pollen-derived carbohydrate substrates indicating resource partitioning as the basis of coexistence. Our results show that despite longstanding host association, gut bacterial interactions can be recapitulatedin vitroproviding insights about bacterial coexistence when combined within vivoexperiments.
An ALE meta-analytic review of musical expertise
Authors: Criscuolo Antonio , Pando-Naude Victor , Bonetti Leonardo , Vuust Peter , Brattico Elvira
Published: March 2021

Through long-term training, music experts acquire complex and specialized sensorimotor skills, which are paralleled by continuous neuro-anatomical and -functional adaptations. The underlying neuroplasticity mechanisms have been extensively explored in decades of research in music, cognitive, and translational neuroscience. However, the absence of a comprehensive review and quantitative meta-analysis prevents the plethora of variegated findings to ultimately converge into a unified picture of the neuroanatomy of musical expertise. Here, we performed a comprehensive neuroimaging meta-analysis of publications investigating neuro-anatomical and -functional differences between musicians (M) and non-musicians (NM). Eighty-four studies were included in the qualitative synthesis. From these, 58 publications were included in coordinate-based meta-analyses using the anatomic/activation likelihood estimation (ALE) method. This comprehensive approach delivers a coherent cortico-subcortical network encompassing sensorimotor and limbic regions bilaterally. Particularly, M exhibited higher volume/activity in auditory, sensorimotor, interoceptive, and limbic brain areas and lower volume/activity in parietal areas as opposed to NM. Notably, we reveal topographical (dis-)similarities between the identified functional and anatomical networks and characterize their link to various cognitive functions by means of meta-analytic connectivity modelling. Overall, we effectively synthesized decades of research in the field and provide a consistent and controversies-free picture of the neuroanatomy of musical expertise.
A completely resolved phylogenetic tree of British spiders
Authors: Breitling Rainer
Published: March 2021

The recent accumulation of increasingly densely sampled phylogenetic analyses of spiders has greatly advanced our understanding of evolutionary relationships within this group. Here, this diverse literature is reviewed and combined with earlier morphological analyses in an attempt to reconstruct the first fully resolved phylogeny for the spider fauna of the British Isles. The resulting tree highlights parts of the group where data are still too limited for a confident assessment of relationships, proposes a number of deviations from previously suggested phylogenetic hypotheses, and can serve as a framework for evolutionary and ecological interpretations of the biology of British spiders, as well as a starting point for future studies on a larger geographical scale.
High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation
Authors: Rico Daniel , Kent Daniel , Karataraki Nefeli , Mikulasova Aneta , Berlinguer-Palmini Rolando , Walker Brian A. , Javierre Biola M. , Russell Lisa J. , Brackley Chris A.
Published: March 2021

Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to genome 3D structure remains poorly understood. Here we used the highly-predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogeneCCND1in healthy and malignant B-cells. After confirming that the model gives good predictions of Hi-C data for the non-malignant human B-cell derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involvingCCND1and the immunoglobulin heavy chain locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a singleIGHsuper-enhancer is inserted next toCCND1leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodelling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequenceper se. Simulations of theIGH-CCND1reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassingCCND1and theIGHsuper-enhancers. We predicted how the structure and expression ofCCND1changes in these different cell lines, validating this using qPCR and fluorescencein situhybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation break-points.
α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity
Authors: Santos Jaime , Gracia Pablo , Navarro Susanna , Peña-Diaz Samuel , Pujols Jordi , Cremades Nunilo , Pallarès Irantzu , Ventura Salvador
Published: March 2021

α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein pathogenic assemblies with high affinity and selectivity is a long-pursued objective. Here, we have exploited the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind selectively to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into an unprecedented anti-aggregation potency and the ability to abrogate the oligomers toxicity. With a structure-function relationship in hand, we identified a human peptide expressed in the brain and in the gastrointestinal tract with exceptional binding, antiaggregation, and detoxifying properties, which suggests it might play a protective role against synucleinopathies. The chemical entities we describe here represent a new therapeutic paradigm and are promising tools to assist diagnosis by selectively detecting α-synuclein pathogenic species in biofluids.
An ecological explanation for hyperallometric scaling of reproduction
Authors: Potter Tomos , Felmy Anja
Published: March 2021

In wild populations, large individuals have disproportionately higher reproductive output than smaller individuals. Some theoretical models explain this pattern – termed reproductive hyperallometry – by individuals allocating a greater fraction of available energy towards reproductive effort as they grow. Here, we propose an ecological explanation for this observation: differences between individuals in rates of resource assimilation, where greater assimilation causes both increased reproduction and body size, resulting in reproductive hyperallometry at the level of the population. We illustrate this effect by determining the relationship between size and reproduction in wild and lab-reared Trinidadian guppies. We show that (i) reproduction increased disproportionately with body size in the wild but not in the lab, where resource competition was eliminated and food availability restricted; (ii) in the wild, hyperallometry was greatest during the wet season, when resource competition is strongest; and (iii) detection of hyperallometric scaling of reproduction at the population level was inevitable if individual differences in assimilation were ignored. We propose that ecologically-driven variation in assimilation – caused by size-dependent resource competition, niche expansion, and chance – contributes substantially to hyperallometric scaling of reproduction in natural populations. We recommend that mechanistic models incorporate such ecologically-caused variation when seeking to explain reproductive hyperallometry.
Whole Genome Assembly and Annotation of Northern Wild Rice,Zizania palustrisL., Supports a Whole Genome Duplication in theZizaniaGenus
Authors: Haas Matthew , Kono Thomas , Macchietto Marissa , Millas Reneth , McGilp Lillian , Shao Mingqin , Duquette Jacques , Hirsch Candice N. , Kimball Jennifer
Published: March 2021

Northern Wild Rice (NWR;Zizania palustrisL.) is an aquatic grass native to North America that is notable for its nutritious grain. This is an important species with ecological, cultural, and agricultural significance, specifically in the Great Lakes region of the United States. Using long- and short-range sequencing, Hi-C scaffolding, and RNA-seq data from eight tissues, we generated an annotated whole genomede novoassembly of NWR. The assembly is 1.29 Gb, highly repetitive (∼76.0%), and contains 46,421 putative protein-coding genes. The expansion of retrotransposons within the genome and a whole genome duplication prior to theZizania-Oryzaspeciation event have both led to an increase in genome size of NWR in comparison withO. sativaandZ. latifolia. Both events depict a genome rapidly undergoing change over a short evolutionary time. Comparative analyses revealed conservation of large syntenic blocks withOryza sativaL., which were used to identify putative seed shattering genes. Estimates of divergence times revealed theZizaniagenus diverged fromOryza∼26-30 million years ago (MYA), while NWR andZizania latifoliadiverged from one another ∼6-8 MYA. Comparative genomics confirmed evidence of a whole genome duplication in theZizaniagenus and provided support that the event was prior to the NWR-Z. latifoliaspeciation event. This high-quality genome assembly and annotation provides a valuable resource for comparative genomics in the Oryzeae tribe and provides an important resource for future conservation and breeding efforts of NWR.
Environmental, structural and taxonomic diversity factors drive aboveground carbon stocks in a semi-deciduous tropical rainforest strata in Cameroon
Authors: Zekeng Jules Christian , van der Sande Masha T. , Fobane Jean Louis , Sebego Reuben , Mphinyane Wanda N. , Ebanga Paul André , Mbolo Marguerite Marie Abada
Published: March 2021

Tropical forests play an important role in biodiversity conservation and ecosystem functioning. Few studies have teased apart the independent effects of biotic and abiotic factors on aboveground carbon across tree size groups and the whole tree community level in a tropical semi-deciduous rainforest. This study aims to analyze the relative and independent effects of abiotic (topography, soil fertility/texture and disturbance) and biotic factors on carbon stocks across tree size groups, as well as at the whole tree community in semi-deciduous plots, including logged plots.

We used data from 30 1-ha plots and 22,064 trees distributed in a semi-deciduous tropical rainforest of Cameroon. For each plot, we quantified disturbance, topography and eleven soil conditions. Besides, we quantified three taxonomic richness and diversity Gini index. We used structural equation models to test the hypothesis that all drivers have independent, positive effects on aboveground carbon stocks across tree-sized groups and the whole tree community.

The logging disturbance decreased aboveground carbon stocks for the whole tree community and trees size groups across our site except for large trees. Topographical factors (i.e., slope and elevation) increased aboveground carbon (AGC) of the whole tree community and the large trees. In contrast, soil nitrogen (Nsoil) and clay proportion increased AGC of the small stems and understorey trees groups. This study found that biotics factors have some indirect and direct effects on AGC. Taxonomic diversity through niche complementarity had a positive relationship with aboveground carbon stocks across the trees size groups and the whole tree community, while diversity Gini index had strongest relationships with aboveground carbon stocks.

The significant effects of structural diversity on aboveground carbon stocks of the whole tree community, large trees, and understory trees highlight the importance of maintaining a layered structure and tall trees in the forest.
Comparison of domain adaptation techniques for white matter hyperintensity segmentation in brain MR images
Authors: Sundaresan Vaanathi , Zamboni Giovanna , Dinsdale Nicola K. , Rothwell Peter M. , Griffanti Ludovica , Jenkinson Mark
Published: March 2021

Robust automated segmentation of white matter hyperintensities (WMHs) in different datasets (domains) is highly challenging due to differences in acquisition (scanner, sequence), population (WMH amount and location) and limited availability of manual segmentations to train supervised algorithms. In this work we explore various domain adaptation techniques such as transfer learning and domain adversarial learning methods, including domain adversarial neural networks and domain unlearning, to improve the generalisability of our recently proposed triplanar ensemble network, which is our baseline model. We evaluated the domain adaptation techniques on source and target domains consisting of 5 different datasets with variations in intensity profile, lesion characteristics and acquired using different scanners. For transfer learning, we also studied various training options such as minimal number of unfrozen layers and subjects required for finetuning in the target domain. On comparing the performance of different techniques on the target dataset, unsupervised domain adversarial training of neural network gave the best performance, making the technique promising for robust WMH segmentation.
A metal ion orients mRNA to ensure accurate 2’-Oribosyl methylation of the first nucleotide of the SARS-CoV-2 genome
Authors: Viswanathan Thiruselvam , Misra Anurag , Chan Siu-Hong , Qi Shan , Dai Nan , Arya Shailee , Martinez-Sobrido Luis , Gupta Yogesh K.
Published: March 2021

The SARS-CoV-2 nsp16/nsp10 enzyme complex modifies the 2’-OH of the first transcribed nucleotide of the viral mRNA by covalently attaching a methyl group to it. The 2’-Omethylation of the first nucleotide converts the status of mRNA cap from Cap-0 to Cap-1, and thus, helps the virus evade immune surveillance in the host cell. Here, we report two structures of nsp16/nsp10 representing pre- and post-release states of the RNA product (Cap-1). We observe overall widening of the enzyme upon product formation, and an inward twisting motion in the substrate binding region upon product release. These conformational changes reset the enzyme for the next round of catalysis. The structures also identify a unique binding mode and the importance of a divalent metal ion for 2’-Omethylation. We also describe underlying structural basis for the perturbed enzymatic activity of a clinical variant of SARS-CoV-2, and a previous SARS-CoV outbreak strain.
Primed to Die: An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss and Cochlear Damage in Homozygous Foxo3-knockout Mice
Authors: Beaulac Holly J. , Gilels Felicia , Zhang Jingyuan , Jeoung Sarah , White Patricia M.
Published: March 2021

The prevalence of noise-induced hearing loss (NIHL) continues to increase, with limited therapies available for individuals with cochlear damage. We have previously established that the transcription factor FOXO3 is necessary to preserve outer hair cells (OHCs) and hearing thresholds up to two weeks following a mild noise exposure in mice. The mechanisms by which FOXO3 preserves cochlear cells and function are unknown. In this study, we analyzed the immediate effects of mild noise exposure on wild-type,Foxo3heterozygous (Foxo3+/KO), andFoxo3knock-out (Foxo3KO/KO) mice to better understand FOXO3’s role(s) in the mammalian cochlea. We used confocal and multiphoton microscopy to examine well-characterized components of noise-induced damage including calcium regulators, oxidative stress, necrosis, and caspase-dependent and -independent apoptosis. Lower immunoreactivity of the calcium buffer oncomodulin inFoxo3KO/KOOHCs correlated with cell loss beginning 4 hours post-noise exposure. Using immunohistochemistry, we identified parthanatos as the cell death pathway for OHCs. Oxidative stress response pathways were not significantly altered in FOXO3’s absence. We used RNA sequencing to identify and RT-qPCR to confirm differentially expressed genes. We further investigated a gene downregulated in the unexposedFoxo3KO/KOmice that may contribute to OHC noise susceptibility. Glycerophosphodiester Phosphodiesterase Domain Containing 3 (GDPD3), a possible endogenous source of lysophosphatidic acid (LPA), has not previously been described in the cochlea. As LPA reduces OHC loss after severe noise exposure, we treated noise exposedFoxo3KO/KOmice with exogenous LPA. LPA treatment delayed immediate damage to OHCs but was insufficient to ultimately prevent their death or prevent hearing loss. These results suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, possibly through sustaining endogenous LPA levels.
Large-scale design and refinement of stable proteins using sequence-only models
Authors: Singer Jedediah M. , Novotney Scott , Strickland Devin , Haddox Hugh K. , Leiby Nicholas , Rocklin Gabriel J. , Chow Cameron M. , Roy Anindya , Bera Asim K. , Motta Francis C. , Cao Longxing , Strauch Eva-Maria , Chidyausiku Tamuka M. , Ford Alex , Ho Ethan , Mackenzie Craig O. , Eramian Hamed , DiMaio Frank , Grigoryan Gevorg , Vaughn Matthew , Stewart Lance J. , Baker David , Klavins Eric
Published: March 2021

Engineered proteins generally must possess a stable structure in order to achieve their designed function. Stable designs, however, are astronomically rare within the space of all possible amino acid sequences. As a consequence, many designs must be tested computationally and experimentally in order to find stable ones, which is expensive in terms of time and resources. Here we report a neural network model that predicts protein stability based only on sequences of amino acids, and demonstrate its performance by evaluating the stability of almost 200,000 novel proteins. These include a wide range of sequence perturbations, providing a baseline for future work in the field. We also report a second neural network model that is able to generate novel stable proteins. Finally, we show that the predictive model can be used to substantially increase the stability of both expert-designed and model-generated proteins.
Platelet transcriptome yields progressive markers in chronic myeloproliferative neoplasms and identifies putative targets of therapy
Authors: Shen Zhu , Du Wenfei , Perkins Cecelia , Fechter Lenn , Natu Vanita , Maecker Holden , Rowley Jesse , Gotlib Jason , Zehnder James , Krishnan Anandi
Published: March 2021

Predicting disease progression remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs) as a model, we identify the blood platelet transcriptome as a proxy for highly sensitive progression biomarkers that also enables prediction of advanced disease via machine learning algorithms. Using RNA sequencing (RNA-seq), we derive disease-relevant gene expression in purified platelets from 120 peripheral blood samples constituting two time-separated cohorts of patients diagnosed with one of three MPN subtypes at sample acquisition – essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), and healthy donors (n=21). The MPN platelet transcriptome reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy and discriminates each clinical phenotype. Leveraging this dataset that shows a characteristic progressive expression gradient across MPN, we develop a machine learning model (Lasso-penalized regression) and predict advanced subtype MF at high accuracy and under two conditions of external validation: i) temporal: our two Stanford cohorts, AUC-ROC of 0.96; and ii) geographical: independently published data of an additional n=25 MF and n=46 healthy donors, AUC-ROC of 0.97). Lasso-derived signatures offer a robust core set of < 5 MPN transcriptome markers that are progressive in expression. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis-associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs demonstrates a proof of principle for disease risk stratification and progression beyond genetic data alone, with potential utility in other progressive disorders.

Highlights

Leveraging two independent and mutually validating MPN patient cohorts, we identify progressive transcriptomic markers that also enable externally validated prediction in MPNs.

Our platelet RNA-Seq data identifies impaired protein homeostasis as prominent in MPN progression and offers putative targets of therapy.

VISUAL ABSTRACT
Synaptotagmin rings as high sensitivity regulators of synaptic vesicle docking and fusion
Authors: Zhu Jie , McDargh Zachary A. , Li Feng , Krishnakumar Shyam , Rothman James E. , O’Shaughnessy Ben
Published: March 2021

Synchronous release at neuronal synapses is accomplished by a machinery that senses calcium influx and fuses the synaptic vesicle and plasma membranes to release neurotransmitters. Previous studies suggested the calcium sensor Synaptotagmin (Syt) is a facilitator of vesicle docking and both a facilitator and inhibitor of fusion. On phospholipid monolayers, the Syt C2AB domain spontaneously oligomerized into rings that are disassembled by Ca2+, suggesting Syt rings may clamp fusion as membrane-separating “washers” until Ca2+-mediated disassembly triggers fusion and release (Wang et al., 2014). Here we combined mathematical modeling with experiment to measure mechanical properties of Syt rings and to test this mechanism. Consistent with experiment, the model quantitatively recapitulates observed Syt ring-induced dome and volcano shapes on phospholipid monolayers, and predicts rings are stabilized by anionic phospholipid bilayers or bulk solution with ATP. The selected ring conformation is highly sensitive to membrane composition and bulk ATP levels, a property that may regulate vesicle docking and fusion in ATP-rich synaptic terminals. We find the Syt molecules hosted by a synaptic vesicle oligomerize into a halo, unbound from the vesicle, but in proximity to sufficiently PIP2-rich plasma membrane (PM) domains the PM-bound trans Syt ring conformation is preferred. Thus, the Syt halo serves as landing gear for spatially directed docking at PIP2-rich sites that define the active zones of exocytotic release, positioning the Syt ring to clamp fusion and await calcium. Our results suggest the Syt ring is both a Ca2+-sensitive fusion clamp and a high-fidelity sensor for directed docking.

Significance

Synchronous neurotransmitter release relies on directed docking of synaptic vesicles at active zones in axon terminals, where calcium influx activates membrane fusion and release. In vitro, the calcium sensor Synaptotagmin oligomerizes into rings disassembled by calcium. Here, experiment and modeling suggest the Synaptotagmin molecules hosted by an undocked vesicle oligomerize into a tethered, unbound halo in ATP-rich synaptic terminals. The halo directs vesicle docking to PIP2-rich plasma membrane domains in active zones, where the trans-bound ring conformation is favored, interposed between the membranes to clamp fusion until calcium triggers ring disassembly and neurotransmitter release. The mechanism exploits the extreme sensitivity of Synaptotagmin ring binding preferences to solution and membrane composition, with ~15 -fold-enhanced sensitivity for rings of ~15 molecules.
Intriguing effects of selection intensity on the evolution of prosocial behaviors
Authors: McAvoy Alex , Rao Andrew , Hauert Christoph
Published: March 2021

In many models of evolving populations, genetic drift has an outsized role relative to natural selection, or vice versa. While there are many scenarios in which one of these two assumptions is reasonable, intermediate balances between these forces are also biologically relevant. In this study, we consider some natural axioms for modeling intermediate selection intensities, and we explore how to quantify the long-term evolutionary dynamics of such a process. To illustrate the sensitivity of evolutionary dynamics to drift and selection, we show that there can be a “sweet spot” for the balance of these two forces, with sufficient noise for rare mutants to become established and sufficient selection to spread. This balance allows prosocial traits to evolve in evolutionary models that were previously thought to be unconducive to the emergence and spread of altruistic behaviors. Furthermore, the effects of selection intensity on long-run evolutionary outcomes in these settings, such as when there is global competition for reproduction, can be highly non-monotonic. Although intermediate selection intensities (neither weak nor strong) are notoriously difficult to study analytically, they are often biologically relevant; and the results we report suggest that they can elicit novel and rich dynamics in the evolution of prosocial behaviors.

Author summary

Theoretical models of populations have been useful for assessing when and how traits spread, in large part because they are simple. Rather than being used to reproduce empirical data, these idealized models involve relatively few parameters and are utilized to gain a qualitative understanding of what promotes or suppresses a trait. For prosocial traits, which entail a cost to self to help another, one thing that mathematical models often suggest is that competition to reproduce must be localized, meaning an individual must be fitter than just a small subset of the population in order to produce an offspring. We show here that this finding is not robust. Such traits can indeed proliferate when there is global competition for reproduction, which we demonstrate by increasing the degree to which fitness affects birth rates. Since this kind of “stronger selection” has also been observed empirically, we discuss how it is incorporated into theoretical models more broadly.
Good host - bad host: molecular and evolutionary basis for survival, its failure, and virulence factors of the zoonotic nematodeAnisakis pegreffii
Authors: Trumbić Željka , Hrabar Jerko , Palevich Nikola , Carbone Vincenzo , Mladineo Ivona
Published: March 2021

Parasitism is a highly successful life strategy and a driving force in genetic diversity that has evolved many times over. Consequently, parasitic organisms have adopted a rich display of traits associated with survival that guarantees an effective “communication” with the host immunity and a balance with surrounding microbiome. However, gain/loss of hosts along the evolutionary axis represents a complex scenario that as contemporary onlookers, we can observe only after a long time displacement. The zoonotic and monophyletic Anisakidae diverged from its terrestrial sister group Ascarididae 150-250 Ma, although a split from their common ancestral host, a terrestrial amniote, seemingly happened already in Early Carboniferous (360.47 Ma). Faced with the sea-level rise during the Permian-Triassic extinction (215 Ma), anisakids acquired a semiaquatic tetrapod host, and as a result of lateral host-switches in Cenozoic, colonised marine mammals, co-evolving with their “new hosts”. Although contemporary anisakids have lost the ability to propagate in terrestrial hosts, they can survive for a limited time in humans. To scrutinize anisakid versatility to infect evolutionary-distant host, we performed transcriptomic profiling of larvae infecting the accidental host (rat) and compared it to that of larvae infecting an evolutionary-familiar, paratenic host (fish). Identified differences and the modeling of handful of shared transcripts, provides the first insights into evolution of larval nematode virulence, warranting further investigation of shared transcript as potential drug therapy targets. Our findings have also revealed some key intrinsic cues that direct larval fate during infection.