bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-thermal structural transformation of diamond driven by x-rays
Authors: Heimann Philip , Hartley Nicholas J. , Inoue Ichiro , Tkachenko Victor , Antoine Andre , Dorchies Fabien , Falcone Roger , Gaudin Jérôme , Höppner Hauke , Inubushi Yuichi , Kapcia Konrad J. , Lee Hae Ja , Lipp Vladimir , Martinez Paloma , Medvedev Nikita , Tavella Franz , Toleikis Sven , Yabashi Makina , Yabuuchi Toshinori , Yamada Jumpei , Ziaja Beata
Published: October 2023

Intense x-ray pulses can cause the non-thermal structural transformation of diamond. At the SACLA XFEL facility, pump x-ray pulses triggered this phase transition, and probe x-ray pulses produced diffraction patterns. Time delays were observed from 0 to 250 fs, and the x-ray dose varied from 0.9 to 8.0 eV/atom. The intensity of the (111), (220), and (311) diffraction peaks decreased with time, indicating a disordering of the crystal lattice. From a Debye–Waller analysis, the rms atomic displacements perpendicular to the (111) planes were observed to be significantly larger than those perpendicular to the (220) or (311) planes. At a long time delay of 33 ms, graphite (002) diffraction indicates that graphitization did occur above a threshold dose of 1.2 eV/atom. These experimental results are in qualitative agreement with XTANT+ simulations using a hybrid model based on density-functional tight-binding molecular dynamics.
Primal quantization postulate for quantum fields
Authors: Haase Richard W.
Published: October 2023

We formulate a theory of quantum fields underpinned solely by the full geometric algebra structure generated by the vector space of spacetime. A modified dynamical equation of a field with associated background field potentials, distinct from Dirac’s equation, is developed and corrects the inertial potential that acts on the field. A discrete wavenumber spectrum with a possible correlation to the mass spectrum of elementary particles is obtained, and explicit expressions are derived. The formulation is mathematically driven and constitutes what we refer to as the primal field quantization postulate. While manifestly a relativistic quantum field theory, our formulation may provide a natural account of mass hierarchy and family generation. A fourth family of elementary particles is predicted, indicating that lepton and quark oscillations across generation members, as well as quantum decay processes and fluctuations, may need modifying.
Always trust your gut?
Authors: Vallerossa Francesco , Bardel Camilla
Published: October 2023

The study examines how three undergraduate beginner students of Italian as L3 make sense of Italian tense-aspect morphology based on other languages. All students had knowledge of Swedish, English, and French, in each case acquired in a particular chronological order. The participants completed two C-tests and three interpretation tests of aspectual contrasts in English, French, and Italian. The latter was complemented by written comments. The results of the Italian interpretation test varied depending on tense-aspect configurations. A qualitative analysis of the comments revealed four categories of metalinguistic reflections, referring to: (i) explicit rules, (ii) intuition, (iii) other languages, and (iv) uncertain/unknown, differently distributed among the students. The results suggest that the students relied on their L1(s) as well as their L2(s) depending on type of transfer, whether linguistic or conceptual, which is discussed in light of some recent L3 models.
Complete Hemifacial Paralysis Post-facelift: Making Sense of a Plastic Surgeon's Worst Nightmare
Authors: Venditto Chelsea M , Grotting James C , Auersvald Andre , Johnson Debra J , Labbé Daniel , Hodgkinson Darryl , Barrera Alfonso , Warren Richard J , Botti Giovanni , Von Laeken Nancy , Bald Madeline
Published: October 2023

Background

Postrhytidectomy hemifacial paralysis is a frightening clinical condition affecting the proximal facial nerve and most often associated with Bell's palsy. Associated symptoms are common and include auditory, salivary, vestibular, and gustatory complaints.

Objectives

The aim of the study was to provide increased awareness of postrhytidectomy hemifacial paralysis secondary to Bell's palsy in the plastic surgery community.

Methods

Following a roundtable discussion with the senior author's (J.C.G.) plastic surgery colleagues located all over the world, 8 surgeons reported having had firsthand experience with hemifacial paralysis in patients following facelift. Descriptions of their cases, including preoperative, intraoperative, and postoperative courses were collected and reported.

Results

A total of 10 cases of postrhytidectomy hemifacial paralysis were analyzed based on results of a clinical questionnaire. Eight of the 10 cases involved all facial nerve branches, with 2 cases sparing the marginal mandibular branch. The vast majority of cases were referred to a neurologist and steroids initiated. Two patients were returned to the operating room for exploration. Associated symptoms reported included pain in the ear, hearing loss, ocular symptoms such as tearing or dryness, vestibular symptoms such as vertigo, changes in taste, and in 1 patient an electric-shock type sensation to the face.

Conclusions

Hemifacial paralysis associated with Bell's palsy following rhytidectomy is a rare but known clinical entity that should be included in the preoperative informed consent process before facelift. Current management trends are neurology referral and steroid initiation.

Level of Evidence: 4
Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial
Authors: Goldsmith Scott R , Covut Fahrettin , Fiala Mark , Xiang Zhifu , Iqbal Zahid , Moore Nathan , Bradtke Elizabeth , Christen Brandon , Rettig Michael P , Christ Stephanie , Gehrs Leah , Street Emily , Wallace Nicholas , Ritchey Julie , Gao Feng , Pachter Jonathan , Parikh Bijal , Dubberke Erik R , DiPersio John F
Published: October 2023

Background

Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness.

Methods

We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis.

Results

Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%–88%) compared to 62% (95% CI, 32%–86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22–1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines.

Conclusions

In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation.

Clinical Trials Registration

NCT04372602.
Beetles and lichens: tracing the origins and evolution of lichenophagy within the darkling beetle tribe Helopini (Coleoptera: Tenebrionidae)
Authors: Ntatsopoulos Konstantinos , Nabozhenko Maxim V , Jelinscaia Lagou Loudmila , Chigray Ivan A , Gagarina Ludmila V , Alpagut Keskin Nurşen , Keskin Bekir , Papadopoulou Anna
Published: October 2023

Although the complex evolutionary history of lichen-forming fungi has gained considerable attention, particularly regarding the long-debated role of these organisms in shaping early terrestrial ecosystems, the evolution of lichenivory and its potential impact on the diversification of lichenophages have been largely neglected. With > 800 described species worldwide and a broad geographical distribution, the tribe Helopini (Coleoptera: Tenebrionidae) represents a diverse, yet poorly studied, group of predominantly lichenophagous beetles. Using a dataset of 52 ingroup taxa and five gene fragments, a first phylogenetic hypothesis of the tribe was generated, which was subsequently used for reconstructing the ancestral state of the trophic and habitat associations of the beetles and for estimating a time frame of diversification. Our phylogenetic reconstruction sheds light on the higher-level systematics of the tribe, supporting the current subtribal division of the group while also providing a framework for understanding the intergeneric relationships within subtribes. The results also indicate an Early Cretaceous origin of the tribe, highlighting the close association between Helopini and lichen-forming fungi since the emergence of the group. Nevertheless, at least seven independent switches from lichenophagy to alternative feeding habits have occurred since the middle Eocene, which can be linked temporally to transitions from forests to open habitats.
Photobacterium obscurum sp. nov., a marine bacterium isolated from the coast of Qingdao
Authors: Hong Wen , Wang Xiaolei , Yuan Yalin , Liu Ronghua , Zhao Wenbin , Xue Chun-Xu , Zhang Xiao-Hua
Published: October 2023

A Gram-stain-negative, facultative anaerobic, rod-shaped strain, named SDRW27T, was isolated from offshore seawater collected near Qingdao. Strain SDRW27T was able to grow at 16–37 °C (optimum, 28 °C), pH 6.0–9.0 (optimum, pH 6.0) and in the presence of 1–7 % (w/v) NaCl (optimum, 3 %). Phylogenetic analysis using 16S rRNA gene sequences indicated that strain SDRW27T was most closely related to

Photobacterium toruni

H01100410BT (97.89 % sequence similarity),

Photobacterium andalusiense

H01100409BT (97.89 %) and

Photobacterium leiognathi

ATCC 25521T (97.82 %). The predominant fatty acids were summed feature 3 (C16 : 1 ω7c and/or iso-C15 : 0 2-OH), summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) and C16 : 0. The polar lipids of strain SDRW27T comprised phosphatidylglycerol, phosphatidylinositol dimannoside, phosphatidylcholine, phosphatidylethanolamine and three unidentified lipids. The major respiratory quinone was ubiquinone-8. The G+C content was 47.71 mol%. The genome size was 5.84 Mbp, including 85 contigs with an N50 value of 223 542. The average nucleotide identity (ANI) values of SDRW27T with its three most similar strains,

P. toruni

H01100410BT,

P. andalusiense

H01100409BT and

P. leiognathi

ATCC 25521T, were 71.36, 71.58 and 72.23 %, respectively (all lower than the 95–96 % ANI threshold), and the DNA–DNA hybridization (DDH) values were 20.4, 20.8 and 20.4 % (all lower than the 70 % DDH threshold). The obtained results of polyphasic analysis demonstrate that strain SDRW27T represents a novel species, for which the name Photobacterium obscurum sp. nov. is proposed. The type strain is SDRW27T (=MCCC 1K06286T=KCTC 82892T).
OMEinfo: Global Geographic Metadata for -omics Experiments
Authors: Crown Matthew , Bashton Matthew
Published: October 2023

Microbiome studies increasingly associate geographical features like rurality and climate types with microbiomes. However, microbiologists/bioinformaticians often struggle to access and integrate rich geographical metadata from sources such as GeoTIFFs; and inconsistent definitions of rurality, for example, can hinder cross-study comparisons. To address this, we present OMEinfo, a Python-based tool for automated retrieval of consistent geographical metadata from user-provided location data. OMEinfo leverages open data sources such as the Global Human Settlement Layer, Köppen-Geiger climate classification models, and Open-Data Inventory for Anthropogenic Carbon dioxide, to ensure metadata accuracy and provenance. OMEinfo’s Dash application enables users to visualise their sample metadata on an interactive map and to investigate the spatial distribution of metadata features, which is complemented by data visualisation to analyse patterns and trends in the geographical data before further analysis. The tool is available as a Docker container, providing a portable, lightweight solution for researchers. Through its standardised metadata retrieval approach and incorporation of FAIR and Open data principles, OMEinfo promotes reproducibility and consistency in microbiome metadata. To demonstrate its utility, OMEinfo is utilised to replicate the results of a previous study linking population density to soil sample alpha diversity. As the field continues to explore the relationship between microbiomes and geographical features, tools like OMEinfo will prove vital in developing a robust, accurate, and interconnected understanding of these interactions, whilst having applicability beyond this field to any studies utilising location-based metadata. Finally, we release the OMEinfo annotation dataset, a collection of 5.3 million OMEinfo annotated samples from the ENA, for use in a retrospective analysis of sequencing samples, and highlight a number of ways researchers and sequencing read repositories can improve the quality of underlying metadata submitted to these public stores.

Availability

OMEinfo is freely available and released under an MIT licence. OMEinfo source code is available athttps://github.com/m-crown/OMEinfo/

Contact

matthew.crown@northumbria.ac.uk,matthew.bashton@northumbria.ac.uk
Genotype-specific nonphotochemical quenching responses to nitrogen deficit are linked to chlorophyll a to b ratios
Authors: Sahay Seema , Grzybowski Marcin , Schnable James C. , Głowacka Katarzyna
Published: October 2023

Non-photochemical quenching (NPQ) protects plants from photodamage caused by excess light energy. The mechanism of NPQ appears to be conserved across flowering plants. However, substantial variation in NPQ has been reported within different genotypes of the same species grown under the environmental conditions. Individual maize genotypes from a diversity panel exhibited a range of responses to low nitrogen with some genotypes exhibiting increased NPQ between control and low nitrogen conditions and others exhibiting no change. These patterns were consistent for the same genotypes across multiple field seasons. NPQ increases under low nitrogen were correlated with shifts in the ratio of chlorophyllato chlorophyllbconsistent with a decrease in reaction centers. Both photosynthetic capacity and dry biomass accumulation decreased more in maize genotypes which were unable to maintain constant NPQ levels between control and low N conditions. Collectively these results suggest that the ability to maintain sufficient numbers of reaction centers under low nitrogen conditions and avoid dissipating a greater proportion of absorbed light energy via the NPQ pathway may play a key role in increasing carbon fixation and productivity in nitrogen-limited environments.

Highlights

Substantial variation in NPQ kinetics exists in maize on both low and control N.

In early and late-vegetative stages a similar portion of genotypes increased, no-change or decreasedNPQmaxin response to low N while in the post-flowering stage substantially more genotypes decreasedNPQmax.

In low nitrogen conditions, theNPQmaxstrongly correlates with shifts in Chla/Chlbratios.
Replication stress underlies genomic instability at CTCF/cohesin-binding sites in cancer
Authors: Faseela Elangoli Ebrahimkutty , Notani Dimple , Sabarinathan Radhakrishnan
Published: October 2023

CCCTC-binding factor (CTCF) and cohesin play a significant role in the formation of chromatin loops and topologically associating domains (TADs), which influence gene expression and DNA replication. CTCF/cohesin-binding sites (CBSs) present at the loop anchors and TAD boundaries are frequently mutated in cancer; however, the molecular mechanisms underlying this remain unclear. Here, we investigate whether the binding of CTCF/cohesin on DNA imposes constraints on DNA replication, leading to replication stress and genomic instability. Our results reveal that CTCF and cohesin remain bound to DNA during replication (S phase) in cancer cells (HeLa). Further, examination of replication stress through imaging revealed colocalization of DNA damage response proteins (MRE11 and STN1) with CTCF/cohesin in the S phase. In addition, ChIP-seq of the DNA damage response/repair proteins (MRE11, STN1, γH2AX and RAD51) showed high enrichment of these proteins at CBSs (as compared to their immediate flanking regions and control sites) and positively correlated with the binding strength of CTCF/cohesin at CBSs in the S phase. Moreover, analysis of somatic mutations from cancer genomes supports that the enrichment of mutations at CBSs is significantly higher in samples harbouring somatic copy number deletion in MRE11 and STN1 compared to wild-type samples. Together, these results demonstrate that the binding of CTCF/cohesin on the DNA during the S phase causes replication stress and DNA strand breaks, and this could lead to genome instability at CBSs observed in cancer.
The rapid diversification of Boletales is linked to Early Eocene and Mid-Miocene Climatic Optima
Authors: Wu Gang , Wu Kui , Halling Roy E. , Horak Egon , Xu Jianping , Li Guang-Mei , Lee Serena , Pecoraro Lorenzo , Arzu Roberto Flores , Ndolo Ebika Sydney T. , Aouali Souhila , Persiani Anna Maria , Yorou Nourou S. , Xu Xin , Feng Bang , Li Yan-Chun , Yang Zhu-Liang
Published: October 2023

Investigating the mechanisms that underpin the diversity and distribution patterns of species is fundamental in ecology and evolution. However, the study of fungi, particularly the ectomycorrhizal group, has been relatively constrained in this field.

We conducted a high-resolution phylogenomic analysis of Boletales, an ecologically and economically significant group of fungi, covering 83 genera across 15 families. We subsequently investigated its evolutionary history using sequences at four genes obtained from 984 species across 121 genera within 15 families.

The findings unveiled that Boletales likely originated in Early Jurassic and underwent two remarkable episodes of rapid diversification, commencing in early Eocene (∼54 Mya) and early Miocene (∼17 Mya) epochs. The notable surges were predominantly driven by ectomycorrhizal clades, with a specific emphasis on East Asia and North America. These expansions were strongly correlated with the warm-humid paleoclimates during the Early Eocene Climatic Optimum and Mid-Miocene Climatic Optimum, as well as the rapid expansion of Fagales and Pinaceae hosts.

This study provides novel insights into the spatiotemporal evolution of fungi, highlighting the synergistic impact of abiotic factors, such as warm and humid paleoclimates, and the biotic factor of rapid diversification of host plants on the fungal diversification.
Marker-based CRISPR screening reveals a MED12-p63 interaction that activates basal identity in pancreatic ductal adenocarcinoma
Authors: Maia-Silva Diogo , Schier Allison C. , Skopelitis Damianos , Kechejian Vahag , Alpsoy Aktan , Liverpool Jynelle , Taatjes Dylan J. , Vakoc Christopher R.
Published: October 2023

The presence of basal lineage characteristics signifies hyper-aggressive human adenocarcinomas of the breast, bladder, and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor p63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to classical PDAC. Taken together, our comprehensive genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics.
Identification of CD44 as a key mediator of cell traction force generation in hyaluronic acid-rich extracellular matrices
Authors: Cheung Brian C. H. , Chen Xingyu , Davis Hannah J. , Nordmann Cassidy S. , Toth Joshua , Hodgson Louis , Segall Jeffrey E. , Shenoy Vivek B. , Wu Mingming
Published: October 2023

Mechanical properties of the extracellular matrix (ECM) critically regulate a number of important cell functions including growth, differentiation and migration. Type I collagen and glycosaminoglycans (GAGs) are two primary components of ECMs that contribute to mammalian tissue mechanics, with the collagen fiber network sustaining tension, and GAGs withstanding compression. The architecture and stiffness of the collagen network are known to be important for cell-ECM mechanical interactions via integrin cell surface adhesion receptors. In contrast, studies of GAGs in modulating cell-ECM interactions are limited. Here, we present experimental studies on the roles of hyaluronic acid (HA, an unsulfated GAG) in single tumor cell traction force generation using a recently developed 3D cell traction force microscopy method. Our work reveals that CD44, a cell surface adhesion receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreasing tumor cells’ propensity to remodel the collagen network, attenuating traction force generation, transmission distance, and tumor invasion. Our findings point to a novel role for CD44 in traction force generation, which can be a potential therapeutic target for diseases involving HA rich ECMs such as breast cancer and glioblastoma.
Environmental DNA Reveals the Geographic Distributions of Two Eel Species,Anguilla japonicaandA. marmorata, in Western Kyushu, Japan
Authors: Ono Yurika , Tsuchida Shimpei , Hirasaka Katsuya , Myosho Taijun , Fujimoto Shingo , Shimizu Kenichi , Yagi Mitsuharu
Published: October 2023

Anguillid eels migrate thousands of kilometres from their spawning grounds, dispersing across a vast geographic area to fresh and brackish water habitats, where they settle and grow. Japanese eels (Anguilla japonica) and giant mottled eels (A. marmorata) are both found in Japan, although their distributions differ. However, details of these differences are unknown. We hypothesised that distribution patterns of Japanese and giant mottled eels must be different between and within rivers along the northwest coast of Kyushu, Japan. Environmental DNA (eDNA) analysis was conducted at 87 sites in 23 rivers. Japanese eel eDNA was detected in 19 rivers (82.6%) and that of giant mottled eels was detected in 8 (34.8%). eDNA for Japanese eels was detected at 6 of 9 sites in the North (66.7%), 13 of 23 sites in Omura (56.5%) and 37 of 55 sites in the South (67.3%). In contrast, giant mottled eel eDNA was detected at 1 of 9 sites in the North (11.1%), no sites in Omura and 15 of 55 sites in the South (27.3%). There was no correlation between eDNA concentrations of the two species at 10 sites in the five rivers where eDNA of both species was detected, implying that their habitat preference differ. This partially reveals dispersal and settlement mechanisms of these eel species.
TRILL: Orchestrating Modular Deep-Learning Workflows for Democratized, Scalable Protein Analysis and Engineering
Authors: Martinez Zachary A , Murray Richard M. , Thomson Matt W.
Published: October 2023

Abstract

Deep-learning models have been rapidly adopted by many fields, partly due to the deluge of data humanity has amassed. In particular, the petabases of biological sequencing data enable the unsupervised training of protein language models that learn the “language of life.” However, due to their prohibitive size and complexity, contemporary deep-learning models are often unwieldy, especially for scientists with limited machine learning backgrounds. TRILL (TRaining andInference using theLanguage ofLife) is a platform for creative protein design and discovery. Leveraging several state-of-the-art models such as ESM-2, DiffDock, and RFDiffusion, TRILL allows researchers to generate novel proteins, predict 3-D structures, extract high-dimensional representations of proteins, functionally classify proteins and more. What sets TRILL apart is its ability to enable complex pipelines by chaining together models and effectively merging the capabilities of different models to achieve a sum greater than its individual parts. Whether using Google Colab with one GPU or a supercomputer with hundreds, TRILL allows scientists to effectively utilize models with millions to billions of parameters by using optimized training strategies such as ZeRO-Offload and distributed data parallel. Therefore, TRILL not only bridges the gap between complex deep-learning models and their practical application in the field of biology, but also simplifies the orchestration of these models into comprehensive workflows, democratizing access to powerful methods. Documentation:https://trill.readthedocs.io/en/latest/home.html.
Allosteric Modulation of YAP/TAZ-TEAD Interaction by Palmitoylation and Small Molecule Inhibitors
Authors: Mills Kira R. , Misra Jyoti , Torabifard Hedieh
Published: October 2023

The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, they translocate into the nucleus, where they associate with TEAD transcription factors. This partnership is instrumental in regulating the transcription of pro-growth and anti-apoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes an auto-palmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. Utilizing molecular dynamics simulations, our investigation not only provides a detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences YAP and TAZ binding to TEAD in distinct manners. This discovery holds significant implications for the design and deployment of future molecular interventions targeting this interaction.
Individual canopy tree species maps for the National Ecological Observatory Network
Authors: Weinstein Ben. G. , Marconi Sergio , Zare Alina , Bohlman Stephanie A. , Singh Aditya , Graves Sarah J. , Magee Lukas , Johnson Daniel J. , Record Sydne , Rubio Vanessa E. , Swenson Nathan G. , Townsend Philip , Veblen Thomas T. , Andrus Robert A. , White Ethan P.
Published: October 2023

The ecology of forest ecosystems depends on the composition of trees. Capturing fine-grained information on individual trees at broad scales provides a unique perspective on forest ecosystems, forest restoration and responses to disturbance. Individual tree data at wide extents promises to increase the scale of forest analysis, biogeographic research, and ecosystem monitoring without losing details on individual species composition and abundance. Computer vision using deep neural networks can convert raw sensor data into predictions of individual canopy tree species through labeled data collected by field researchers. Using over 40,000 individual tree stems as training data, we create landscape-level species predictions for over 100 million individual trees across 24 sites in the National Ecological Observatory Network. Using hierarchical multi-temporal models fine-tuned for each geographic area, we produce open-source data available as 1 km2shapefiles with individual tree species prediction, as well as crown location, crown area and height of 81 canopy tree species. Site-specific models had an average performance of 79% accuracy covering an average of six species per site, ranging from 3 to 15 species per site. All predictions are openly archived and have been uploaded to Google Earth Engine to benefit the ecology community and overlay with other remote sensing assets. We outline the potential utility and limitations of these data in ecology and computer vision research, as well as strategies for improving predictions using targeted data sampling.
Early antiviral CD4 and CD8 T cell responses and antibodies are associated with upper respiratory tract clearance of SARS-CoV-2
Authors: Ramirez Sydney I , Lopez Paul G , Faraji Farhoud , Parikh Urvi M , Heaps Amy , Ritz Justin , Moser Carlee , Eron Joseph J , Wohl David A , Currier Judith S , Daar Eric S , Greninger Alex L , Klekotka Paul , Grifoni Alba , Weiskopf Daniela , Sette Alessandro , Peters Bjoern , Hughes Michael D , Chew Kara W , Smith Davey M , Crotty Shane ,   ACTIV-2/A5401 Study Team
Published: October 2023

T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, samples were assessed for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4 and CD8 T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4 T cell and CD8 T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4 and CD8 T cells during acute COVID-19.
The biochemical impact of extracting an embedded adenylate kinase domain using circular permutation
Authors: Coleman Tom , Shin John , Silberg Jonathan J. , Shamoo Yousif , Atkinson Joshua T.
Published: October 2023

Adenylate kinases (AKs) are phosphotransferases that are frequently employed as models to investigate protein structure-function relationships. Prior studies have shown that AK homologs of different stabilities retain cellular activity in cells following circular permutation that split the AMP binding domain into fragments coded at different ends of the primary structure, such that this domain was no longer embedded as a continuous polypeptide within the core domain. Herein, we show mesophilic and thermophilic AKs having this topological restructuring retain activity and substrate-binding characteristics of the parental AK. While permutation decreased the activity of both AK homologs at physiological temperatures, the catalytic activity of the thermophilic AK increased upon permutation when assayed >30°C below the melting temperature of the native AK. The thermostabilities of the permuted AKs were uniformly lower than native AKs, and they exhibited multi-phasic unfolding transitions, unlike the native AKs, which presented cooperative thermal unfolding. In addition, proteolytic digestion revealed that permutation destabilized each AK, and mass spectrometry suggested that the new termini within the AMP binding domain were responsible for the increased proteolysis sensitivity. These findings illustrate how changes in contact order can be used to tune enzyme activity and alter folding dynamics in multidomain enzymes.

Graphical abstract
ASSESSING TARGET SPECIFICITY OF THE SMALL MOLECULE INHIBITOR MARIMASTAT TO SNAKE VENOM TOXINS: A NOVEL APPLICATION OF THERMAL PROTEOME PROFILING
Authors: Smith Cara F. , Modahl Cassandra M. , Ceja-Galindo David , Larson Keira Y. , Maroney Sean P. , Bahrabadi Lilyrose , Brandehoff Nicklaus P. , Perry Blair W. , McCabe Maxwell C. , Petras Daniel , Lomonte Bruno , Calvete Juan J. , Castoe Todd A. , Mackessy Stephen P. , Hansen Kirk C. , Saviola Anthony J.
Published: October 2023

New treatments that circumvent the pitfalls of traditional antivenom therapies are critical to address the problem of snakebite globally. Numerous snake venom toxin inhibitors have shown promising cross-species neutralization of medically significant venom toxinsin vivoandin vitro. The development of high-throughput approaches for the screening of such inhibitors could accelerate their identification, testing, and implementation, and thus holds exciting potential for improving the treatments and outcomes of snakebite envenomation worldwide. Energetics-based proteomic approaches, including Thermal Proteome Profiling (TPP) and Proteome Integral Solubility Alteration (PISA), assays represent “deep proteomics” methods for high throughput, proteome-wide identification of drug targets and ligands. In the following study, we apply TPP and PISA methods to characterize the interactions between venom toxin proteoforms inCrotalus atrox(Western Diamondback Rattlesnake) and the snake venom metalloprotease (SVMP) inhibitor marimastat. We investigate its venom proteome-wide effects and characterize its interactions with specific SVMP proteoforms, as well as its potential targeting of non-SVMP venom toxin families. We also compare the performance of PISA thermal window and soluble supernatant with insoluble precipitate using two inhibitor concentrations, providing the first demonstration of the utility of a sensitive high-throughput PISA-based approach to assess the direct targets of small molecule inhibitors for snake venom.
Cost-effectiveness analysis of COVID-19 booster doses and oral antivirals in the Indo-Pacific
Authors: Bilgin Gizem Mayis , Munira Syarifah Liza , Lokuge Kamalini , Glass Kathryn
Published: October 2023

Background

Decision-makers in middle-income countries need evidence on the cost-effectiveness of COVID-19 booster doses and oral antivirals to appropriately prioritise these healthcare interventions.

Methods

We used a dynamic transmission model to assess the cost-effectiveness of COVID-19 booster doses and oral antivirals in Fiji, Indonesia, Papua New Guinea, and Timor-Leste. We conducted cost-effectiveness analysis from both healthcare and societal perspectives using 3% discounting for ongoing costs and health benefits. We developed an interactive R Shiny which allows the user to vary key model assumptions, such as the choice of discounting rate, and view how these assumptions affect model results.

Findings

Booster doses were cost saving and therefore cost-effective in all four middle-income settings from both healthcare and societal perspectives using 3% discounting. Providing oral antivirals was cost-effective from a healthcare perspective if procured at a low generic ($25 United States Dollars) or middle-income reference price ($250 United States Dollars); however, their cost-effectiveness was strongly influenced by rates of wastage or misuse, and the ongoing costs of care for patients hospitalised with COVID-19. Interestingly, the cost or wastage of rapid antigen tests did not appear strongly influential over the cost-effectiveness of oral antivirals in any of the four study settings.

Conclusions

Our results support that government funded COVID-19 booster programs continue to be cost-effective in middle-income settings. Oral antivirals demonstrate the potential to be cost-effective if procured at or below a middle-income reference price of $250 USD per schedule. Further research should quantify the rates of wastage or misuse of oral COVID-19 antivirals in middle-income settings.
Is Gauchian genotyping ofGBA1variants reliable?
Authors: Tayebi Nahid , Lichtenberg Jens , Hertz Ellen , Sidransky Ellen
Published: October 2023

Biallelic mutations inGBA1result in Gaucher disease (GD), the inherited deficiency of glucocerebrosidase. Variants inGBA1are also a common genetic risk factor for Parkinson disease (PD). Currently, some PD centers screen for mutantGBA1alleles to stratify patients who may ultimately benefit fromGBA1-targeted therapeutics. However, accurately detecting variants, especially recombinant alleles resulting from a crossover betweenGBA1and its pseudogene, is challenging, impacting studies of both GD andGBA1-associated parkinsonism. Recently, the software tool Gauchian was introduced to identifyGBA1variants from whole genome sequencing. We evaluated Gauchian in 90 Sanger-sequenced patients with GD and fiveGBA1heterozygotes. While Gauchian genotyped most patients correctly, it missed some rare orde novomutations due to its limited internal database and over-reliance on intergenic structural variants. This resulted in misreported homozygosity, incomplete genotypes, and undetected recombination events, limiting Gauchian’s utility in variant screening and precluding its use in diagnostics.
Genetic Analysis and Natural History of Parkinson’s Disease Due to the LRRK2 G2019S Variant
Authors: Kmiecik Matthew J. , Micheletti Steven , Coker Daniella , Heilbron Karl , Shi Jingchunzi , Stagaman Keaton , Filshtein Sonmez Teresa , Fontanillas Pierre , Shringarpure Suyash , Schloetter Madeleine , Rowbotham Helen M. , Cannon Paul , Shelton Janie F. , Hinds David A. , Tung Joyce Y. ,   23andMe Research Team, Holmes Michael V. , Aslibekyan Stella , Norcliffe-Kaufmann Lucy
Published: October 2023

TheLRRK2 G2019Svariant is the most common cause of monogenic Parkinson’s Disease (PD); however, questions remain regarding the penetrance, clinical phenotype, and natural history of carriers.

We performed a 3.5 year prospective longitudinal online study in a large number of 1,286 genotypedLRRK2 G2019Scarriers and 109,154 controls, with and without Parkinson’s disease (PD) recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every six months, as well as demographics, family histories, and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modeling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of allLRRK2 G2019Scarriers in the 23andMe database and identified regions of the world where carrier frequencies are highest.

We observed that despite a one year longer disease duration (p=0.016),LRRK2 G2019Scarriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behavior disorder (RBD), and hyposmia (allp-values<0.0002). The cumulative incidence of PD inG2019Scarriers by age 60 was 8.66%.G2019Scarriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk inG2019Scarriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that theG2019Svariant was later introduced to Spanish colonial territories in the Americas.

Our results suggestLRRK2 G2019SPD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD, and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases ofLRRK2PD inG2019Scarriers. We show that polygenic burden may contribute to the development of PD in theLRRK2 G2019Scarrier population. Collectively, the results should help support screening programs and candidate enrichment strategies for upcoming trials ofLRRK2inhibitors in early-stage disease.
Assessing mechanical agency during apical apoptotic cell extrusion
Authors: Anjum Sommer , Turner Llaran , Atieh Youmna , Eisenhoffer George T. , Davidson Lance
Published: October 2023

Epithelial tissues maintain homeostasis through the continual addition and removal of cells. Homeostasis is necessary for epithelia to maintain barrier function and prevent the accumulation of defective cells. Unfit, excess, and dying cells can be removed from epithelia by the process of extrusion. Controlled cell death and extrusion in the epithelium of the larval zebrafish tail fin coincides with oscillation of cell area, both in the extruding cell and its neighbors. Both cell-autonomous and non-autonomous factors have been proposed to contribute to extrusion but have been challenging to test by experimental approaches. Here we develop a dynamic cell-based biophysical model that recapitulates the process of oscillatory cell extrusion to test and compare the relative contributions of these factors. Our model incorporates the mechanical properties of individual epithelial cells in a two-dimensional simulation as repelling active particles. The area of cells destined to extrude oscillates with varying durations or amplitudes, decreasing their mechanical contribution to the epithelium and surrendering their space to surrounding cells. Quantitative variations in cell shape and size during extrusion are visualized by a hybrid weighted Voronoi tessellation technique that renders individual cell mechanical properties directly into an epithelial sheet. To explore the role of autonomous and non-autonomous mechanics, we vary the biophysical properties and behaviors of extruding cells and neighbors such as the period and amplitude of repulsive forces, cell density, and tissue viscosity. Our data suggest that cell autonomous processes are major contributors to the dynamics of extrusion, with the mechanical microenvironment providing a less pronounced contribution. Our computational model based onin vivodata serves as a tool to provide insights into the cellular dynamics and localized changes in mechanics that promote elimination of unwanted cells from epithelia during homeostatic tissue maintenance.
Integrating brainstem and cortical functional architectures
Authors: Hansen Justine Y. , Cauzzo Simone , Singh Kavita , García-Gomar María Guadalupe , Shine James M. , Bianciardi Marta , Misic Bratislav
Published: October 2023

The brainstem is a fundamental component of the central nervous system yet it is typically excluded fromin vivohuman brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function. Here we use high-resolution 7 Tesla fMRI to derive a functional connectome encompassing cortex as well as 58 brainstem nuclei spanning the midbrain, pons and medulla. We identify a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex. Patterns of connectivity between brainstem and cerebral cortex manifest as multiple emergent phenomena including neurophysiological oscillatory rhythms, patterns of cognitive functional specialization, and the unimodal-transmodal functional hierarchy. This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters. We replicate all findings using 3 Tesla data from the same participants. Collectively, we find that multiple organizational features of cortical activity can be traced back to the brainstem.
Chromokinesin Klp-19 regulates microtubule overlap and dynamics during anaphase inC. elegans
Authors: Zimyanin Vitaly , Magaj Magdalena , Manzi Nadia Ingabire , Yu Che-Hang , Gibney Theresa , Chen Yu-Zen , Basaran Mustafa , Horton Xavier , Siller Karsten , Pani Ariel , Needleman Daniel , Dickinson Daniel J. , Redemann Stefanie
Published: October 2023

Recent studies have highlighted the significance of the spindle midzone, the region between the segregating chromosomes, in ensuring proper chromosome segregation. By combining 3D electron tomography, cutting-edge light microscopy and a novel single cellin vitroessay allowing single molecule tracking, we have discovered a previously unknown role of the regulation of microtubule dynamics within the spindle midzone ofC. elegansby the chromokinesin KLP-19, and its relevance for proper spindle function. Using Fluorescence recovery after photobleaching and a combination of second harmonic generation and two-photon fluorescence microscopy, we found that the length of the antiparallel microtubule overlap zone in the spindle midzone is constant throughout anaphase, and independent of cortical pulling forces as well as the presence of the microtubule bundling protein SPD-1. Further investigations of SPD-1 and KLP-19 inC. elegans, the homologs of PRC1 and KIF4a, suggest that KLP-19 regulates the overlap length and functions independently of SPD-1. Our data shows that KLP-19 plays an active role in regulating the length of microtubules within the midzone as well as the size of the antiparallel overlap region throughout mitosis. Depletion of KLP-19 in mitosis leads to an increase in microtubule length and thus microtubule-based interactions in the spindle midzone, which affects spindle dynamics and force transmission. Our data shows that by localizing KLP-19 to the spindle midzone in anaphase microtubule dynamics can be locally controlled allowing the formation of a functional midzone.

KLP-19 controls microtubule length in the spindle midzone ofC. elegans, affecting spindle dynamics and force transmission during mitosis.
Dictyostelium discoideum-assisted pharmacognosy of plant resources for discovering antivirulence molecules targetingKlebsiella pneumoniae
Authors: Hernández Marcos , Areche Carlos , Castañeta Grover , Rojas Diego , Varas Macarena A. , Marcoleta Andrés E. , Chávez Francisco P.
Published: October 2023

The rise of antibiotic-resistant bacterial strains poses a significant global health challenge, underscoring the critical need for innovative strategies to address this threat. Natural products and their derivatives have emerged as a promising reservoir for drug discovery. The social amoebaDictyostelium discoideumis an advantageous model organism in this effort. Using this invertebrate model, we introduce a novel perspective to screen natural plant extracts for molecules with potential antivirulence activity. As a proof of concept, we established a simple high-throughput assay to screen for antivirulence molecules targetingKlebsiella pneumoniaeamong extracts ofHelenium aromaticum. Thus, we aimed to identify compounds attenuatingK. pneumoniaevirulence without inducing cytotoxic effects on amoeba cells. Notably, the methanolic root extract ofH. aromaticumbut not other extracts fulfilled these prerequisites. Further analysis via UHPLC-ESI-MS/MS led to the identification of 24 chemical compounds boasting potential antivirulence attributes. This research underscores the potential of employingD. discoideum-assisted pharmacognosy for unearthing novel antivirulence agents against multidrug-resistant pathogens.

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