bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling the Long-term Natural History of Branch Duct Intraductal Papillary Mucinous Neoplasm
Authors: Assawasirisin Charnwit , Fagenholz Peter , Qadan Motaz , Hernandez-Barco Yasmin , Aimprasittichai Satita , Kambadakone Avinash , Mino-Kenudson Mari , Ike Amarachi , Chen Sheng-Yin , Sheng Chen , Brugge William , Warshaw Andrew L. , Lillemoe Keith D. , Fernández-del Castillo Carlos
Published: September 2024

Objective:

To describe the long-term natural history of branch duct intraductal papillary mucinous neoplasm (BD-IPMN).

Background:

The BD-IPMN is a known precursor of pancreatic cancer, yet its long-term natural history is largely unknown.

Methods:

We retrospectively reviewed patients with BD-IPMN who were followed at the Massachusetts General Hospital for at least 10 years without surgical intervention. Patient and cyst characteristics, development of worrisome features (WF), need for surgery, and malignancy were recorded. The risk of pancreatic cancer in this cohort was compared with the general population by determining the standardized incidence ratio.

Results:

Three hundred sixteen patients with BD-IPMN who were followed for at least 10 years without intervention were identified. The median age was 63 years, and the median follow-up was 13.5 years (range: 10–28.8 years). Median cyst size at diagnosis was 1.2 cm (IQR: 0.8–1.7), was 1.8 cm (IQR: 1.2–2.6) at 10 years, and increased to 2.0 cm (IQR: 1.3–3.0) by the end of surveillance. At the 10-year mark, 24% of patients had WF, and by the end of surveillance, an additional 20% had developed WF or high-risk stigmata. 8.2% of patients developed pancreatic malignancy (high-grade dysplasia or invasive cancer). The standardized incidence ratio for pancreatic cancer was 9.28 (95% CI: 5.82–14.06), with almost two-thirds of invasive cancers occurring within the pancreatic cyst.

Conclusions:

After 10 years of surveillance for BD-IPMN without intervention, the disease continues to progress, and 1 of every 12 patients will develop malignancy. The risk of pancreatic cancer appears to be 9 times higher than in the comparable age-matched population.
Service specification for senior care workers with traditional Chinese medicine specialty
Authors: Zou Qi , Tang Qin , Wang Lei , Geng Jiawei , Deng Baofeng , Yu Zhen , An Ayue , Wei Lixin , Tong Xiaoying , Rong Peijing
Published: September 2024

Senior care workers specializing in traditional Chinese medicine (TCM) healthcare have become an indispensable force in institutional care, community care, and home care. The first Chinese nursing service team aimed to improve the health of the elderly by providing continuous services for physical and mental well-being, disease prevention, physical amelioration, and overall health enhancement using TCM concepts, methods, and technologies. The primary purpose of formulating this TCM health and elderly care worker service specification was to standardize services within the TCM elderly care industry, ensuring that the elderly receive better health and elderly care services supported by technical expertise. This specification outlined the basic requirements for TCM health and elderly care workers, including standards for service content, service quality control, service evaluation, and improvement. It primarily focused on the content and requirements of TCM health and elderly care services, such as constitution identification, life care, acupoint healthcare, and TCM auxiliary nursing for elderly individuals with chronic diseases. This specification is applicable to TCM health and elderly care personnel at various levels of hospitals and healthcare institutions and is noted for its strong applicability and effectiveness.
Fly Fam161 is an essential centriole and cilium transition zone protein with unique and diverse cell type-specific localizations
Authors: Jaiswal Ankit , Boring Andrew , Mukherjee Avik , Avidor-Reiss Tomer
Published: September 2024

Family with sequence similarity 161 (Fam161) is an ancient family of microtubule-binding proteins located at the centriole and cilium transition zone (TZ) lumen that exhibit rapid evolution in mice. However, their adaptive role is unclear. Here, we used flies to gain insight into their cell type-specific adaptations. Fam161 is the sole orthologue of FAM161A and FAM161B found in flies. Mutating Fam161 results in reduced male reproduction and abnormal geotaxis behaviour. Fam161 localizes to sensory neuron centrioles and their specialized TZ (the connecting cilium) in a cell type-specific manner, sometimes labelling only the centrioles, sometimes labelling the centrioles and cilium TZ and sometimes labelling the TZ with varying lengths that are longer than other TZ proteins, defining a new ciliary compartment, the extra distal TZ. These findings suggest that Fam161 is an essential centriole and TZ protein with a unique cell type-specific localization in fruit flies that can produce cell type-specific adaptations.
Body size modulates the extent of seasonal diet switching by large mammalian herbivores in Yellowstone National Park
Authors: Littleford-Colquhoun Bethan L. , Geremia Chris , McGarvey Lauren M. , Merkle Jerod A. , Hoff Hannah K. , Anderson Heidi , Segal Carlisle R. , Kartzinel Rebecca Y. , Maywar Ian J. , Nantais Natalie , Moore Camela , Kartzinel Tyler R.
Published: September 2024

Prevailing theories about animal foraging behaviours and the food webs they occupy offer divergent predictions about whether seasonally limited food availability promotes dietary diversification or specialization. Emphasis on how animals compete for food predominates in work on the foraging ecology of large mammalian herbivores, whereas emphasis on how the diversity of available foods generally constrains dietary opportunity predominates work on entire food webs. Reconciling predictions about what promotes dietary diversification is challenging because species’ different body sizes and mobilities modulate how they seek and compete for resources—the mechanistic bases of common predictions may not pertain to all species equally. We evaluated predictions about five large-herbivore species that differ in body size and mobility in Yellowstone National Park using GPS tracking and dietary DNA. The data illuminated remarkably strong and significant correlations between body size and five key indicators of diet seasonality (
R
2
= 0.71–0.80). Compared to smaller species, bison and elk showed muted diet seasonality and maintained access to more unique foods when winter conditions constrained food availability. Evidence from GPS collars revealed size-based differences in species’ seasonal movements and habitat-use patterns, suggesting that better accounting for the allometry of foraging behaviours may help reconcile disparate ideas about the ecological drivers of seasonal diet switching.
Brain shapes of large-bodied, flightless ratites (Aves: Palaeognathae) emerge through distinct developmental allometries
Authors: Forcellati Meghan R. , Green Todd L. , Watanabe Akinobu
Published: September 2024

Comparative neuroanatomical studies have long debated the role of development in the evolution of novel and disparate brain morphologies. Historically, these studies have emphasized whether evolutionary shifts along conserved or distinct developmental allometric trends cause changes in brain morphologies. However, the degree to which interspecific differences between variably sized taxa originate through modifying developmental allometry remains largely untested. Taxa with disparate brain shapes and sizes thus allow for investigation into how developmental trends contribute to neuroanatomical diversification. Here, we examine a developmental series of large-bodied ratite birds (approx. 60–140 kg). We use three-dimensional geometric morphometrics on cephalic endocasts of common ostriches, emus and southern cassowaries and compare their developmental trajectories with those of the more modestly sized domestic chicken, previously shown to be in the same allometric grade as ratites. The results suggest that ratites and chickens exhibit disparate endocranial shapes not simply accounted for by their size differences. When shape and age are examined, chickens partly exhibit more accelerated and mature brain shapes than ratites of similar size and age. Taken together, our study indicates that disparate brain shapes between these differently sized taxa have emerged from the evolution of distinct developmental allometries, rather than simply following conserved scaling trends.
Easy to gain but hard to lose: the evolution of the knee sesamoid bones in Primates—a systematic review and phylogenetic meta-analysis
Authors: Fragoso Vargas Nelly A. , Berthaume Michael A.
Published: September 2024

Sesamoids are variably present skeletal elements found in tendons and ligaments near joints. Variability in sesamoid size, location and presence/absence is hypothesized to enable skeletal innovation, yet sesamoids are often ignored. Three knee sesamoids—the cyamella, medial fabella and lateral fabella—are present in primates, but we know little about how they evolved, if they are skeletal innovations, or why they are largely missing from Hominoidea. Our phylogenetic comparative analyses suggest that sesamoid presence/absence is highly phylogenetically structured and contains phylogenetic signal. Models suggest that it is easy to gain but difficult/impossible to lose knee sesamoids and that the fabellae may have similar developmental/evolutionary pathways that are distinct from the cyamella. Sesamoid presence/absence is uncorrelated to the mode of locomotion, suggesting that sesamoid biomechanical function may require information beyond sesamoid presence, such as size and location. Ancestral state reconstructions were largely uninformative but highlighted how reconstructions using parsimony can differ from those that are phylogenetically informed. Interestingly, there may be two ways to evolve fabellae, with humans evolving fabellae differently from most other primates. We hypothesize that the ‘re-emergence’ of the lateral fabella in humans may be correlated with the evolution of a unique developmental pathway, potentially correlated with the evolution of straight-legged, bipedal locomotion.
Amycolatopsis nalaikhensis sp. nov. and Amycolatopsis carbonis sp. nov., two novel actinobacteria with antimicrobial activity isolated from a coal mining site in Mongolia
Authors: Oyuntsetseg Bilguun , Kim Seung Bum
Published: September 2024

An erratum of this article has been published full details can be found at

https://doi.org/10.1099/ijsem.0.006541

Two-novel filamentous actinobacteria designated strains 2-2T and 2-15T were isolated from soil of a coal mining site in Mongolia, and their taxonomic positions were determined using a polyphasic approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that each of the strains formed a distinct clade within the genus Amycolatopsis. The 16S rRNA gene sequence similarity analysis showed that both strains were mostly related to Amycolatopsis rhabdoformis NCIMB 14900T with 99.0 and 99.4% sequence similarity, respectively. The genome-based comparison indicated that strain 2-2T shared the highest digital DNA–DNA hybridization value of 35.6% and average nucleotide identity value of 86.9% with Amycolatopsis pretoriensis DSM 44654T, and strain 2-15T shared the corresponding values of 36.5 and 87.9% with A. rhabdoformis NCIMB 14900T, all of which being well below the thresholds for species delineation. The chemotaxonomic properties of both strains were typical of the genus Amycolatopsis. In silico prediction of chemotaxonomic markers was also carried out, and the results were consistent with the chemotaxonomic profiles of the genus. Genome mining for secondary metabolite production in strains 2-2T and 2-15T revealed the presence of 29 and 24 biosynthetic gene clusters involved in the production of polyketide synthase, non-ribosomal peptide synthetase, ribosomally synthesized and post-translationally modified peptides, lanthipeptide, terpenes, siderophore, and a number of other unknown type compounds. Both strains showed broad antifungal activity against several filamentous fungi and also antibacterial activity against methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii. The phenotypic, biochemical, and chemotaxonomic properties indicated that both strains could be clearly distinguished from other species of Amycolatopsis, and thus the names Amycolatopsis nalaikhensis sp. nov. (type strain, 2-2T=KCTC 29695T=JCM 30462T) and Amycolatopsis carbonis (type strain, 2-15T=KCTC 39525T=JCM 30563T) are proposed accordingly.
A near-complete genome assembly of the bearded dragonPogona vitticepsprovides insights into the origin ofPogonasex chromosomes
Authors: Guo Qunfei , Pan Youliang , Dai Wei , Guo Fei , Zeng Tao , Chen Wanyi , Mi Yaping , Zhang Yanshu , Shi Shuaizhen , Jiang Wei , Cai Huimin , Wu Beiying , Zhou Yang , Wang Ying , Yang Chentao , Shi Xiao , Yan Xu , Chen Junyi , Cai Chongyang , Yang Jingnan , Xu Xun , Gu Ying , Dong Yuliang , Li Qiye
Published: September 2024

Background

The agamid dragon lizardPogona vitticepsis one of the most popular domesticated reptiles to be kept as pets worldwide. The capacity of breeding in captivity also makes it emerging as a model species for a range of scientific research, especially for the studies of sex chromosome origin and sex determination mechanisms.

Results

By leveraging the CycloneSEQ and DNBSEQ sequencing technologies, we conducted whole genome and long-range sequencing for a captive-bred ZZ male to construct a chromosome-scale reference genome forP. vitticeps. The new reference genome is ∼1.8 Gb in length, with a contig N50 of 202.5 Mb and all contigs anchored onto 16 chromosomes. Genome annotation assisted by long-read RNA sequencing greatly expanded theP. vitticepslncRNA catalog. With the chromosome-scale genome, we were able to characterize the whole Z sex chromosome for the first time. We found that over 80% of the Z chromosome remains as pseudo-autosomal region (PAR) where recombination is not suppressed. The sexually differentiated region (SDR) is small and occupied mostly by transposons, yet it aggregates genes involved in male development, such asAMH,AMHR2andBMPR1A. Finally, by tracking the evolutionary origin and developmental expression of the SDR genes, we proposed a model for the origin ofP. vitticepssex chromosomes which considered the Z-linkedAMHas the master sex-determining gene.

Conclusions

Our study provides novel insights into the sex chromosome origin and sex determination of this model lizard. The near-completeP. vitticepsreference genome will also benefit future study of amniote evolution and may facilitate genome-assisted breeding.
Ablation of LRP6 in alpha-smooth muscle actin-expressing cells abrogates lung inflammation and fibrosis upon bleomycin-induced lung injury
Authors: Sung Eun-Ah , Dozmorov Mikhail G. , Song SuJeong , Aung Theingi , Park Min Hee , Sime Patricia J. , Chae Wook-Jin
Published: September 2024

Low-density lipoprotein receptor-related protein 6 (LRP6) is a receptor for Wnt ligands. Tissue fibrosis is a progressive pathological process with excessive extracellular matrix proteins (ECM) deposition. Myofibroblasts, identified by alpha-smooth muscle actin (αSMA) expression, play an important role in tissue fibrosis by producing ECM production. Here we found that Wnt antagonist Dickkopf1 (DKK1) induced gene expressions associated with inflammation and fibrosis in lung fibroblasts. We demonstrated that genetic deletion of LRP6 in αSMA-expressing cells usingActa2-creLrp6fl/fl(Lrp6AKO) mice abrogated bleomycin (BLM)-induced lung inflammation and fibrosis phenotype, suggesting an important role of LRP6 in modulating inflammation and fibrotic processes in the lung. Our results highlight the crucial role of LRP6 in fibroblasts in regulating inflammation and fibrosis upon BLM-induced lung injury.
Neural-symbolic hybrid model for myosin complex in cardiac ventriculum decodes structural bases for inheritable heart disease from its genetic encoding
Authors: Burghardt Thomas P.
Published: September 2024

Background

Human ventriculum myosin (βmys) powers contraction sometimes in complex with myosin binding protein C (MYBPC3). The latter regulates βmys activity and impacts overall cardiac function. Nonsynonymous single nucleotide variants (SNVs) change protein sequence in βmys or MYBPC3 causing inheritable heart diseases by affecting the βmys/MYBPC3 complex. Muscle genetics encode instructions for contraction informing native protein construction, functional integration, and inheritable disease impairment. A digital model decodes these instructions and evolves by continuously processing new information content from diverse data modalities in partnership with the human agent.

Methods

A general neural-network contraction model characterizes SNV impacts on human health. It rationalizes phenotype and pathogenicity assignment given the SNVs genetic characteristics and in this sense decodes βmys/MYBPC3 complex genetics and implicitly captures ventricular muscle functionality. When a SNV modified domain locates to an inter-protein contact in βmys/MYBPC3 it affects complex coordination. Domains involved, one in βmys and the other in MYBPC3, form coordinated domains (co-domains). Co-domains are bilateral implying potential for their SNV modification probabilities to respond jointly to a common perturbation to reveal their location. Human genetic diversity from the serial founder effect is the common systemic perturbation coupling co-domains that are mapped by a methodology called 2-dimensional correlation genetics (2D-CG).

Results

Interpreting the general neural-network contraction model output involves 2D-CG co-domain mapping that provides natural language expressed structural insights. It aligns machine-learned intelligence from the neural network model with human provided structural insight from the 2D-CG map, and other data from the literature, to form a neural-symbolic hybrid model integrating genetic and protein interaction data into a nascent digital twin. This process is the template for combining new information content from diverse data modalities into a digital model that can evolve. The nascent digital twin interprets SNV implications to discover disease mechanism, can evaluate potential remedies for efficacy, and does so without animal models.

Highlights

Neural-symbolic hybrid model decodes muscle genetics into contraction mechanisms And evolves in virtuous cycleOptimize-Interpret-Revise-Repeataided by human partner Nascent digital twin unravels inheritable disease mechanism without animal models And estimates cardiac phenotype coupling strength to myosin thick-filament structures
A semi-parametric multiple imputation method for high-sparse, high-dimensional, compositional data
Authors: Sohn Michael B. , Scheible Kristin , Gill Steven R.
Published: September 2024

High sparsity (i.e., excessive zeros) in microbiome data, which are high-dimensional and compositional, is unavoidable and can significantly alter analysis results. However, efforts to address this high sparsity have been very limited because, in part, it is impossible to justify the validity of any such methods, as zeros in microbiome data arise from multiple sources (e.g., true absence, stochastic nature of sampling). The most common approach is to treat all zeros as structural zeros (i.e., true absence) or rounded zeros (i.e., undetected due to detection limit). However, this approach can underestimate the mean abundance while overestimating its variance because many zeros can arise from the stochastic nature of sampling and/or functional redundancy (i.e., different microbes can perform the same functions), thus losing power. In this manuscript, we argue that treating all zeros as missing values would not significantly alter analysis results if the proportion of structural zeros is similar for all taxa, and we propose a semi-parametric multiple imputation method for high-sparse, high-dimensional, compositional data. We demonstrate the merits of the proposed method and its beneficial effects on downstream analyses in extensive simulation studies. We reanalyzed a type II diabetes (T2D) dataset to determine differentially abundant species between T2D patients and non-diabetic controls.
Recruitment of SH3P2–DRP1A by HYCCIN2 Drives Membrane Tubulation in Arabidopsis Embryonic Cell Plate Formation
Authors: Hsu Ya-Wen , Juan Chine-Ta , Guo Cian-Ling , Wang Huei-Jing , Jauh Guang-Yuh
Published: September 2024

Cytokinesis marks the culmination of cell division when the cytoplasm undergoes division to yield two daughter cells. This intricate process encompasses various biological phenomena, including the organization of the cytoskeleton and the dynamics of vesicles. The development of the cell plate aligns with alterations in the cytoskeleton structure and vesicles derived from thetrans-Golgi, ultimately resulting in the formation of the planar cell plate. Nevertheless, the coordination of these processes in plants remains to be determined. Here, we introduce HYCCIN-CONTAINING2 (HYC2) as a pivotal cytoskeleton cross-linking protein that accumulates at phragmoplasts and plays a crucial role in cell plate formation. A genetic study involving the depletion of HYC2 post-anaphase in Arabidopsis revealed HYC2’s function in cell plate formation. HYC2 interacted with dynamin-related protein 1A (DRP1A) and SH3 domain-containing protein 2 (SH3P2), essential for membrane tubulation during cell plate formation. The recruitment of SH3P2 and DRP1A to the cell plate and phragmoplast organization was compromised in homozygoushyc2-2mutant globular embryos. Our results shed light on the cytoskeletal function of HYC2 in assembling the cell plate, potentially by guiding vesicles containing SH3P2–DRP1A to the planar cell plate.

Significance statement

During plant cell division, a new membrane is constructed at the division plane, and vesicles fuse to form a transient compartment known as the cell plate. This structure undergoes stabilization via membrane remodeling events, including tubulation, to generate robust membrane intermediates. Apart from DRP1A and SH3P2, our understanding of other protein components involved in membrane remodeling still needs to be completed. HYC2 is a plant counterpart to the human Hyccin protein involved in neuronal myelination and displaying bundling capabilities for microtubules and microfilaments. Our study demonstrates that HYC2 is crucial in recruiting proteins during membrane tubulation in the cell plate formation in developing Arabidopsis embryos. These findings underscore the molecular function and vital role of the Hyccin protein in cell plate formation.

One Sentence Summary

Plant HYC2 displays bundling capabilities for microtubules and microfilaments to recruit DRP1A and SH3P2 during membrane tubulation in the cell plate formation in developing Arabidopsis embryos.
Autoantigen TRIM21 (Ro52) assembles pro-inflammatory immune complexes following lytic cell death
Authors: Jones Esther L. , Demarco Benjamin , de Jong Madelon M.E , Cai Han , Hill Sarah , Glass Ryan E. , Harris Gemma , Nayar Saba , Fisher Benjamin A. , Gérard Audrey , Bezbradica Jelena S. , Dustin Lynn B.
Published: September 2024

Sjögren’s disease (SjD) causes localised and systemic inflammation due to autoantibody production against intracellular proteins, such as TRIM21/Ro52. TRIM21 is an E3 ubiquitin ligase which binds antibody Fc domains on opsonised pathogens, which have escaped extracellular immunity and entered cytosols; TRIM21 ubiquitinates these, driving their proteasomal degradation. How and why TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis/necroptosis) but not apoptosis. Released TRIM21 binds circulating antibody Fc domains, and forms large immune complexes (ICs). These are further enhanced with TRIM21/Ro52 seropositive SjD plasma antibodies, where interactions are mediated via both Fc and F(ab’)2domains. TRIM21-ICs are taken up by macrophages, which in high interferon environments drive pro-inflammatory responses, antigen presentation, and inflammatory and metabolic transcriptional changes. Whilst many cytosolic proteins are released by dead cells, due to its high affinity for antibodies, TRIM21 can generate large ICs. This may perpetuate inflammation and antigen presentation, causing TRIM21 to be highly autoimmunogenic.

One Sentence Summary

How the intracellular protein TRIM21 becomes an autoantigen.
The FAIR Data Point Populator: collaborative FAIRification and population of FAIR Data Points
Authors: Wijnbergen Daphne , Kaliyaperumal Rajaram , Burger Kees , Bonino da Silva Santos Luiz Olavo , Mons Barend , Roos Marco , Mina Eleni
Published: September 2024

Background

Use of the FAIR principles (Findable, Accessible, Interoperable and Reusable) allows the rapidly growing number of biomedical datasets to be optimally (re)used. An important aspect of the FAIR principles is metadata. The FAIR Data Point specifications and reference implementation have been designed as an example on how to publish metadata according to the FAIR principles. Various tools to create metadata have been created, but many of these have limitations, such as interfaces that are not intuitive, metadata that does not adhere to a common metadata schema, limited scalability, and inefficient collaboration. We aim to address these limitations in the FAIR Data Point Populator.

Results

The FAIR Data Point Populator consists of a GitHub workflow together with Excel templates that have tooltips, validation and documentation. The Excel templates are targeted towards non-technical users, and can be used collaboratively in online spreadsheet software. A more technical user then uses the GitHub workflow to read multiple entries in the Excel sheets, and transform it into machine readable metadata. This metadata is then automatically uploaded to a connected FAIR Data Point. We applied the FAIR Data Point Populator on the metadata of two datasets, and a patient registry. We were then able to run a query on the FAIR Data Point Index, in order to retrieve one of the datasets.

Conclusion

The FAIR Data Point Populator addresses several limitations of other tools. It makes creating metadata easier, ensures adherence to a common metadata schema, allows bulk creation of metadata entries and increases collaboration. As a result of this, the barrier of entry for FAIRification is lower, which enables the creation of FAIR data by more people.
Biomanufacturing of a functional microbial phytase in an insect host
Authors: Retief C. , Kumar S. , Tepper K. , Maselko M.
Published: September 2024

Background

Insects, such as Black Soldier Flies (Hermetia illucens), are increasingly used as sustainable animal feed ingredients that can be reared on plentiful organic substrates such as agricultural residues and pre-consumer food waste. Genetically engineering insects to heterologously express feed additive enzymes has the potential to generate more value from organic waste, while improving livestock health and productivity.

Phytases are widely used feed additive enzymes that hydrolyse the phosphate groups from the myo-inositol backbone of phytic acid, a phosphate rich antinutrient compound that monogastric animals cannot efficiently digest. Dietary phytase supplementation improves absorption of phosphorous, proteins, and cationic nutrients, while mitigating the negative environmental effects of phytic acid rich excreta.

Results

We evaluated the potential of using insects to biomanufacture microbial feed additive enzymes by engineering the model insect,Drosophila melanogaster, to express phytases. One histidine acid phytase, three beta propellor phytases, three purple acid phosphatases, and one PTP-like phytase were selected for screening inD. melanogaster. Transgenic flies expressing the AppA histidine acid phytase fromE. colihad 27.82 FTU/g of phytase activity, which exceeds the 0.5-1.0 FTU/g required in animal feed. Maximum activity from AppA phytase expressed byD. melanogasterwas observed at pH 5 and 55 °C, however, more than 50% of phytase activity was present at 25 °C and pH 2.

Here we demonstrate that insects may be suitable hosts for the heterologous expression of a microbial phytase enzyme with applications for improving animal feed nutrition and organic waste valorisation.
Discovery of novel quinoline papain-like protease inhibitors for COVID-19 through topology constrained molecular generative model
Authors: Shang Jinsai , Ran Ting , Lu Yongzhi , Yang Qi , Zhang Guihua , Zhou Peiqi , Li Wenqi , Xu Minyuan , Tang Jielin , Dai Minxian , Zhong Jinpeng , Chen Hua , He Pan , Zhou Anqi , Xue Bao , Chen Jiayi , Zhang Jiyun , Wu Kunzhong , Wu Xinyu , Tang Miru , Chen Xinwen , Chen Hongming
Published: September 2024

Papain-like protease (PLpro) plays a critical role in both viral polyprotein processing and host antiviral immune suppression in SARS-CoV-2 infection, which causes COVID-19. Although several drugs have been approved for COVID-19, such as Remdesivir, Nirmatrelvir, etc., none of the PLproinhibitors have been approved for the treatment of COVID-19. The advent of artificial intelligence-based drug design methods has significantly accelerated the process of drug discovery. In current study, by harnessing the power of a topology constrained molecular generative model, we discovered a novel series of PLproinhibitors with strong potency against prevalent SARS-CoV-2 variants. Following a structure based computational approach for optimization, our lead compound, GZNL-2002, achieved decent PLproinhibitory potency and favorable pharmacokinetic properties, which warrants further development as a potential candidate compound for COVID-19 disease.
Quantitative site-specific glycoproteomics by ZenoTOF reveals glyco-signatures for breast cancer diagnosis
Authors: Yang Yi , Zhao Dan , Luo Ji , Lin Ling , Lin Yuxiang , Shan Baozhen , Chen Hongxu , Qiao Liang
Published: September 2024

Intact glycopeptide characterization by mass spectrometry has proven a versatile tool for site-specific glycoproteomics analysis and biomarker screening. Here, we present a method using the ZenoTOF instrument with optimized fragmentation for intact glycopeptide identification and demonstrate its ability to analyze large-cohort glycoproteomes. From 124 clinical serum samples of breast cancer, non-cancerous diseases, and non-disease controls, a total of 6901 unique site-specific glycans on 807 gly-cosites of proteins were detected. Much more differences of glycoproteome were observed in breast diseases than the proteome. By employing machine learning, 15 site-specific glycans were determined as potential glyco-signatures in detecting breast cancer. The results demonstrate that our method provides a powerful tool in glycoproteomic analyses for biomarker discovery studies.
Force variability is a potential biomarker of motor impairment in hemispheric stroke survivors
Authors: Shi Fandi , Rymer William Zev , Son Jongsang
Published: September 2024

During voluntary isometric contractions of upper extremity muscles in individuals with chronic stroke, the magnitude of force variability appears to increase consistently as force increases. However, research on how such force variability changes with increasing motor impairment remains limited. This study aims to determine whether force variability is increased on the paretic side during either index finger abduction or elbow flexion in the same group of stroke survivors, and whether these changes are consistent across different muscles. Force variability was assessed using the standard deviation of force during sustained isometric contractions. Linear mixed-effects models were implemented to test whether force variability is changed on the paretic side post stroke, and whether such alterations show dependence on force level and on the degree of impairment. The results demonstrated a significant increase in force variability on the paretic side across force levels during finger abduction, while force variability for elbow flexion was increased only at high force levels. In addition, the force variability appears to increase as isometric elbow flexion force increases, whereas no clear trend was found during index finger abduction. The increase in force variability demonstrated moderate-strong dependence on the reduction in maximum muscle strength on the paretic side during elbow flexion, suggesting that monitoring force variability could potentially serve as a quantitative diagnostic tool for assessing severity of impairment in motor control and for raising potential mechanisms at the motor unit level.
Achieving high-resolution single-cell segmentation in convoluted cancer spheroids via Bayesian optimization and deep-learning
Authors: Mogollon Isabel , Feodoroff Michaela , Neto Pedro , Montedeoca Alba , Pietiänen Vilja , Paavolainen Lassi
Published: September 2024

Understanding cellular function within 3D multicellular spheroids is essential for advancing cancer research, particularly in studying cell-stromal interactions as potential targets for novel drug therapies. However, accurate single-cell segmentation in 3D cultures is challenging due to dense cell clustering and the impracticality of manual annotations. We present a high-throughput (HT) 3D single-cell analysis pipeline that combines optimized wet-lab conditions, deep learning (DL)-based segmentation models, and Bayesian optimization to address these challenges. By using live-cell nuclear and cytoplasmic dyes, we achieved clear and uniform staining of cell populations in renal cancer and immune T-cell monocultures and cocultures, improving single-cell detection in spheroids. Our pipeline integrates image preprocessing and DL models based on 3DUnet architecture, enabling robust segmentation of densely packed 3D structures. Bayesian optimization, guided by a custom objective function, was employed to refine segmentation parameters and improve quality based on biologically relevant criteria. The pipeline successfully segments cells under various drug treatments, revealing drug-induced changes not detectable by bulk conventional assays. This approach has potential for application to more complex biological samples, including, organoid co-cultures, diverse drug treatments, and integration with additional immunostaining assays, paving the way for detailed HT analyses of single-cell responses.
Exploring the sequence and structural determinants of the energy landscape from thermodynamically stable and kinetically trapped subtilisins: ISP1 and SbtE
Authors: Hood Miriam R. , Marqusee Susan
Published: September 2024

A protein’s energy landscape, all accessible conformations, their populations, and dynamics of interconversion, is encoded in its primary sequence. While how a protein’s primary sequence encodes its native state is well understood, how sequence encodes the kinetic barriers such as unfolding and refolding is not. Here we have looked at two subtiliase homologs from theBacillus subtilis, Intracellular Subtilisin Protease 1 (ISP1) and Subtilisin E (SbtE), that are expected to have very different dynamics. As an intracellular protein, ISP1 has a small pro-domain thought to act simply as a zymogen, whereas the extracellular SbtE has a large pro-domain required for folding. The stability and kinetics of ISP1 and ProSbtE have been previously characterized. We now directly compare their energy landscapes with and without the pro-domain, examining global and local energetics of the mature proteases and the effect of each pro-domain. We find that ISP1’s pro-domain has limited impact on the energy landscape of the mature protein while without the pro-domain, SbtE is thermodynamically unstable and kinetically trapped. The pro-domains show opposite effects on the flexibility of the core of the protein: in the absence of its pro-domain, ISP1’s core becomes more flexible while SbtE’s core becomes more rigid. ISP1 contains a unique conserved insertion, which points to a potential source for these differences. These homologs are an example of how changes in the primary sequence can dramatically alter a proteins energy landscape, and highlight the need for large scale, high-throughput studies on the relationship between primary sequence and conformational dynamics.
LYMTACs: Chimeric Small Molecules Repurpose Lysosomal Membrane Proteins for Target Protein Relocalization and Degradation
Authors: Nalawansha Dhanusha A. , Mazis Georgios , Husemoen Gitte , Ashton Kate S. , Deng Weixian , Wurz Ryan P. , Tran Anh T. , Lanman Brian A. , Xie Jiansong , Guenette Robert G. , Li Shiqian , Smith Christopher E. , Archunan Suresh , Agnihotram Manoj K. , Sadhukhan Arghya , Kapoor Rajiv , Koirala Sajjan , De Sousa E Melo Felipe , Potts Patrick Ryan
Published: September 2024

Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development ofLYsosomeMembraneTArgetingChimeras(LYMTACs) as a novel small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. To extend these findings, we show that oncogenic, membrane-associated KRASG12Dprotein can be tethered to RNF152, inducing KRAS relocalization to the lysosomal membrane, inhibiting downstream phospho-ERK signaling, and leading to lysosomal degradation of KRASG12Din a LYMTAC-dependent manner. Notably, potent cell killing could be attributed to the multi-pharmacology displayed by LYMTACs, which differentiates the LYMTAC technology from existing modalities. Thus, LYMTACs represent a proximity-based therapeutic approach that promises to expand the target space for challenging membrane proteins through targeted protein relocalization and degradation.
Modeling the antigenic evolution of seasonal influenza viruses with PREDAC for vaccine strain selection in the season of 2025
Authors: Peng Yousong , Du Xiangjun , Mi Liu , Ding Xiao , Meng Jing , Han Wenjie , Yang Lei , Huang Weijuan , Jiang Taijiao , Wang Dayan
Published: September 2024

Introduction

The antigenic evolution of seasonal influenza viruses have been reported to be discontinuous as clusters. Timely identification of antigenic clusters could help for influenza virus vaccine strain selections.

Methods

Here, we revealed the antigenic evolution of seasonal influenza viruses, including A(H3N2), A(H1N1pdm) and B-Victoria, using our previously developed PREDAC methods, and identified antigenic clusters of seasonal influenza viruses based on existing HA protein sequences in GISAID database.

Results

During the last six months (2024.2∼2024.7), for the influenza A(H3N2) virus, the antigenic clusters DA21 (A/Darwin/6/2021-like and A/Massachusetts/18/2022-like) continuously dominated and nearly all viruses are antigenic similar to the current vaccine strain A/Massachusetts/18/2022; for the influenza A(H1N1pdm) virus, the antigenic cluster SY21 (A/Sydney/5/2021-like and A/Victoria/4897/2022-like) dominated and nearly all viruses are antigenic similar to the current vaccine strain A/Victoria/4897/2022; for the influenza B-Victoria, antigenic clusters AU21 (B/Austria/1359417/2021-like) dominated and nearly all viruses are antigenic similar to the current vaccine strain B/Austria/1359417/2021.

Conclusion

The analysis suggests that there is no need to update the vaccine strains in the flu season of 2025 on the aspect of antigenicity.
Mechanisms of urate transport and uricosuric drugs inhibition in human URAT1
Authors: Guo Wenjun , Wei Miao , Li Yunfeng , Xu Jiaxuan , Zang Jiahe , Chen Yuezhou , Chen Lei
Published: September 2024

High urate levels in circulation lead to the accumulation of urate crystals in joints and ultimately inflammation and gout1. The reabsorption process of urate in the kidney by the urate transporter URAT1 plays a pivotal role in controlling serum urate levels2. Pharmacological inhibition of URAT1 by uricosuric drugs is a valid strategy for gout management3. Despite the clinical significance of URAT1, its structure and mechanism remain elusive. Here, we report the structures of human URAT1 (hURAT1) in complex with substrate urate or inhibitors benzbromarone and verinurad at resolution ranges from 3.0 to 3.3 Å. Urate-bound hURAT1 adopts the outward-facing conformation. Urate is wrapped in the center of hURAT1 by five phenylalanines and coordinated by two positively charged residues on each side. Uricosuric compounds benzbromarone and verinurad occupy the urate-binding site of hURAT1 in the inward-facing conformation. Structural comparison between different conformations of hURAT1 reveals the rocker-switch-like mechanism for urate transport. Benzbromarone and verinurad exert their inhibitory effect by blocking not only the binding of urate but also the structural isomerization of hURAT1.
Decomposed interaction testing improves detection of genetic modifiers of the relationship of dietary omega-3 fatty acid intake and its plasma biomarkers with hsCRP in the UK Biobank
Authors: Westerman Kenneth E. , Patel Chirag J. , Meigs James B. , Chasman Daniel I. , Manning Alisa K.
Published: September 2024

Discovery and translation of gene-environment interactions (GxEs) influencing clinical outcomes is limited by low statistical power and poor mechanistic understanding. Molecular omics data may help address these limitations, but their incorporation into GxE testing requires principled analytic approaches. We focused on genetic modification of the established mechanistic link between dietary long-chain omega-3 fatty acid (dN3FA) intake, plasma N3FA (pN3FA), and chronic inflammation as measured by high sensitivity CRP (hsCRP). We considered an approach that decomposes the overall genetic effect modification into components upstream and downstream of a molecular mediator to increase the potential to discover gene-N3FA interactions. Simulations demonstrated improved power of the upstream and downstream tests compared to the standard approach when the molecular mediator for many biologically plausible scenarios. The approach was applied in the UK Biobank (N = 188,700) with regression models that used measures of dN3FA (based on fish and fish oil intake), pN3FA (% of total fatty acids measured by nuclear magnetic resonance), and hsCRP. Mediation analysis showed that pN3FA fully mediated the dN3FA-hsCRP main effect relationship. Next, we separately tested modification of the dN3FA-hsCRP (“standard”), dN3FA-pN3FA (“upstream”), and pN3FA-hsCRP (“downstream”) associations. The knownFADS1-3locus variant rs174535 reachedp= 1.6x10-12in the upstream discovery analysis, with no signal in the downstream analysis (p= 0.94). It would not have been prioritized based on a naïve analysis with dN3FA exposure and hsCRP outcome (p= 0.097), indicating the value of the decomposition approach. Gene-level enrichment testing of the genome-wide results further prioritized two genes from the downstream analysis,CBLL1andMICA, with links to immune cell counts and function. In summary, a molecular mediator-focused interaction testing approach enhanced statistical power to identify GxEs while homing in on relevant sub-components of the dN3FA-hsCRP pathway.
The impact of tobacco control policies on illicit tobacco trade: A scoping review
Authors: Meciar Isabel , Gartner Coral , McLay Ariel , Puljević Cheneal
Published: September 2024

Introduction

There are concerns that progressively stringent tobacco control policies will result in increased illicit tobacco trade (ITT). We reviewed the international evidence base to identify studies examining the impact of tobacco control polices on ITT.

Methods

Guided by JBI scoping review methodology, we searched six databases (PubMed, CINAHL, EMBASE, PsycINFO, Scopus, and Web of Science) in 2022 and 2024 for original research published in English since 2000. One reviewer screened titles and abstracts, and two reviewers screened full-text articles against inclusion criteria. We report the results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Checklist.

Results

We identified 60 articles examining the impact of eight tobacco control policies or combination of policies on the ITT, including tobacco tax increases or decreases (n=43); menthol bans (n=5); decreasing allowable cigarette filter ventilation levels (n=1); standardised packaging (n=5); tobacco sales bans (n=1); a substantial reduction in the number of tobacco retailers (n=1); a very low nicotine content mandate (VLNC; n=2); and multicomponent policy interventions (n=4).

Conclusions

The available evidence is predominantly focused on the impact of tobacco tax increases on the ITT, with equal numbers of studies describing an increase in the ITT or no impact on the ITT, countering claims that tobacco tax increases are the primary driver of increased ITT. Evidence on the impact of other tobacco control policies on the ITT is limited. Collaborative efforts to develop accurate and consistent methods to assess the ITT are needed.

Implications

To our knowledge, this scoping review is the first to synthesise the available evidence on the association between multiple tobacco control policies and ITT. Findings suggest that evidence for the association between tobacco tax increases and ITT is mixed, with an equal number of studies (n=18) describing an increase or no impact of this policy on ITT. Evidence for the impact of other policies was limited; the only policies with some evidence for increasing the ITT include tobacco sales bans (n=1), a concurrent tobacco sales and smoking ban (n=2), and a hypothetical VLNC standard mandate (n=2).
Preschool musicality is associated with school-age communication abilities through genes related to rhythmicity
Authors: de Hoyos Lucía , Verhoef Ellen , Okbay Aysu , Vermeulen Janne R , Figaroa Celeste , Lense Miriam , Fisher Simon E , Gordon Reyna L , Pourcain Beate St
Published: September 2024

Early-life musical engagement is an understudied but developmentally important and heritable precursor of later (social) communication and language abilities. This study aims to uncover the aetiological mechanisms linking musical to communication abilities. We derived polygenic scores (PGS) for self-reported beat synchronisation abilities (PGSrhythmicity) in children (N≤6,737) from the Avon Longitudinal Study of Parents and Children and tested their association with preschool musical (0.5-5 years) and school-age (social) communication and cognition-related abilities (9-12 years). We further assessed whether relationships between preschool musicality and school-age communication are shared through PGSrhythmicity, using structural equation modelling techniques. PGSrhythmicitywere associated with preschool musicality (Nagelkerke-R2=0.70-0.79%), and school-age communication and cognition-related abilities (R2=0.08-0.41%), but not social communication. We identified links between preschool musicality and school-age speech-and syntax-related communication abilities as captured by known genetic influences underlying rhythmicity (shared effect β=0.0065(SE=0.0021),p=0.0016), above and beyond general cognition, strengthening support for early music intervention programmes.