bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroimmune changes underscore pain-associated behaviors and disc herniations in SM/J mice
Authors: Novais Emanuel J. , Ottone Olivia K. , Brown Eric V. , Madhu Vedavathi , Tran Victoria A. , Dighe Abhijit S. , Solga Michael D. , Manchel Alexandra , Lepore Angelo C. , Risbud Makarand V.
Published: February 2024

There are no appropriate mouse models to study the pathophysiology of spontaneous disc herniations and associated pain pathology. We demonstrate that SM/J mice show a high incidence of age-associated lumbar disc herniations with neurovascular innervations. Transcriptomic comparisons of the SM/J annulus fibrosus with human tissues showed shared pathways related to immune cell activation and inflammation. Notably, aged SM/J mice showed increased pain sensitization and neuroinflammatory signatures associated with altered extracellular matrix regulation in the DRGs and spinal cord. There were increased T cells in the vertebral marrow, and CyTOF analysis showed increased splenic CD8+T cells, nonspecific activation of CD8+memory T cells, and enhanced IFN-γ production in the myeloid compartment. ScRNA-seq of PBMCs in SM/J showed more B cells, with lower proportions of T cells, monocytes, and granulocytes. This study identifies SM/J mice as a clinically-relevant model to study the pathophysiology of spontaneous disc herniations and highlights a causative axis for chronic discogenic pain with novel contributors from the primary lymphoid organs (spleen and vertebral marrow), circulation, and the nervous system.

One-Sentence Summary

The novel SM/J mouse model shows a neuroimmune axis drives chronic back pain, a leading cause of years lived with disability.
PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4
Authors: Nguyen-Dien Giang Thanh , Townsend Brendan , Kulkarni Prajakta , Kozul Keri-Lyn , Ooi Soo Siang , Eldershaw Denaye , Weeratunga Saroja , Liu Meihan , Jones Mathew JK , Millard S Sean , Ng Dominic CH , Pagano Michele , Komander David , Lazarou Michael , Collins Brett M , Pagan Julia K
Published: February 2024

Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, andFBXL4mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both basal and induced mitophagy. Disruption of the phosphatase activity of PPTC7 is not required for BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-NIX/BNIP3 and PPTC7-FBXL4 interactions and their disruption interferes with both NIX/BNIP3 degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts NIX/BNIP3-induced mitophagy.
Large herbivores link plant phenology and abundance in arctic tundra
Authors: Post Eric , Higgins R. Conor , Bøving Pernille Sporon , John Christian , Post Mason , Kerby Jeff
Published: February 2024

Plant phenology has been well studied in relation to abiotic conditions and climate change, but poorly studied in relation to herbivory. In contrast, plant abundance dynamics have been well studied in relation to abiotic conditions and herbivory, but poorly studied in relation to phenology. Consequently, the contribution of herbivory to plant phenological dynamics and therefrom to plant abundance dynamics remains obscure. We conducted a nine-year herbivore exclusion experiment to investigate whether herbivory might link plant phenological and abundance dynamics in arctic tundra. From 2009 - 2017 we monitored annual green-up timing and abundance of nine plant taxa, including deciduous shrubs, forbs, and graminoids, on plots that were either grazed or experimentally exclosed from herbivory by caribou (Rangifer tarandus) and muskoxen (Ovibos moschatus). In 62% of cases, green-up occurred earlier under herbivory, and in 75% of cases abundance was greater under herbivory, compared to green-up and abundance under herbivore exclusion. Moreover, taxa that responded to herbivory with earlier green-up also had comparatively greater abundance later in the growing season. Conversely, taxa that responded to herbivory with delayed green-up exhibited comparatively lower abundance later in the growing season. Hence, well-documented influences of large herbivores on plant abundance and community composition in arctic tundra may, at least to some extent, relate to influences of herbivory on plant phenology. We recommend that ongoing and future assessments of the contribution of herbivores to plant abundance and community responses to climate change, especially in the Arctic, should also consider impacts of herbivores on plant phenology.
Toxoplasmatype II effector GRA15 has limited influencein vivo
Authors: Merritt Emily F. , Kochanowsky Joshua A. , Hervé Perrine , Watson Alison A. , Koshy Anita A.
Published: February 2024

Toxoplasma gondiiis an intracellular parasite that establishes a long-term infection in the brain of many warm-blooded hosts, including humans and rodents. Like all obligate intracellular microbes,Toxoplasmauses many effector proteins to manipulate the host cell to ensure parasite survival. While some of these effector proteins are universal to allToxoplasmastrains, some are polymorphic betweenToxoplasmastrains. One such polymorphic effector is GRA15. Thegra15allele carried by type II strains activates host NF-κB signaling, leading to the release of cytokines such as IL-12, TNF, and IL-1β from immune cells infected with type II parasites. Prior work also suggested that GRA15 promotes early host control of parasitesin vivo, but the effect of GRA15 on parasite persistence in the brain and the peripheral immune response has not been well defined. For this reason, we sought to address this gap by generating a new IIΔgra15strain and comparing outcomes at 3 weeks post infection between WT and IIΔgra15infected mice. We found that the brain parasite burden and the number of macrophages/microglia and T cells in the brain did not differ between WT and IIΔgra15infected mice. In addition, while IIΔgra15infected mice had a lower number and frequency of splenic M1-like macrophages and frequency of PD-1+ CTLA-4+ CD4+ T cells and NK cells compared to WT infected mice, the IFN-γ+ CD4 and CD8 T cell populations were equivalent. In summary, our results suggest thatin vivoGRA15 may have a subtle effect on the peripheral immune response, but this effect is not strong enough to alter brain parasite burden or parenchymal immune cell number at 3 weeks post infection.
SHOOTMERISTEMLESSautoactivation: A prerequisite for fruit metamorphosis
Authors: Dong Yang , Hu Zhi-Cheng , Majda Mateusz , Sun Hao-Ran , Zhang Yao , Ding Yi-Ning , Yuan Quan , Su Tong-Bing , Lü Tian-Feng , Gao Feng , Xu Gui-Xia , Smith Richard S. , Østergaard Lars
Published: February 2024

In animals and plants, organ shape is primarily determined during primordium development by carefully coordinated growth and cell division1-3. Rare examples of post-primordial change in morphology (reshaping) exist that offer tractable systems to study mechanisms required for organ-shape determination and diversification. One such example is the heart-shape formation ofCapsellafruits that occurs by reshaping the ovate spheroid gynoecium upon fertilization4. Here we use whole-organ live-imaging to show that dynamic changes in growth and cell division coupled with local maintenance of meristematic identity drivesCapsellafruit-shape formation. At the molecular level, we reveal an auxin-induced mechanism ultimately descending on a singlecisregulatory element to mediate morphological alteration. This element resides in the promoter of theCapsella rubella SHOOTMERISTEMLESS5(CrSTM) gene. The CrSTM meristem identity factor positively regulates its own expression through binding to this element thereby providing a feed-forward loop at the position and time when protrusions emerge to form the heart. Independent evolution of the STM-binding element inSTMpromoters across Brassicaceae species correlates with those undergoing a gynoecium-to-fruit metamorphosis. Accordingly, genetic and phenotypic studies showed that the STM-binding element is required to facilitate the shape transition and reveals a conserved molecular mechanism for organ morphogenesis.
Cryptic genetic variation shapes the fate of gene duplicates in a protein interaction network
Authors: Dibyachintan Soham , Dube Alexandre K , Bradley David , Lemieux Pascale , Dionne Ugo , Landry Christian R
Published: February 2024

Paralogous genes are often redundant for long periods of time before they diverge in function. While their functions are preserved, paralogous proteins can accumulate mutations that, through epistasis, could impact their fate in the future. By quantifying the impact of all single-amino acid substitutions on the binding of two myosin proteins to their interaction partners, we find that the future evolution of these proteins is highly contingent on their regulatory divergence and the mutations that have silently accumulated in their protein binding domains. Differences in the promoter strength of the two paralogs amplify the impact of mutations on binding in the lowly expressed one. While some mutations would be sufficient to non-functionalize one paralog, they would have minimal impact on the other. Our results reveal how functionally equivalent protein domains could be destined to specific fates by regulatory and cryptic coding sequence changes that currently have little to no functional impact.
Engineering oncogenic hotspot mutations onSF3B1via CRISPR-directed PRECIS mutagenesis
Authors: Fernandez Mike , Jia Qiong , Yu Lei , Wang Xuesong , Hart Kevyn , Jia Zhenyu , Lin Ren-Jang , Wang Lili
Published: February 2024

SF3B1is the most recurrently mutated RNA splicing factor in cancer; However, its study has been hindered by a lack of disease-relevant cell line models. Here, we compared four genome engineering platforms to establishSF3B1mutant cell lines: CRISPR-Cas9 editing, AAV HDR editing, base editing (ABEmax, ABE8e), and prime editing (PE2, PE3, PE5Max). We showed that prime editing via PE5max achieved the most efficientSF3B1K700E editing across a wide range of cell lines. We further refined our approach by coupling prime editing with a with a fluorescent reporter that leverages aSF3B1mutation-responsive synthetic intron to mark prime edited cells. Calling this approach prime editing coupled intron-assisted selection (PRECIS), we then introduced the K700E hotspot mutation into two chronic lymphocytic leukemia (CLL) cell lines, HG-3 and MEC-1, and demonstrated that our PRECIS-engineered cells faithfully recapitulate the altered splicing and copy number variation (CNV) events frequently found in CLL patients withSF3B1mutation. Our results showcase PRECIS as an efficient and generalizable method for engineering genetically faithfulSF3B1mutant models, shed new light on the role ofSF3B1mutation in cancer biology, and enables generation of novelSF3B1mutant cell lines in any cellular context.
A Mendelian randomization study identifies proteins involved in neurodegenerative diseases
Authors: Belbasis Lazaros , Morris Sam , van Duijn Cornelia , Bennett Derrick , Walters Robin
Published: February 2024

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS) using large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization (MR) study by selecting instrumental variables for the abundance of over 2,700 proteins measured by either Olink or SomaScan platforms in plasma from UK Biobank and the deCODE Health Study. We also used the latest publicly-available GWAS for the diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 10,244 protein-disease associations, identifying 122 associations which were statistically significant (5% false discovery rate). Out of 57 associations (58%) tested using an instrumental variable from both Olink and SomaScan platforms, 33 (58%) were statistically significant in both platforms. Evidence of co-localisation between plasma protein abundance and disease risk (posterior probability >0.80) was identified for 46 protein-disease pairs. Twenty-three out of 46 protein-disease associations correspond to genetic loci not previously reported by genome-wide association studies. The newly-associated proteins for AD are involved in complement (C1S, C1R), microglia (SIRPA, PRSS8) and lysosomal functions (CLN5). A protein newly-associated with PD (CTF1) is involved in the interleukin-6 pathway, two proteins for ALS (TPP1, TNFSF13) are involved in lysosomal and astrocyte function, respectively, and proteins associated with MS are involved in blood-brain barrier function (TYMP, VEGFB), the oligodendrocyte function (PARP1), the structure of the node of Ranvier and function of dorsal root ganglion (NCS1, FLRT3, CDH15), and the response to viral infections including Epstein-Barr virus (PVR, WARS1). Our study demonstrates how harnessing large-scale genomic and proteomic data can yield novel insights into the role of plasma proteome in the pathogenesis of neurodegenerative diseases.
Quantitative susceptibility mapping for detection of kidney stones, hemorrhage differentiation and cyst classification in ADPKD
Authors: Schumacher Karl , Prince Martin R. , Blumenfeld Jon D , Rennert Hanna , Hu Zhongxiu , Dev Hreedi , Wang Yi , Dimov Alexey V.
Published: February 2024

Background and purpose The objective is to demonstrate feasibility of quantitative susceptibility mapping (QSM) in autosomal dominant polycystic kidney disease (ADPKD) patients and to compare imaging findings with traditional T1/T2w magnetic resonance imaging (MRI). Methods Thirty-three consecutive patients (11 male, 22 female) diagnosed with ADPKD were initially selected. QSM images were reconstructed from the multiecho gradient echo data and compared to co-registered T2w, T1w and CT images. Complex cysts were identified and classified into distinct subclasses based on their imaging features. Prevalence of each subclass was estimated. Results QSM visualized two renal calcifications measuring 9 and 10 mm, and three pelvic phleboliths measuring 2 mm but missed 24 calcifications measuring 1mm or less and 1 larger calcification at the edge of the field of view. A total of 121 complex T1 hyperintense/T2 hypointense renal cysts were detected. 52 (43%) cysts appeared hyperintense on QSM consistent with hemorrhage; 60 (49%) cysts were isointense with respect to simple cysts and normal kidney parenchyma, while the remaining 9 (7%) were hypointense. The presentation of the latter two complex cyst subtypes is likely indicative of proteinaceous composition without hemorrhage. Conclusions Our results indicate that QSM of ADPKD kidneys is possible and uniquely suited to detect large renal calculi without ionizing radiation, and able to identify properties of complex cysts unattainable with traditional approaches.
Digital divide is amplifying cognitive disparities among the older population: a community-based cohort study in China
Authors: Li Yumeng , Liu Chen , Sun Jiaqing , Zhang Junying , Li Xin , Zhang Zhanjun
Published: February 2024

Objectives

To investigate the potential impact of the digital divide on individuals’ cognitive function and its association with the development and reversion of mild cognitive impairment (MCI).

Methods

This cohort study used data from Beijing Aging Brain Rejuvenation (BABRI) study applying a multistage cluster sampling design in 2008-2020. Analysis of Covariance (ANCOVA), mixed linear models, and Cox proportional hazards models were used to model the association of digital divide and multi-domain cognition.

Results

Among the 10098 participants, nearly half of them (48.9%) failed to overcome the digital divide, resulting in the worse performance in processing speed (F=10.67,p<0.001). The causal model indicated that individuals’ physical and mental health joint educational and occupational prestige affected the resource they achieved ultimately caused the digital divide. Moreover, longitudinal data revealed that both the elderly who successfully crossed the digital divide during the tracking process and those who had already done so prior to tracking showed significantly slower rates of decline in processing speed (B=-1.98,p<0.05; B=-2.62,p<0.01) and general cognitive function (B=3.50,p<0.001; B=3.13,p<0.01). Additionally, overcoming the digital divide also exhibited a lower risk of developing into MCI (HR, 0.5; 95% CI, 0.34-0.74; HR, 0.43; 95% CI, 0.29-0.62) and a greater probability of reversion from MCI to normal cognition (HR, 6.00; 95% CI, 3.77-9.56; HR, 9.22; 95% CI, 5.63-15.11).

Conclusions

Overcoming the digital divide was significantly associated with better performance and lower aging rate of cognitive function, as well as a lower risk of developing into MCI and a higher probability of reversion from MCI into NC.
mTOR controls growth and internal architecture of human breast cancer spheroids
Authors: Hötte Katharina , Fischer Sabine C. , Schmitz Alexander , Koch Michael , Saeifar Sanam , Stelzer Ernst H.K. , Pampaloni Francesco
Published: February 2024

mTOR is a serine/threonine kinase participating in two distinct functional complexes: mTORC1 and mTORC2. mTORC1 regulates protein translation, cell cycle progression and autophagy. mTORC2 controls cell survival, proliferation and actin cytoskeleton reorganization. mTOR signaling is often deregulated during breast cancer. We investigated how mTOR and its downstream process autophagy determine the inner architecture of solid tumor aggregates at multiple levels. We focused on structures, which are morphologically altered during progression of cancer, including: nuclei number and volume, cell density, number, shape and volume of polarized structures. We developed a breast cancer spheroid model, in which the effects of mTOR and autophagy modulation were investigated by pharmacological inhibition mTOR signaling and induction autophagy, as well as using ATG7 KO spheroids. Spheroids were imaged with light sheet-based fluorescence microscopy and data were quantitatively analyzed. Our data suggest that mTORC1 regulates the spheroid volume, cell number and size. mTORC2 controls nuclei volume and determines growth and elongation of polarized acini inside a spheroid.
Genetic diversity within a tree and alternative indexes for different evolutionary effects
Authors: Iwasa Yoh , Tomimoto Sou , Satake Akiko
Published: February 2024

Trees, living for centuries, accumulate somatic mutations in their growing trunks and branches, causing genetic divergence within a single tree. Stem cell lineages in a shoot apical meristem accumulate mutations independently and diverge from each other. In plants, somatic mutations can alter the genetic composition of reproductive organs and gametes, impacting future generations. To evaluate the genetic variation among a tree’s reproductive organs, we consider three indexes: mean pairwise phylogenetic distance, phylogenetic diversity (PD; sum of branch lengths in molecular phylogeny), and parent-offspring phylogenetic distance (DPO). The tissue architecture of trees facilitated the accumulation of somatic mutations, which have various evolutionary effects, including enhancing fitness under strong sib competition and intense host-pathogen interactions, efficiently eliminating deleterious mutations through epistasis, and increasing genetic variance in the population. Choosing appropriate indexes for the genetic diversity of somatic mutations depends on the specific aspect of evolutionary influence being assessed.
Mechanism of phage sensing and abortion by toxin-antitoxin-chaperone systems
Authors: Mets Toomas , Kurata Tatsuaki , Ernits Karin , Johansson Marcus J. O. , Craig Sophie Z. , Evora Gabriel Medina , Buttress Jessica A. , Odai Roni , Coppieters‘t Wallant Kyo , Nakamoto Jose A. , Shyrokova Lena , Egorov Artyom A. , Doering Christopher Ross , Brodiazhenko Tetiana , Laub Michael T. , Tenson Tanel , Strahl Henrik , Martens Chloe , Harms Alexander , Garcia-Pino Abel , Atkinson Gemma C. , Hauryliuk Vasili
Published: February 2024

Toxin-antitoxins (TAs) are prokaryotic two-gene systems comprised of a toxin neutralised by an antitoxin. Toxin-antitoxin-chaperone (TAC) systems additionally include a SecB-like chaperone that stabilises the antitoxin by recognising its chaperone addiction (ChAD) element. TACs have been shown to mediate antiphage defence, but the mechanisms of viral sensing and restriction are unexplored. We identify and characterise twoEscherichia coliantiphage TAC systems containing HigBA and CmdTA TA units, HigBAC and CmdTAC. The HigBAC is triggered through recognition of the gpV major tail protein of phage λ. Both the ChAD and gpV are recognised by the HigC chaperone through analogous aromatic molecular patterns, explaining the mechanism of activation. We show that the CmdT ADP-ribosyltransferase toxin modifies mRNA to shut down protein synthesis. We establish the modularity of TACs by creating a hybrid broad-spectrum antiphage system combining the CmdTA TA warhead with the HigC chaperone phage sensor.

Highlights

E. coliHigBAC and CmdTAC are translation-targeting phage immunity TAC systems HigC chaperone recognises phage λ major tail protein to trigger HigBAC toxicity

CmdT ADP-ribosyltransferase toxin abrogates translation through modification of mRNA HigC combined with CmdTA yields hybrid broad-spectrum antiphage defence system
Roles of C/EBPα, GATA2, TGF-β-signaling, and epigenetic regulation in the expression of basophil-specific protease genes
Authors: Tojima Ryotaro , Nagata Kazuki , Ito Naoto , Arai Takahiro , Ishii Kenta , Ito Tomoka , Kasakura Kazumi , Nishiyama Chiharu
Published: February 2024

In the present study, we analyzed the transcriptional regulation of genes encoding basophil-specific proteases Mcpt8 and Mcpt11 to clarify the molecular mechanisms by which the commitment between basophil and mast cell (MC) is determined. We used bone marrow-derived (BM) cells maintained in the presence of IL-3, in which basophil-like cells and MC-like cells exist. Knock down (KD) and overexpression of a transcription factor C/EBPα showed thatCebpamRNA levels were associated with those ofMcpt8andPrss34(a gene symbol of Mcpt11). Treatment with trichostatin A (TSA), a histone deacetylase inhibitor, decreased mRNA levels ofCebpa,Mcpt8, andPrss34in BM cells, whereas these mRNA levels were increased by the treatment with an inhibitor of DNA methyltransferase. TSA treatment upregulated mRNA levels ofGata1andMitfin BM cells, andMitfKD but notGata1KD increased mRNA levels ofCebpaandPrss34. Furthermore,Gata2KD significantly decreased mRNA levels ofMcpt8andPrss34without affectingCebpamRNA level. In addition, mRNA levels ofGata1andMitfwere increased in BM cells transfected withCebpasiRNA, and decreased inCebpa-overexpressing BM cells. We also found the TGF-β treatment increased mRNA levels ofMcpt8,Prss34, along with upregulation ofGata2andCebpatranscription.

Taken together, we conclude that the transcription of basophil-specific protease genes was positively regulated by C/EBPα, GATA2, and TGF-β signaling with modification of epigenetic regulation.
Biochemical characterization of naturally occurring mutations in SARS-CoV-2 RNA-dependent RNA polymerase
Authors: Danda Matěj , Klimešová Anna , Kušková Klára , Dostálková Alžběta , Pagáčová Aneta , Prchal Jan , Kapisheva Marina , Ruml Tomáš , Rumlová Michaela
Published: February 2024

Since the emergence of SARS-CoV-2, mutations in all subunits of the RNA-dependent RNA polymerase (RdRp) of the virus have been repeatedly reported. Although RdRp represents a primary target for antiviral drugs, experimental studies exploring the phenotypic effect of these mutations have been limited. This study focuses on the phenotypic effects of substitutions in the three RdRp subunits: nsp7, nsp8, and nsp12, selected based on their occurrence rate and potential impact. We employed nano-differential scanning fluorimetry and microscale thermophoresis to examine the impact of these mutations on protein stability and RdRp complex assembly. We observed diverse impacts; notably, a single mutation in nsp8 significantly increased its stability as evidenced by a 13 °C increase in melting temperature, whereas certain mutations in nsp7 and nsp8 reduced their binding affinity to nsp12 during RdRp complex formation. Using a fluorometric enzymatic assay, we assessed the overall effect on RNA polymerase activity. We found that most of the examined mutations altered the polymerase activity, often as a direct result of changes in stability or affinity to the other components of the RdRp complex. Intriguingly, a combination of nsp8 A21V and nsp12 P323L mutations resulted in a 50% increase in polymerase activity. Additionally, some of the examined substitutions in the RdRp subunits notably influenced the sensitivity of RdRp to Remdesivir®, highlighting their potential implications for therapeutic strategies. To our knowledge, this is the first biochemical study to demonstrate the impact of amino acid mutations across all components constituting the RdRp complex in emerging SARS-CoV-2 subvariants.

Significance statement

While the impact of SARS-CoV-2 spike protein mutations has been extensively explored, our understanding of mutations within the RNA-dependent RNA polymerase (RdRp), crucial for viral replication and a key target for antivirals like Remdesivir, remains limited with studies conducted solelyin silico. We focused on selected RdRp mutations identified from December 2019 to June 2022, assessing their effects on enzyme stability, complex assembly, and activity. Advanced biochemical analyses reveal how these mutations can alter RdRp functionality, providing insights into viral evolution and resistance mechanisms. This study, pioneering in assessing the biochemical implications of RdRp mutations, provides invaluable insights into their roles in viral replication and antiviral resistance, hereby opening new pathways for developing therapies against the continuously evolving SARS-CoV-2 variants.
ADELLE: A global testing method for Trans-eQTL mapping
Authors: Akinbiyi Takintayo , McPeek Mary Sara , Abney Mark
Published: February 2024

Understanding the genetic regulatory mechanisms of gene expression is a challenging and ongoing problem. Genetic variants that are associated with expression levels are readily identified when they are proximal to the gene (i.e., cis-eQTLs), but SNPs distant from the gene whose expression levels they are associated with (i.e., trans-eQTLs) have been much more difficult to discover, even though they account for a majority of the heritability in gene expression levels. A major impediment to the identification of more trans-eQTLs is the lack of statistical methods that are powerful enough to overcome the obstacles of small effect sizes and large multiple testing burden of trans-eQTL mapping. Here, we propose ADELLE, a powerful statistical testing framework that requires only summary statistics and is designed to be most sensitive to SNPs that are associated with multiple gene expression levels, a characteristic of many trans-eQTLs. In simulations, we show that for detecting SNPs that are associated with 0.1%–2% of 10,000 traits, among the 7 methods we consider ADELLE is clearly the most powerful overall, with either the highest power or power not significantly different from the highest for all settings in that range. We apply ADELLE to a mouse advanced intercross line data set and show its ability to find trans-eQTLs that were not significant under a standard analysis. This demonstrates that ADELLE is a powerful tool at uncovering trans regulators of genetic expression.
β-amino acids reduce ternary complex stability and alter the translation elongation mechanism
Authors: Cruz-Navarrete F. Aaron , Griffin Wezley C. , Chan Yuk-Cheung , Martin Maxwell I. , Alejo Jose L. , Natchiar S. Kundhavai , Knudson Isaac J. , Altman Roger B. , Schepartz Alanna , Miller Scott J. , Blanchard Scott C.
Published: February 2024

Templated synthesis of proteins containing non-natural amino acids (nnAAs) promises to vastly expand the chemical space available to biological therapeutics and materials. Existing technologies limit the identity and number of nnAAs than can be incorporated into a given protein. Addressing these bottlenecks requires deeper understanding of the mechanism of messenger RNA (mRNA) templated protein synthesis and how this mechanism is perturbed by nnAAs. Here we examine the impact of both monomer backbone and side chain on formation and ribosome-utilization of the central protein synthesis substate: the ternary complex of native, aminoacylated transfer RNA (aa-tRNA), thermally unstable elongation factor (EF-Tu), and GTP. By performing ensemble and single-molecule fluorescence resonance energy transfer (FRET) measurements, we reveal the dramatic effect of monomer backbone on ternary complex formation and protein synthesis. Both the (R) and (S)-β2isomers of Phe disrupt ternary complex formation to levels belowin vitrodetection limits, while (R)- and (S)-β3-Phe reduce ternary complex stability by approximately one order of magnitude. Consistent with these findings, (R)- and (S)-β2-Phe-charged tRNAs were not utilized by the ribosome, while (R)- and (S)-β3-Phe stereoisomers were utilized inefficiently. The reduced affinities of both species for EF-Tu ostensibly bypassed the proofreading stage of mRNA decoding. (R)-β3-Phe but not (S)-β3-Phe also exhibited order of magnitude defects in the rate of substrate translocation after mRNA decoding, in line with defects in peptide bond formation that have been observed for D-α-Phe. We conclude from these findings that non-natural amino acids can negatively impact the translation mechanism on multiple fronts and that the bottlenecks for improvement must include consideration of the efficiency and stability of ternary complex formation.
Global variation in the ratio of sapwood to leaf area explained by optimality principles
Authors: Xu Huiying , Wang Han , Prentice I. Colin , Harrison Sandy P. , Rowland Lucy , Mencuccini Maurizio , Sanchez-Martinez Pablo , He Pengcheng , Wright Ian J. , Sitch Stephen , Ye Qing
Published: February 2024

The sapwood area supporting a given leaf area (vH) reflects a coordinated coupling between carbon uptake, water transport and loss at a whole plant level. Worldwide variation invHreflects diverse plants strategies adapt to prevailing environments, and impact the evolution of global carbon and water cycles. Why such a variation has not been convincingly explained yet, thus hinder its representation in Earth System Models. Here we hypothesize that optimalvHtends to mediate between plant hydraulics and leaf photosynthesis so that leaf water loss matches water supply. By compiling and testing against two extensive datasets, we show that our hypothesis explains nearly 60% ofvHvariation responding to light, vapour pressure deficit, temperature, and sapwood conductance in a quantitively predictable manner. Sapwood conductance or warming-enhanced hydraulic efficiency reduces the demand on sapwood area for a given total leaf area and, whereas brightening and air dryness enhance photosynthetic capacities consequently increasing the demand. This knowledge can enrich Earth System Models where carbon allocation and water hydraulics play key roles in predicting future climate-carbon feedback.
Multi-omics clustering analysis carries out the molecular specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies
Authors: Wang Zhenglin , Han Qijun , Hu Xianyu , Wang Xu , Sun Rui , Huang Siwei , Chen Wei
Published: February 2024

Background

Thyroid cancer is the most prevalent endocrine malignancy, Recent classifications highlight the importance of molecular characteristics in TC, including BRAF, TERT, and RET fusion gene mutations, which are crucial for diagnosis, prognosis, and targeted therapy. This study aims to explore molecular subtypes of TC to identify new biomarkers and improve patient selection for targeted therapies.

Methods

This study utilized multi-omics data from the TCGA-THCA dataset and additional cohorts (GSE29265, GSE33630, GSE54958, GSE65074) involving a total of 539 patients. Various data types, including DNA methylation, gene mutations, mRNA, LncRNA, and miRNA expression, were analyzed. The study employed consensus clustering algorithms to identify molecular subtypes and used various bioinformatics tools to analyze genetic alterations, signaling pathways, immune infiltration, and responses to chemotherapy and immunotherapy. The statistical significance was established at P < 0.05.

Results

Two prognostically relevant thyroid cancer subtypes, termed CS1 and CS2, were identified. CS2 was associated with a poorer prognosis of shorter progression-free survival times (P < 0.001). CS1 exhibited higher copy number alterations but lower tumor mutation burden (TMB) than CS2. Notably, CS2 showed higher TMB and cytolytic activity scores, suggesting a potential for higher immunogenicity. Different pathway activations were observed between subtypes, with CS2 showing activation in cell proliferation and immune-related pathways. Drug sensitivity analysis indicated CS2’s higher sensitivity to cisplatin, doxorubicin, paclitaxel, and sunitinib, whereas CS1 was more sensitive to bicalutamide and FH535. The different activated pathways and sensitive to drugs for subtypes were further validated in external cohort. After dimensionality reduction, five genes of CXCL17, LCN2, MUC1, SERPINA1, and SLC34A2 were validated that can distinguish subtypes across pan-cohorts. 24 paired tumor and adjacent normal tissues by immunohistochemical staining further show the prognostic value of CXCL17 for advanced thyroid cancer.

Conclusion

The study revealed two distinct molecular subtypes of thyroid cancer with significant implications for prognosis, genetic alterations, pathway activation, and treatment response. These findings underscore the potential of multi-omics approaches in enhancing personalized medicine in thyroid cancer.
Correlates of non-dipping blood pressure in persons with and without hypertension
Authors: Liweleya Situmbeko , Hamooya Benson M. , Mungalu Obrain M. L. , Zimba Sharon D. , Masenga Sepiso K.
Published: February 2024

Background

Blood pressure (BP) is known to follow a circadian rhythm with 10% to 15% lower values during the night than daytime. Non-dipping BP refers to the absence of BP dipping and has been associated with the development of target organ damage. The general goal of this study was to determine the correlates of non-dipping BP in persons with and without hypertension.

Methods

This was a cross-sectional study that recruited 98 participants at Chikankata Mission General Hospital. The outcome variable of the study was non-dipping BP, with sociodemographic and clinical explanatory variables. We used SPSS version 22 to describe and make inferences.

Results

The median (interquartile range (IQR)) age of participants was 42 years (34.7-52) and 54.1% (53/98) had hypertension while 45.9% (45/98) were normotensive. The proportion of females was slightly higher (59.2%, n=58) than that of males (40.2%, n=40), this being similar in hypertensives but equal in normotensives. The median (IQR) age of hypertensives was higher compared to the normotensives, 46 (40-56) vs. 35 (25-41) years.

The prevalence of non-dipping BP was 38.8% overall and higher among those with hypertension (54.7%) compared to the normotensive group (20%). The factors associated with non-dipping BP in the multivariate analysis were age (adjusted odds ratios (AOR) of 1.15; 95% CI: 1.05 - 1.25), spot urine sodium (AOR of 1.16; 95% CI: 0.99 - 1.36), daytime systolic blood pressure (SBP) load (AOR of 1.28; 95% CI: 1.06 - 1.55), daytime diastolic blood pressure (DBP) load (AOR of 0.77; 95% CI: 0.65 - 0.92), and nighttime DBP load (AOR of 1.10; 95% CI: 1.02, 1.18). However, this was abrogated by hypertension status albeit among normotensives only age remained significantly associated with non-dipping BP, none of the factors remained significantly associated with non-dipping BP among persons with hypertension.

Conclusion

The prevalence of non-dipping BP was high, among hypertensives. This provides insights into the intricate links between BP patterns, sociodemographic and clinical characteristics but further underscores the need for mechanistic researches to further advance the understanding of mechanisms of associated characteristics.
Fluorosurfactants in groundwater increase the incidence of chronic health conditions among California Medicare beneficiaries
Authors: Neas Lucas M. , Steinhardt William , Hill K. Lloyd , Short Riley , Hubal Elaine , Reich Brian J , Yang Shu , Sheng Alvin , Rappold Ana G.
Published: February 2024

Background

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants with emerging environmental and regulatory concerns.

Objectives

This study aimed to estimate the burden of PFAS exposures through ground water on the incidence of chronic health conditions among Medicare beneficiaries aged 65 years and older.

Methods

We estimated PFAS groundwater concentrations for every ZIP code tabulated area (ZCTA) in California counties where 25 percent or more of the population’s drinking water was derived from groundwater. We calculated the annual incidence of non-cancer chronic health conditions among 1,696,247 Medicare beneficiaries aged 65 and older by residential ZCTA over the seven-year study period (2011-2017). A Poisson regression model was used to estimate associations between PFAS groundwater concentration and chronic condition incidence with an offset for the number of beneficiary-years at risk and adjusting for bias due to non-random sampling of wells, use of groundwater for drinking water, demographic characteristics, and lung cancer incidence as a control for smoking.

Results

Results suggest an association between a 10 ng/L increment in PFAS contaminated groundwater and chronic health conditions including hypertension (+1.15%, 95% confidence interval (CI) 1.01, 1.30), chronic kidney disease (+0.83%, 95% CI 0.68, 0.99) and cataracts (+1.50%, 95% CI 1.35, 1.66).

Discussion

This small increment in the incidence rate would produce an additional 1,700 new cases of hypertension each year in the study population.
Deep Learning Model Using Continuous Skin Temperature Data Predicts Labor Onset
Authors: Basavaraj Chinmai , Grant Azure D. , Aras Shravan G. , Erickson Elise N.
Published: February 2024

Background

Changes in body temperature anticipate labor onset in numerous mammals, yet this concept has not been explored in humans.

Methods

We evaluated patterns in continuous skin temperature data in 91 pregnant women using a wearable smart ring. Additionally, we collected daily steroid hormone samples leading up to labor in a subset of 28 pregnancies and analyzed relationships among hormones and body temperature trajectory. Finally, we developed a novel autoencoder long-short-term-memory (AE-LSTM) deep learning model to provide a daily estimation of days until labor onset.

Results

Features of temperature change leading up to labor were associated with urinary hormones and labor type. Spontaneous labors exhibited greater estriol to α-pregnanediol ratio, as well as lower body temperature and more stable circadian rhythms compared to pregnancies that did not undergo spontaneous labor. Skin temperature data from 54 pregnancies that underwent spontaneous labor between 34 and 42 weeks of gestation were included in training the AE-LSTM model, and an additional 40 pregnancies that underwent artificial induction of labor or Cesarean without labor were used for further testing. The model was trained only on aggregate 5-minute skin temperature data starting at a gestational age of 240 until labor onset. During cross-validation AE-LSTM average error (true – predicted) dropped below 2 days at 8 days before labor, independent of gestational age. Labor onset windows were calculated from the AE-LSTM output using a probabilistic distribution of model error. For these windows AE-LSTM correctly predicted labor start for 79% of the spontaneous labors within a 4.6-day window at 7 days before true labor, and 7.4-day window at 10 days before true labor.

Conclusion

Continuous skin temperature reflects progression toward labor and hormonal status during pregnancy. Deep learning using continuous temperature may provide clinically valuable tools for pregnancy care.
Resilliance Among Turkish Adolescents: A Multi-Level Approach
Authors: Çakir Gökhan , Işik Utku , Ustun Umit Dogan , Su Nihan , Gumusgul Osman
Published: February 2024

Introduction

The objective of this study is to determine the components that contribute to psychological resilience in adolescents and to determine if physical exercise, emotion control, or self-efficacy are more effective predictors of resilience.

Methods

Data from participants was collected through a personal information form, the International Physical Activity Questionnaire—Short Form, the Self-Efficacy Scale for Children, the Emotion Regulation Scale for Children and Adolescents, and the Psychological Resilience Scale for Children and Adolescents. The data were gathered online from 16 out of the 81 provinces in Turkey, representing 7 different regions, using convenience sampling. The study sample comprised 505 adolescents, with 309 females and 196 males. The average age of the participants was 15.66 years, with a standard deviation of 1.34. The data obtained from the students was analyzed using SPSS 27.0 statistical software. The Chi-Square test was employed to establish the correlation between the demographic features of adolescents and their levels of physical activity. The relationship between the independent variables and the dependent variable was determined using correlation analysis and hierarchical regression analysis.

Results

The results suggest that physical exercise, the ability to regulate emotions through reappraisal, and self-efficacy are significant indicators of adolescents’ resilience.

Conclusions

The research conclusions point out that self-efficacy has a greater impact on psychological resilience compared to physical activity and emotion regulation.
Clinical Pattern and Outcome of Patients with Acute Kidney Injury in the Emergency Department of Saint Paul’s Hospital Millennium Medical College
Authors: Assefa Berihu , Gebremedhin Yemane , Bahta Benyam , Worku Frehiwot , Mamo Dirijit , Sultan Menbeu , Kalifa Mohammed
Published: February 2024

Background

Worldwide, 13.3 million people experience Acute Kidney Injury (AKI) each year. 85% of individuals impacted are thought to reside in underdeveloped nations. AKI continues to be one of the most widespread diseases in the world, although little is known about its clinical profile or outcome. The ability to pinpoint particular causes enables the implementation of targeted therapy and the development of preventative measures.

The main goal of this study was to identify the patterns and outcomes of patients with AKI in the emergency department of Saint Paul’s Hospital Millennium Medical College (SPHMMC).

Method and materials

A cross-sectional study was conducted at the emergency department of SPHMMC in Addis Ababa, Ethiopia, from June 1-2021 to June 1-2022. Google Forms was used to collect the data, which was then cleaned up in Microsoft Excel before being sent to SPSS version 25 for analysis. To evaluate demographic, clinical profile, and outcome determinants, descriptive statistics, and binary logistic regression analysis were utilized. A paired samples T-test was used to compare the patient’s laboratory findings at admission and discharge.

Results

Among the 222 AKI patients included in the study 110 (49.5%) were males and 112 (50.5%) were females. The mean age of presentation was 48+18 years old. The majority of patients were from Addis Ababa (41.4%) and the Oromia region (40.5%). The most common causes of AKI were infections (26.2%), acute glomerulonephritis (20.4%), volume depletion (18.5%), and obstructive uropathy (16.6%). Uremic encephalopathy, infection, malignancy, potassium at discharge from emergency, and low initial Glasgow coma scale (GCS) significantly contributed to the death. The presence of nephrotoxic antibiotics, infection, and hyponatremia significantly contributed to the admission rate to the wards and intensive care unit (ICU).

Conclusion

In conclusion, infection is the dominant cause and mortality predictor of AKI at SPHMMC. The majority of patients with infections were sepsis (78.1%), pyelonephritis (11.4%), and pneumonia (10.3%). Early initiation of antibiotics in the emergency is better for a good outcome.
Oomycete communities in lowland tropical forest soils vary in abundance and are composed of saprophytes and pathogens of seeds and seedlings of multiple plant species.
Authors: Broders Kirk , Capador-Barreto Hernan , Iriarte Gloria , Wright Joseph , Baur Moritz , Espinosa-Ortega Hilario , Spear Erin
Published: February 2024

Premise: The soils in lowland tropics are teeming with microbial life which can impact plant community structure and diversity through plant-soil feedbacks. While bacteria and fungi have been the focus of most studies in the tropics, the oomycetes may have an outsized effect on seed and seedling health and survival, given their affinity for environments with increased precipitation and temperature. Methods: We assessed the diversity and pathogenicity of oomycete species present in a lowland tropical forest in Panama. We used both a culture dependent leaf-baiting assay and culture independent soil DNA metabarcoding methods to quantify zoospore abundance and species diversity. A subset of the isolates from the baiting assay were used to evaluate pathogenicity and aggressiveness on seedlings of three tree species. Key results: Oomycetes are ubiquitous and common members of the soil microbial community in lowland tropical forests and zoospore abundance was far greater compared to similar studies from temperate and mediterranean forests. We also observed variation in oomycete species ability to infect host plants. Species of Pythium were more aggressive, while species of Phytopythium caused less disease but were more diverse and commonly isolated from the soil. Finally, we found that individual hosts accumulate a distinct oomycete community and was the only factor that had an effect community structure. Conclusions: Collectively, these finding demonstrate that oomycetes are ubiquitous, host-generalist pathogens and saprophytes, that have the potential to impact seed and seedling survival in lowland tropical forests