bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebrospinal fluid levels of NfM in relation to NfL and pNfH as prognostic markers in amyotrophic lateral sclerosis
Authors: Olofsson Jennie , Bergström Sofia , Mravinacová Sára , Kläppe Ulf , Öijerstedt Linn , Zetterberg Henrik , Blennow Kaj , Ingre Caroline , Nilsson Peter , Månberg Anna
Published: July 2024

Objective

To evaluate the prognostic potential of neurofilament medium chain (NfM) in CSF from patients with ALS and explore its relationship with the extensively studied neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH).

Method

CSF levels of NfL, NfM, and pNfH were analysed in 235 samples from patients with ALS, ALS mimics, and healthy controls in a well-characterized cohort from Karolinska ALS Clinical Research Centre in Stockholm, Sweden. NfM levels were analysed using an antibody-based suspension bead-array and NfL and pNfH levels were measured using standard ELISA. Clinical data, including ALS Revised Functional Rating Scale (ALSFRS-R), and survival outcomes were utilized for disease progression estimations.

Result

Increased NfM levels were observed in patients with ALS compared with mimics and healthy controls, consistent with the results observed for NfL and pNfH. Similar to NfL and pNfH, significant associations of NfM levels with disease progression were found, with higher levels in fast progressors compared with slow progressors, both in total progression and the ALSFRS-R subscores. For all neurofilaments, higher survival probability was observed for patients with low CSF levels. Additionally, all three proteins showed similar predictive performance for disease progression rates (AUC 0.85-0.86). Although there was no statistical difference between the curves, combining them slightly improved the performance (AUC 0.86-0.87).

Conclusion

Based on this cross-sectional study, the prognostic value provided by NfM aligns with the more established markers, NfL and pNfH. However, additional investigations with independent cohorts and longitudinal studies are needed to further explore the potential added value of NfM.
The relationship between anxiety and levels of Alzheimer’s disease plasma biomarkers
Authors: Bernard Mark A. , Boutajangout Allal , Debure Ludovic , Ahmed Wajiha , Briggs Anthony Q. , Boza-Calvo Carolina , Vedvyas Alok , Marsh Karyn , Bubu Omonigho M. , Osorio Ricardo S. , Wisniewski Thomas , Masurkar Arjun V.
Published: July 2024

Anxiety is highly prevalent in Alzheimer’s disease (AD), correlating with CSF/PET biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/Aβ42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration.
Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling
Authors: Mangum Kevin D. , Li Qinmengge , Bauer Tyler M. , Wolf Sonya J. , Shadiow James , Moon Jadie Y. , Barrett Emily C. , Joshi Amrita D. , Ahmed Zara , Wasikowski Rachael , Boyer Kylie , Obi Andrea T. , Davis Frank M. , Chang Lin , Tsoi Lam C. , Gudjonsson Johann , Gallagher Katherine A.
Published: July 2024

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the humanJMJD3gene and show that the minor C allele increasesJMJD3transcription in SMCs via increased SP1 binding to theJMJD3promoter. Using our novel SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss ofJmjd3in SMCs results in HTN, mechanistically, due to decreasedEDNRBexpression and a compensatory increase inEDNRAexpression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation betweenJMJD3andEDNRBexpression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.

Graphical Abstract
MELD-XI Predicts Severe Right Ventricular Failure after HeartMate 3 Implantation in a Contemporary Cohort
Authors: Lambert David S. , Picó Ana María , Vincent Justin D. , Deych Elena , Coglianese Erin , Schilling Joel D. , Vader Justin M. , Yang Bin Q.
Published: July 2024

Background

Right ventricular failure (RVF) after left ventricular assist devices (LVAD) is associated with significant morbidity and mortality and identifying patients at risk for severe RVF is an important clinical goal. Current risk prediction models were not developed in contemporary LVAD populations and have limited clinical applicability.

Objectives

To evaluate whether the Model for End Stage Liver Disease – eXcluding INR (MELD-XI) can predict severe RVF after HeartMate 3 (HM3) implantation.

Methods

We retrospectively analyzed all adult patients who received HM3 LVAD as initial implantation at two academic medical centers. We assessed whether MELD-XI is an independent risk factor for severe RVF in multivariate analysis and compared the predictive accuracy of MELD-XI with previously published risk scores. We also investigated the relationship between MELD-XI and markers of right ventricular function and whether MELD-XI was associated with death or pump exchange at 1-year follow-up.

Results

Our study included a total of 246 patients, of which 74 (30%) experienced severe RVF. After adjusting for relevant covariables, MELD-XI was independently associated with severe RVF (OR 1.18, CI 1.09-1.29, p<0.001) and performed similarly to the EUROMACS and Michigan RVF risk scores. In addition, MELD-XI was not reflective of traditional echocardiographic or hemodynamic measures of right ventricular function. Finally, MELD-XI ≥ 14 predicted worse in-hospital mortality.

Conclusions

Among patients undergoing HM3 implantation, MELD-XI is independently associated with an increased risk of RVF and in-hospital mortality.
Illuminating microbial phosphorus cycling in deep-sea cold seep sediments using protein language models
Authors: Zhang Chuwen , He Yong , Wang Jieni , Chen Tengkai , Baltar Federico , Hu Minjie , Liao Jing , Xiao Xi , Li Zhao-Rong , Dong Xiyang
Published: July 2024

Phosphorus is essential for life and critically influences marine productivity. Despite geochemical evidence of active phosphorus cycling in deep-sea cold seep ecosystems, the microbial processes involved remain poorly understood. Traditional sequence-based searches often fail to detect proteins with remote homology. To address this, we developed a protein language model (PLM) named LucaPCycle that integrates sequence and structural information. This PLM-based approach identified 4,606 new phosphorus-cycling protein families based on the non-redundant gene and genome catalogs from global cold seeps, substantially enhancing our understanding of their diversity, ecology, and function. Among previously unannotated sequences, we discovered three novel alkaline phosphatase families (ALP1, ALP2 and ALP3) that feature unique domain organizations and preserved enzymatic capabilities. These results highlight previously overlooked ecological importance of phosphorus cycling within cold seeps, corroborated by data from porewater geochemistry, metatranscriptomics, and metabolomics. We identified a previously unrecognized diversity of archaea contributing to organic phosphorus mineralization and inorganic phosphorus solubilization through various mechanisms. This includes ecologically significant groups such as Asgardarchaeota, anaerobic methanotrophic archaea (ANME), and Thermoproteota. Additionally, viruses can enhance their hosts' (e.g., ANME) phosphorus utilization through the PhoR-PhoB regulatory system and PhnCDE transporter, indirectly influencing methane dynamics. Overall, our PLM-based functional predictions are capable of accessing previously 'hidden' sequence spaces for microbial phosphorus cycling, and can be applied to other various ecosystems.
Microbial Hauberks: Composition and Function of Surface Layer Proteins in Gammaproteobacterial Methanotrophs
Authors: Hamilton Richard , Gebbie William , Bowman Chynna , Mantanona Alex , Kalyuzhnaya Marina G.
Published: July 2024

Many species of proteobacterial methane-consuming bacteria (methanotrophs) form a hauberk-like envelope represented by a surface (S-) layer protein matrix. While several proteins were predicted to be associated with the cell surface, the composition and function of the hauberk matrix remained elusive. Here we report the identification of the genes encoding the hauberk-forming protein in two gamma-proteobacterial (Type I) methanotrophs,Methylotuvimicrobium buryatense5GB1 (EQU24_15540) andMethylotuvimicrobium alcaliphilum20ZR(MEALZ_0971 and MEALZ_0972). The proteins share 40% AA identity with each other and are distantly related to the RsaA proteins fromCaulobacter crescentus(20% AA identity).

Deletion of these genes resulted in loss of the characteristic hauberk pattern on the cell surface. A set of transcriptional fusions between the MEALZ_0971 and a superfolder green fluorescent protein (sfGFP) further confirmed its surface localization. The functional roles of the hauberk and cell-surface associated proteins, including MEALZ_0971, MEALZ_0972, EQU24_15540, and a copper-induced CorA protein, were further investigated via gene expression studies and phenotypic tests. The hauberk core protein shows constitutive expression across 18 growth conditions. TheM. alcaliphilum20ZRΔ0971 showed reduced growth at high salinity, high methanol and metal-limited conditions, suggesting a role in cell-envelope stability and metal scavenging.

Overall, understanding the genetics, composition and cellular functions of the S-layers contributes to our knowledge of methanotroph adaptation to environmental perturbations and opens a promising prospect for (nano)biotechnology applications.
The RRM domain-containing protein Rbp3 interacts with ribosomes and the 3′ ends of mRNAs encoding photosynthesis proteins
Authors: Hemm Luisa , Lichtenberg Elisabeth , Tholen Stefan , Reimann Viktoria , Kakazu Kenta , Machida Sotaro , Mahbub Moontaha , Schilling Oliver , Wilde Annegret , Watanabe Satoru , Mullineaux Conrad W. , Hess Wolfgang R.
Published: July 2024

RNA recognition motif (RRM) domain proteins are crucial RNA-binding proteins (RBPs) across all domains of life. In cyanobacteria, single RRM domain proteins are involved in mRNA targeting to the thylakoid membrane and acclimation to certain stress conditions, but many details of their physiological functions and molecular targets have remained unknown. The model cyanobacteriumSynechocystissp. PCC 6803 has a family of three genes encoding the RRM domain-containing proteins Rbp1, Rbp2 and Rbp3. Here, we verified the RNA-binding activity of Rbp3in vivoand show that cells of a Δrbp3deletion strain had a lower PSI:PSII ratio and pigment content and were significantly smaller than wild-type cells. To identify the set of interacting molecules, co-immunoprecipitation experiments were performed with a strain expressing a C-terminally FLAG-tagged Rbp3. Mass spectrometry of the elution fraction suggested physical proximity between Rbp3, ribosomes, and a very small number of other proteins. The most highly enriched transcript in the co-eluting RNA fraction was thepsaABmRNA. This was corroborated by fluorescentin situhybridization (FISH) analyses showing decreasedpsaAmRNA signals and colocalization with Rbp3-GFP signals and ribosomes. Other enriched mRNAs encode thylakoid, plasma membrane and carboxysome proteins. The Rbp3-mRNA interactions occurred preferentially towards the end of coding regions or the 3′UTRs, although some were also mapped to other regions. Binding assays using Bio-layer Interferometry validated the Rbp3-psaABmRNA interaction, indicating a preference for folded RNA segments near or overlapping the respective stop codons.

Significance statement

The mechanisms by which proteins are produced at specific sites and inserted into the intricate membrane systems of photosynthetic cyanobacteria are only partially understood. While RRM domain proteins are well-studied RNA-binding proteins in eukaryotes, their functions in bacteria remain underexplored. This study reveals that the RRM domain protein Rbp3 in the cyanobacteriumSynechocystissp. PCC 6803 binds mRNAs encoding photosynthetic proteins, plasma membrane proteins and carboxysome proteins and localizes near ribosomes. The bound RNA segments are typically near the ends of coding regions, or in 5′ untranslated regions. These findings suggest that Rbp3 is involved in targeting mRNAs to specific intracellular locations by interacting with structural elements within these mRNA molecules.
SARS-CoV-2 shedding dynamics in human respiratory tract
Authors: Jin Xiangxing , Ren Lili , Ren Xianwen , Wang Jianwei
Published: July 2024

It is crucial to understand how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) sheds in human respiratory tract, but this question is still elusive to understand due to technical limitations. Here we integrated published human metagenomic data of SARS-CoV-2 and developed a novel algorithm named as RedeCoronaVS to systematically dissect SARS-CoV-2 shedding modes with single-cell data as reference. We identify that SARS-CoV-2 particles are the dominant mode of viral shedding in the very early infection phase (≤24 hours after hospitalization). Within the first week after hospitalization, SARS-CoV-2 replicons within host cells dominate SARS-CoV-2 shedding together with viral particles. One week later, viral fragments become the dominant mode in patients with mild or moderate symptoms, but viral replicons still dominate in some patients with severe symptoms. In addition to epithelial cells, SARS-CoV-2 replicons in neutrophils, macrophages, and plasma cells also show important roles and are associate with sampling time and disease severity.
Deletion of HindIIR and HindIIIR improves DNA transfer via electroporation toHaemophilus influenzaeRd
Authors: Hamadache Samir , Huang Yu Kang , Shedeed Adam , Syed Aqil , Karas Bogumil J.
Published: July 2024

Haemophilus influenzaeis a bacterial species of interest for its medical relevance and utility as a model system. Despite its role in several landmark molecular and synthetic biology studies,H. influenzaeremains underexplored as a potential chassis organism. The limited availability of reliable and convenient transformation methods and genetic tools forH. influenzaeare obstacles to this end. However, a strain ofH. influenzaeRd KW20 lacking the type II restriction endonucleases HindII and HindIII has previously been developed. Here, we show that this strain is more readily transformable by electroporation than wild-type Rd KW20. We also developed a series of multi-host plasmids carrying antibiotic selection and fluorescent visual markers based on the pSU20 vector. The availability ofH. influenzaeΔHindII/III, paired with the electroporation method and plasmids presented here, will promote the exploration ofH. influenzaeas a host organism for synthetic biology applications.
The Haemagglutinin Genes of the UK Clade 2.3.4.4b H5N1 Avian Influenza Viruses from 2020 to 2022 Retain Strong Avian Phenotype
Authors: Yang Jiayun , Daines Rebecca , Chang Pengxiang , Karunarathna Thusitha K. , Qureshi Mehnaz , Sadeyen Jean-Remy , James Joe , Banyard Ashley C. , Slomka Marek , Brown Ian H. , Iqbal Munir
Published: July 2024

Since 2020, the United Kingdom (UK) has suffered repeated epizootics of clade 2.3.4.4b H5 high pathogenicity avian influenza viruses (HPAIVs) in wild birds and poultry, resulting in substantial economic losses due to enforced statutory control. The rapid evolution of H5 HPAIVs continues to raise concern with heightened zoonotic and pandemic risks. The immunodominant haemagglutinin glycoprotein (HA) is crucial for influenza virus receptor binding and pH-induced fusion of viral and cellular membranes. Mutations in HA are frequent due to polymerase error, immune pressure and host adaptation, resulting in antigenic modulation and/or an expansion of host tropism, respectively, ultimately hindering control strategies. We evaluated a comprehensive panel of H5 viruses representing prevalent genotypes from UK outbreaks spanning 2020 to 2022 for HA functionality. HA genes from each genotype were assessed through receptor binding, pH of fusion, thermostability and HA inhibition assays to evaluate factors contributing to zoonotic potential, stability, and antigenicity. The viruses only bound to avian receptors and exhibited fusion at a pH of 5.8, above the pH range (pH 5.0 to 5.5) associated with efficient human-to-human transmission. Therefore, these H5 viruses have low immediate zoonotic threat. Contemporary H5 viruses were more thermostable and showed antigenic drift compared to the earlier 2017-2018 clade 2.3.4.4b H5N8 viruses, and N236D in HA was identified as a significant antigenic epitope. The findings of this study underscore the evolving nature of the HA of these viruses and highlight the importance of ongoing surveillance and characterisation efforts to identify factors that might contribute to zoonotic risk.
Heat-killed probioticLevilactobacillus brevisMKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses inCaenorhabditis elegans
Authors: Kumar Arun , Saha Manti Kumar , Kumar Vipin , Bhattacharya Anupam , Barge Sagar , Mukherjee Ashis K. , Kalita Mohan C. , Khan Mojibur R.
Published: July 2024

Background

Proteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin-proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age- related diseases.

Results

This study introduces a novel heat-killedLevilactobacillus brevisstrain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-typeCaenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of- function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptorsqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1,ilys-1,cnc-2,spp-9,spp-21,clec-47, andclec-266) and antioxidation (sod-3andgst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors.

Conclusion

Our research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin- signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.
RBM10 loss induces aberrant splicing of cytoskeletal and extracellular matrix mRNAs and promotes metastatic fitness
Authors: Krishnamoorthy Gnana P. , Glover Anthony R. , Untch Brian R. , Sigcha-Coello Nickole , Xu Bin , Vukel Dina , Liu Yi , Tiedje Vera , Berman Katherine , Tamarapu Prasanna P. , Acuña-Ruiz Adrian , Saqcena Mahesh , de Stanchina Elisa , Boucai Laura , Ghossein Ronald A. , Knauf Jeffrey A. , Abdel-Wahab Omar , Bradley Robert K. , Fagin James A.
Published: July 2024

RBM10 modulates transcriptome-wide cassette exon splicing. Loss-of-functionRBM10mutations are enriched in thyroid cancers with distant metastases. Analysis of transcriptomes and genes mis-spliced by RBM10 loss showed pro-migratory and RHO/RAC signaling signatures. RBM10 loss increases cell velocity. Cytoskeletal and ECM transcripts subject to exon-inclusion events included vinculin (VCL), tenascin C (TNC) and CD44. Knockdown of the VCL exon inclusion transcript inRBM10-null cells reduced cell velocity, whereas knockdown of TNC and CD44 exon-inclusion isoforms reduced invasiveness. RAC1-GTP levels were increased inRBM10-null cells. MouseHrasG12V/Rbm1OKOthyrocytes develop metastases that are reversed by RBM10 or by combined knockdown of VCL, CD44 and TNC inclusion isoforms. Thus,RBM10loss generates exon inclusions in transcripts regulating ECM-cytoskeletal interactions, leading to RAC1 activation and metastatic competency. Moreover, a CRISPR-Cas9 screen for synthetic lethality with RBM10 loss identified NFkB effectors as central to viability, providing a therapeutic target for these lethal thyroid cancers.

RNA splicing factor mutations are common in cancer but connecting phenotypes to specific misspliced genes has been challenging. We show that RBM10 loss leads to exon inclusions of transcripts regulating ECM-cytoskeletal interactions and RAC1-GTP activation, sufficient to promote metastatic fitness.
A HigB-like toxin promotes non-replicatingSalmonellainside macrophages by inhibiting ribonuclease III
Authors: Choi Soomin , Cho Yong-Joon , Baek Seungwoo , Choi Eunna , Kim Yoon Ki , Lee Eun-Jin
Published: July 2024

Many bacteria are often resistant to antibiotic treatment because they can slow down their growth rate, thereby attenuating the drug’s effectiveness. A similar growth-rate control is observed in pathogens that infect and persist inside their hosts. The bacterial toxin-antitoxin (TA) system serves as a non-heritable phenotypic switch by slowing down growth through the expression of a toxin component. Here, we investigated a HigB-like type II toxin from the intracellular bacterial pathogenSalmonellaTyphimurium. Unlike other HigB-like toxins that cleave ribosome-bound mRNAs, it does not exhibit endoribonuclease activity. Instead, it inhibits ribonuclease III, which mediates the initial cleavage for rRNA processing, by directly binding to the dsRNA-binding domain of RNase III, thereby decreasing ribosome assembly and bacterial growth. Given that the formation of HigB-like toxin-mediated non-replicatingSalmonellawithin macrophages is RNase III-dependent, persister formation by inhibiting RNase III is a newly identified strategy for pathogens to survive within host cells.
Zonal Patterning of Extracellular Matrix and Stromal Cell Populations Along a Perfusable Cellular Microchannel
Authors: Chernokal Brea , Ferrick Bryan J. , Gleghorn Jason P.
Published: July 2024

The spatial organization of biophysical and biochemical cues in the extracellular matrix (ECM) in concert with reciprocal cell-cell signaling is vital to tissue patterning during development. However, elucidating the role an individual microenvironmental factor plays using existingin vivomodels is difficult due to their inherent complexity. In this work, we have developed a microphysiological system to spatially pattern the biochemical, biophysical, and stromal cell composition of the ECM along an epithelialized 3D microchannel. This technique is adaptable to multiple hydrogel compositions and scalable to the number of zones patterned. We confirmed that the methodology to create distinct zones resulted in a continuous, annealed hydrogel with regional interfaces that did not hinder the transport of soluble molecules. Further, the interface between hydrogel regions did not disrupt microchannel structure, epithelial lumen formation, or media perfusion through an acellular or cellularized microchannel. Finally, we demonstrated spatially patterned tubulogenic sprouting of a continuous epithelial tube into the surrounding hydrogel confined to local regions with stromal cell populations, illustrating spatial control of cell-cell interactions and signaling gradients. This easy-to-use system has wide utility for modeling three-dimensional epithelial and endothelial tissue interactions with heterogeneous hydrogel compositions and/or stromal cell populations to investigate their mechanistic roles during development, homeostasis, or disease.
Dynamic stress- and inflammatory-based regulation of psychiatric risk loci in human neurons
Authors: Retallick-Townsley Kayla G. , Lee Seoyeon , Cartwright Sam , Cohen Sophie , Sen Annabel , Jia Meng , Young Hannah , Dobbyn Lee , Deans Michael , Fernandez-Garcia Meilin , Huckins Laura M. , Brennand Kristen J.
Published: July 2024

The prenatal environment can alter neurodevelopmental and clinical trajectories, markedly increasing risk for psychiatric disorders in childhood and adolescence. To understand if and how fetal exposures to stress and inflammation exacerbate manifestation of genetic risk for complex brain disorders, we report a large-scale context-dependent massively parallel reporter assay (MPRA) in human neurons designed to catalogue genotype x environment (GxE) interactions. Across 240 genome-wide association study (GWAS) loci linked to ten brain traits/disorders, the impact of hydrocortisone, interleukin 6, and interferon alpha on transcriptional activity is empirically evaluated in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons. Of ∼3,500 candidate regulatory risk elements (CREs), 11% of variants are active at baseline, whereas cue-specific CRE regulatory activity range from a high of 23% (hydrocortisone) to a low of 6% (IL-6). Cue-specific regulatory activity is driven, at least in part, by differences in transcription factor binding activity, the gene targets of which show unique enrichments for brain disorders as well as co-morbid metabolic and immune syndromes. The dynamic nature of genetic regulation informs the influence of environmental factors, reveals a mechanism underlying pleiotropy and variable penetrance, and identifies specific risk variants that confer greater disorder susceptibility after exposure to stress or inflammation. Understanding neurodevelopmental GxE interactions will inform mental health trajectories and uncover novel targets for therapeutic intervention.
Bacteriophage resistance evolution in a honey bee pathogen
Authors: Spencer Emma K. , Eline Yva , Saucedo Lauren , Linzan Kevin , Paull Keera , Miller Craig R. , Peters Tracey L. , Van Leuven James T.
Published: July 2024

Honey bee (Apis mellifera) larvae are susceptible to the bacterial pathogen Paenibacillus larvae, which causes severe damage to bee colonies. Antibiotic treatment requires veterinary supervision in the United States, is not used in many parts of the world, perpetuates problems associated with antibiotic resistance, and can necessitate residual testing in bee products. There is interest in using bacteriophages to treat infected colonies (bacteriophage therapy) and several trials are promising. Nevertheless, the safety of using biological agents in the environment must be scrutinized. In this study we analyzed the ability ofP. larvaeto evolve resistance to several different bacteriophages. We found that bacteriophage resistance is rapidly developed in culture but often results in growth defects. Mutations in the bacteriophage-resistant isolates are concentrated in genes encoding potential surface receptors but are also observed in genes controlling general cellular functions, and in two cases—lysogeny. Testing one of these isolates in bee larvae, we found it to have reduced virulence compared to the parentalP. larvaestrain. We also found that bacteriophages are likely able to counteract resistance evolution. This work suggests that while bacteriophage-resistance may arise, its impact will likely be mitigated by reduced pathogenicity and secondary bacteriophage mutations that overcome resistance.
Inferring cancer type-specific patterns of metastatic spread using Metient
Authors: Koyyalagunta Divya , Ganesh Karuna , Morris Quaid
Published: July 2024

Cancers differ in how they establish metastases. These differences can be studied by reconstructing the metastatic spread of a cancer from sequencing data of multiple tumors. Current methods to do so are limited by computational scalability and rely on technical assumptions that do not reflect current clinical knowledge. Metient overcomes these limitations using gradient-based, multi-objective optimization to generate multiple hypotheses of metastatic spread and rescores these hypotheses using independent data on genetic distance and organotropism. Unlike current methods, Metient can be used with both clinical sequencing data and barcode-based lineage tracing in preclinical models, enhancing its translatability across systems. In a reanalysis of metastasis in 169 patients and 490 tumors, Metient automatically identifies cancer type-specific trends of metastatic dissemination in melanoma, high-risk neuroblastoma, and non-small cell lung cancer. Its reconstructions often align with expert analyses but frequently reveal more plausible migration histories, including those with more metastasis-to-metastasis seeding and higher polyclonal seeding, offering new avenues for targeting metastatic cells. Metient’s findings challenge existing assumptions about metastatic spread, enhance our understanding of cancer type-specific metastasis, and offer insights that inform future clinical treatment strategies of metastasis.
Impact of Equilibrative Nucleoside Transporters TgAT1, TgENT1, and TgENT3 onToxoplasma gondiiInfection and Differentiation
Authors: Goerner Amber , Messina Gabriel , Drogalis Beckham Lea , Martorelli Di Genova Bruno
Published: July 2024

The protozoan parasiteToxoplasma gondiirelies on its host for essential metabolites, including purines, which it cannot synthesize de novo. This study investigates the roles of equilibrative nucleoside transporters (TgENTs), specifically TgAT1, TgENT1, and TgENT3, across different developmental stages ofT. gondii. Utilizing protein-protein BLAST and position-specific iterated BLAST, we identified six genes in theT. gondiigenome with high sequence similarity to human andPlasmodium falciparumENTs, focusing on TgENT1, TgENT3, and TgAT1 due to their expression in tachyzoites and homology to the nucleoside domain.

Our results demonstrate that TgENT3 plays a crucial role during chronic infection, as TgENT3 deletion reduced tissue cysts by 50%. The double knockout of TgAT1 and TgENT3 (ΔTgAT1ΔTgENT3) failed to differentiate into bradyzoites under alkaline stress, indicating that both transporters are important for differentiation. Upregulation of TgENT1 transcripts in ΔTgAT1ΔTgENT3 parasites suggests a compensatory mechanism among TgENTs.

Conditional deletion of TgENT1 revealed its critical role in parasite growth and replication, with auxin-treated parasites showing reduced replication and long-term growth defects. Localization studies using immunofluorescence assays confirmed TgENT1’s association with the plant-like vacuole (PLVAC) membrane, distinguishing it from other ENTs typically found at the plasma membrane.

These findings highlight the distinct and overlapping functions of TgENTs inT. gondii, emphasizing their potential as therapeutic targets for toxoplasmosis. Our study contributes to the broader understanding of nucleoside transporter functions in protozoans and suggests new avenues for drug development targeting ENT function to impair parasite survival and infection.
Isolating perturbative QCD splittings in heavy-ion collisions
Authors: Cunqueiro Leticia , Pablos Daniel , Soto-Ontoso Alba , Spousta Martin , Takacs Adam , Verweij Marta
Published: July 2024

We define a new strategy to scan jet substructure in heavy-ion collisions. The scope is multifold: (i) test the dominance of vacuum jet dynamics at early times, (ii) capture the transition from coherent to incoherent jet energy loss, and (iii) study elastic scatterings in the medium, which are either hard and perturbative or soft and responsible for jet thermalization. To achieve that, we analyze the angular distribution of the hardest splitting, θhard, above a transverse momentum scale, ktmin, in high-pt jets. Sufficiently high values of ktmin target the regime in which the observable is uniquely determined by vacuumlike splittings and energy loss, leaving the jet substructure unmodified compared to proton-proton collisions. Decreasing ktmin enhances the sensitivity to the relation between energy loss and the intrajet structure and, in particular, to observe signatures of color decoherence at small angles. At wider angles it also becomes sensitive to hard elastic scatterings with the medium and, therefore, the perturbative regime of medium response. Choosing ktmin≈0 leads to order one effects of nonperturbative origin such as hadronization and, potentially, soft scatterings responsible for jet thermalization. We perform a comprehensive analysis of this observable with three state-of-the-art jet-quenching Monte Carlo event generators. Our study paves the way for defining jet observables in heavy-ion collisions dominated by perturbative QCD and thus calculable from first principles.

Published by the American Physical Society
2024
Quantum energetics of a noncommuting measurement
Authors: Linpeng Xiayu , Piccione Nicolò , Maffei Maria , Bresque Léa , Prasad Samyak P. , Jordan Andrew N. , Auffèves Alexia , Murch Kater W.
Published: July 2024

When a measurement observable does not commute with a quantum system's Hamiltonian, the energy of the measured system is typically not conserved during the measurement. Instead, energy can be transferred between the measured system and the meter. In this work, we experimentally investigate the energetics of noncommuting measurements in a circuit quantum electrodynamics system containing a transmon qubit embedded in a 3D microwave cavity. We show through spectral analysis of the cavity photons that a frequency shift is imparted on the probe, in balance with the associated energy changes of the qubit. Our experiment provides new insights into foundations of quantum measurement, as well as a better understanding of the key mechanisms at play in quantum energetics.

Published by the American Physical Society
2024
Clogging transition of granular flow in porous structures
Authors: Fang Wenchao , Chen Sheng , Li Shuiqing , Zuriguel Iker
Published: July 2024

The clogging transition of granular flow through a disordered porous structure is investigated by three-dimensional discrete element simulations. Results reveal the existence of an intermittent flow state, which has been already observed for active particles or agitated grains, but is absent in single-pore flows of passive particles. Interestingly, the analysis of the intermittent dynamics shows similar attributes to the bottleneck flow of active grains, i.e., exponential distribution of flowing intervals and power-law tails for the clogging times. Precisely, based on the exponent of the power-law tail, a clogging phase diagram for porous structures is proposed in the plane of the scaled pore size D/dp and the friction coefficient μs. Then, we demonstrate that the intermittency arises from a delay in the dissipation of particles' kinetic energy after clogging imposed by the porous structure. Finally, the maximum achievable particle flow rate driven by gravity is predicted from the Froude number Frm, which linearly scales with the pore size and the friction coefficient.

Published by the American Physical Society
2024
Adaptive strategy optimization in game-theoretic paradigm using reinforcement learning
Authors: Cheong Kang Hao , Zhao Jie
Published: July 2024

Parrondo's paradox refers to the counterintuitive phenomenon whereby two losing strategies, when alternated in a certain manner, can result in a winning outcome. Understanding the optimal sequence in Parrondo's games is of significant importance for maximizing profits in various contexts. However, the current predefined sequences may not adapt well to changing environments, limiting their potential for achieving the best performance. We posit that the optimal strategy that determines which game to play should be learnable through experience. In this Letter, we propose an efficient and robust approach that leverages Q learning to adaptively learn the optimal sequence in Parrondo's games. Through extensive simulations of coin-tossing games, we demonstrate that the learned switching strategy in Parrondo's games outperforms other predefined sequences in terms of profit. Furthermore, the experimental results show that our proposed method can be easily adjusted to adapt to different cases of capital-dependent games and history-dependent games.

Published by the American Physical Society
2024
Hamiltonian Cycles on Ammann-Beenker Tilings
Authors: Singh Shobhna , Lloyd Jerome , Flicker Felix
Published: July 2024

We provide a simple algorithm for constructing Hamiltonian graph cycles (visiting every vertex exactly once) on a set of arbitrarily large finite subgraphs of aperiodic two-dimensional Ammann-Beenker (AB) tilings. Using this result, and the discrete scale symmetry of AB tilings, we find exact solutions to a range of other problems which lie in the complexity class NP-complete for general graphs. These include the equal-weight traveling salesperson problem, providing, for example, the most efficient route a scanning tunneling microscope tip could take to image the atoms of physical quasicrystals with AB symmetries; the longest path problem, whose solution demonstrates that collections of flexible molecules of any length can adsorb onto AB quasicrystal surfaces at density one, with possible applications to catalysis; and the three-coloring problem, giving ground states for the q-state Potts model (q≥3) of magnetic interactions defined on the planar dual to AB, which may provide useful models for protein folding.

Published by the American Physical Society
2024
A comparative study of the effect of high-pressure and low temperature on the crystal structure of lithium xanthinate hydrate
Authors: Gaydamaka Anna , Bogdanov Nikita , Zakharov Boris , Goryainov Sergey , Boldyreva Elena
Published: July 2024

The crystal structure of lithium xanthinate hydrate was studied by single crystal X-ray diffraction and Raman spectroscopy on cooling to 100 K and under compression to 5.3 GPa. A phase transition at ∼4 GPa is observed. No phase transitions occur on cooling. Anisotropy of lattice strain and changes in intermolecular interactions are compared.
Crystal structure and cryomagnetic study of a mononuclear erbium(III) oxamate inclusion complex
Authors: Araujo Junior Cleber R. , Oliveira Willian X. C. , Pinheiro Carlos B. , Pedroso Emerson F. , Nunes Wallace C. , Almeida Adriele A. de , Knobel Marcelo , Julve Miguel , Pereira Cynthia L. M.
Published: July 2024

The synthesis, crystal structure and magnetic properties of an oxamate-containing erbium(III) complex, namely, tetrabutylammonium aqua[N-(2,4,6-trimethylphenyl)oxamato]erbium(III)–dimethyl sulfoxide–water (1/3/1.5), (C16H36N)[Er(C11H12NO3)4(H2O)]·3C2H6OS·1.5H2O or n-Bu4N[Er(Htmpa)4(H2O)]·3DMSO·1.5H2O (1), are reported. The crystal structure of 1 reveals the occurrence of an erbium(III) ion, which is surrounded by four N-phenyl-substituted oxamate ligands and one water molecule in a nine-coordinated environment, together with one tetrabutylammonium cation acting as a counter-ion, and one water and three dimethyl sulfoxide (DMSO) molecules of crystallization. Variable-temperature static (dc) and dynamic (ac) magnetic measurements were carried out for this mononuclear complex, revealing that it behaves as a field-induced single-ion magnet (SIM) below 5.0 K.
Na[GeF5]·2HF: the first quarternary phase in the H–Na–Ge–F system
Authors: Bockmair Valentin , Hoch Constantin , Schusterbauer Irina , Kornath Andreas J.
Published: July 2024

The structure of cis- or trans-bridged [GeF5]− anionic chains have been investigated [Mallouk et al. (1984). Inorg. Chem.
23, 3160–3166] showing the first crystal structures of μ-F-bridged pentafluorogermanates. Herein, we report the second crystal structure of trans-pentafluorogermanate anions present in the crystal structure of sodium trans-pentafluorogermanate(IV) bis(hydrogen fluoride), Na[GeF5]·2HF. The crystal structure [orthorhombic Pca21, a = 12.3786 (3), b = 7.2189 (2), c = 11.4969 (3) Å and Z = 8] is built up from infinite chains of trans-linked [GeF6]2− octahedra, extending along the b axis and spanning a network of pentagonal bipyramidal distorted Na-centred polyhedra. These [NaF7] polyhedra are linked in a trans-edge fashion via hydrogen fluoride molecules, in analogy to already known sodium hydrogen fluorides and potassium hydrogen fluorides.
A novel one-dimensional thiocyanate-bridged cobalt(III) complex: synthesis, crystal structure characterization and Hirshfeld surface analysis
Authors: Mandal Uttam , Rizzoli Corrado , Chakraborty Bikash , Bandyopadhyay Debasis , Mandal Santanu
Published: July 2024

A new one-dimensional thiocyanate-bridged cobalt(III) Schiff base complex, namely, catena-poly[[[4-bromo-2-((Z)-{[2-(thiophen-2-yl)ethyl]imino}methyl)phenolato-κ2
N,O]cobalt(III)]-μ-thiocyanato-κ2
N:S], [Co(SCN)(C13H11BrNOS)2]
n
or [Co(μ1,3-SCN)L
2]
n
(1), where HL is 4-bromo-2-((Z)-{[2-(thiophene-2-yl)ethyl]imino}methyl)phenol, a bidentate Schiff base prepared from the condensation reaction of 5-bromosalicylaldehyde and 2-(thiophen-2-yl)ethylamine, has been synthesized by stirring Co(ClO4)2·6H2O, the Schiff base HL and ammonium thiocyanate (in a 1:2:1 molar ratio) in ethanol medium. The complex was characterized by FT–IR, electronic spectra and single-crystal X-ray diffraction (SC-XRD) studies. The SC-XRD data suggest that the compound crystallizes in the orthorhombic space group Pca21. The CoIII ion in 1 adopts a distorted octahedral geometry, the metal sites being six-coordinated by one thiocyanate N atom and one thiocyanate S atom in apical positions, and by two imine N atoms and two phenolate O atoms from two anionic L
− ligands which form the basal plane. The thiocyanate ligand acts as a μ-1,3 bridge, joining neighbouring CoIII atoms and forming a uniform zigzag one-dimensional polymeric chain. The crystallographic data were also used in the Hirshfeld surface (HS) analysis, which aimed to investigate the nature and quantitative significance of any noncovalent intermolecular interactions inside the crystal lattice. The crystal void parameters have also been computed and show the molecules to be tightly packed.
Managing macromolecular crystallographic data with a laboratory information management system
Authors: Daniel Edward , Wierenga Rik K. , Lehtiö Lari
Published: July 2024

Protein crystallography is an established method to study the atomic structures of macromolecules and their complexes. A prerequisite for successful structure determination is diffraction-quality crystals, which may require extensive optimization of both the protein and the conditions, and hence projects can stretch over an extended period, with multiple users being involved. The workflow from crystallization and crystal treatment to deposition and publication is well defined, and therefore an electronic laboratory information management system (LIMS) is well suited to management of the data. Completion of the project requires key information on all the steps being available and this information should also be made available according to the FAIR principles. As crystallized samples are typically shipped between facilities, a key feature to be captured in the LIMS is the exchange of metadata between the crystallization facility of the home laboratory and, for example, synchrotron facilities. On completion, structures are deposited in the Protein Data Bank (PDB) and the LIMS can include the PDB code in its database, completing the chain of custody from crystallization to structure deposition and publication. A LIMS designed for macromolecular crystallography, IceBear, is available as a standalone installation and as a hosted service, and the implementation of key features for the capture of metadata in IceBear is discussed as an example.
The crystal structure of Shethna protein II (FeSII) from Azotobacter vinelandii suggests a domain swap
Authors: Kabasakal Burak V. , McFarlane Ciaran R. , Cotton Charles A. R. , Schmidt Anna , Kung Andrea , Lieber Lucas , Murray James W.
Published: July 2024

The Azotobacter vinelandii FeSII protein forms an oxygen-resistant complex with the nitrogenase MoFe and Fe proteins. FeSII is an adrenodoxin-type ferredoxin that forms a dimer in solution. Previously, the crystal structure was solved [Schlesier et al. (2016), J. Am. Chem. Soc.
138, 239–247] with five copies in the asymmetric unit. One copy is a normal adrenodoxin domain that forms a dimer with its crystallographic symmetry mate. The other four copies are in an `open' conformation with a loop flipped out exposing the 2Fe–2S cluster. The open and closed conformations were interpreted as oxidized and reduced, respectively, and the large conformational change in the open configuration allowed binding to nitrogenase. Here, the structure of FeSII was independently solved in the same crystal form. The positioning of the atoms in the unit cell is similar to the earlier report. However, the interpretation of the structure is different. The `open' conformation is interpreted as the product of a crystallization-induced domain swap. The 2Fe–2S cluster is not exposed to solvent, but in the crystal its interacting helix is replaced by the same helix residues from a crystal symmetry mate. The domain swap is complicated, as it is unusual in being in the middle of the protein rather than at a terminus, and it creates arrangements of molecules that can be interpreted in multiple ways. It is also cautioned that crystal structures should be interpreted in terms of the contents of the entire crystal rather than of one asymmetric unit.