bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-Term Outcomes of the Treatment for Gastric Tube Cancer After Esophagectomy for Esophageal Cancer
Authors: Kitadani Junya , Hayata Keiji , Goda Taro , Takeuchi Akihiro , Tominaga Shinta , Fukuda Naoki , Nakai Tomoki , Nagano Shotaro , Ojima Toshiyasu , Kawai Manabu
Published: July 2024

Background:

The long-term outcomes of gastric tube cancer (GTC) are unclear. This study therefore aimed to clarify clinicopathologic features and the long-term outcomes of patients with GTC.

Methods:

The 25 patients who were diagnosed with GTC between April 2003 and December 2022 at our hospital were eligible for inclusion in this retrospective study, and this included 27 lesions. We retrospectively evaluated clinicopathologic factors based on hospital records.

Results:

In our cohort, 88% of incidences of GTC were located in the middle or lower gastric tube. As the treatment of GTC, we used endoscopic submucosal dissection, gastrectomy, chemoradiotherapy, chemotherapy, and best supportive care for 16 (59%), 6 (22%), 1 (4%), 1 (4%), and 3 (11%) lesions, respectively. Perforation after endoscopic submucosal dissection was observed in 6 of the 16 lesions. Partial gastric tube resection was performed for 3 patients and total gastric tube resection was performed for 3 patients. One patient who underwent total gastric tube resection died due to acute respiratory distress syndrome. In survival analysis, the 3-year overall survival rate was 52% and the 3-year disease-specific survival rate was 74%. Five patients (20%) died of aspiration pneumonia, 2 patients (8%) of another disease, and 1 patient (4%) of another type of cancer. According to multivariate analysis, independent prognostic factors for overall survival were cN status (HR, 18.021; P=0.004) and complication of aspiration pneumonia (HR, 8.373; P=0.004).

Conclusions:

The occurrence of aspiration pneumonia and cN status were prognostic factors after the treatment for GTC. Assessment of dysphagia and surveillance after treatment for GTC are important to improve the prognosis.
Successful Synergistic Use of Gabapentin With Other Antiepileptic Drugs in the Management of Lance-Adams Syndrome Complicated by Alcohol Withdrawal Seizures: A Case Report
Authors: Chowdhury Danial , McCarthy Caitlin
Published: July 2024

Objective

Lance-Adams syndrome is a rare and debilitating disorder characterized by successful cardiopulmonary resuscitation resulting in myoclonus activity. Alcohol withdrawal seizures from alcohol use disorder may further exacerbate Lance-Adams syndrome. We aim to present a case of Lance-Adams syndrome complicated by alcohol withdrawal seizures and successfully treated with a combination of valproate, clonazepam, and gabapentin.

Materials and Methods

The patient's electronic medical record, direct patient care experiences, and a comprehensive literature search were used for this case report. We report a 41-year-old male patient with Lance-Adams syndrome with concurrent alcohol use disorder. Treatment was improved when adding gabapentin for alcohol use disorder treatment, alongside combination antiepileptic therapy. A PubMed search was conducted to examine Lance-Adams syndrome case reports of successful combination antiepileptic therapy, with a secondary evaluation of patients with concurrent alcohol use disorder.

Results

The literature search yielded 18 articles, which resulted in 21 individual cases in which combination antiepileptic drug therapy was successful in treating myoclonus secondary to Lance-Adams syndrome; however, none of the case reports utilized gabapentin synergistically. One case described Lance-Adams syndrome complicated by alcohol consumption and similar to our patient, the patient used alcohol to abolish myoclonic activity.

Conclusions

To the best of our knowledge, this is the first case report documenting a patient with Lance-Adams syndrome and concurrent alcohol use disorder, with a positive effect of gabapentin use. Gabapentin, when used for alcohol use disorder treatment, may be an appropriate adjunct agent in the management of patients receiving combination antiepileptic therapy for the treatment of Lance-Adams syndrome.
Acupuncture modulation of the ACE/Ang II/AT1R and ACE2/Ang(1-7)/MasR pathways in the rostral ventrolateral medulla reduces sympathetic output and prevents cardiac injury caused by SHR hypertension
Authors: Wu Xiao-li , Zhang Lin , Zhang Jing , Sun Jiao , Li Yin-yin , Yang Ke-zhen , Liu Yu , Gao Xin-yu , Liu Qing-guo
Published: July 2024

Acupuncture can reduce blood pressure, heart rate (HR), and ameliorate cardiac damage by modulating the excitability of the sympathetic nervous system, but the exact mechanism of this effect remains unclear. This study investigated the potential mechanisms of acupuncture in the treatment of cardiac damage in hypertension. Spontaneously hypertensive rats (SHR) were used as the hypertension model with Wistar–Kyoto rats as the control. Manual acupuncture, electroacupuncture, and metoprolol were used as interventions. Systolic and diastolic blood pressure (SBP, DBP) plus HR were monitored with cardiac structure determined using Masson staining. Angiotensin II (Ang II) and norepinephrine in myocardium were detected with ELISA as was Ang(1-7) and gamma aminobutyric acid (GABA) in the rostral ventrolateral medulla (RVLM). Expression of mRNA for collagen type I (Col-I), Col-III, actin α1 (ACTA1), and thrombospondin 4 (THBS4) in myocardium was detected using real-time PCR. Expression of angiotensin converting enzyme (ACE), Ang II, angiotensin II type 1 receptor (AT1R), ACE2, and Mas receptor (MasR) proteins in RVLM was monitored using western blot. After manual acupuncture and electroacupuncture treatment, SHRs showed decreased SBP, DBP and HR, reduced myocardial damage. There was decreased expression of the ACE/Ang II/AT1R axis, and increased expression of the ACE2/Ang(1-7)/MasR axis within the RVLM. GABA levels were increased within the RVLM and norepinephrine levels were decreased in myocardial tissue. Metoprolol was more effective than either manual acupuncture or electroacupuncture. Acupuncture directed against hypertensive cardiac damage may be associated with regulation of ACE/Ang II/AT1R and the ACE2/Ang(1-7)/MasR pathway within the RLVM to reduce cardiac sympathetic excitability.
Identification of anaerobic and aerobic bacteria that can be associated with DFI and their therapeutic in Elnaw teaching hospital
Authors: Ahmed Fathi Sharief , Ibrahim Hiba Siddig , Saeed Mohammed Ibrahim
Published: July 2024

Diabetic foot infection (DFI) is one of the public health concerns especially in the developing countries and it was considered as diabetic foot complications. Adults with diabetes mellitus represent 463 million in 2019 according to the International Diabetes Federation.
The main aim of this study was to identify the anaerobic and aerobic bacteria that related to DFI and their therapeutic regimen for it among diabetic patients in Elnaw teaching hospital - Khartoum state.
This study presented that there wasn’t any an anaerobic organism were isolated while the most often isolated organisms were  gram negative rods (70%)  which represents (65%) in case of diabetic patients.
For all isolated organism S.aureus represents (30%) followed by E.coli (25%) in control group (non-diabetic), while Klebsiella.spp and S.aureus represents (20%) for each; in the clinic room isolates.
Early diagnosis, optimal management and effective antibiotic therapy are necessary to prevent DFI and amputation.
Bioinformatics analysis of the antigenic epitopes of L7/L12 protein in the B- and T-Cells active against  Brucella melitensis

Authors: Zhang Jingjie , Baigued Huricha , Chen Shana , Borigen Haiyan , Tana Tana , Quan Fu , Yang Dezhi
Published: July 2024

Objective: To analyze the physicochemical properties, spatial structure, and protein–protein interactions (PPIs) of L7/L12 protein using bioinformatics methods and predict their B- and T-cell epitopes to lay a theoretical foundation for developing a novel multiepitope vaccine. Methods: The NCBI database was searched for the amino acid sequences of L7/L12 from Brucella melitensis. In addition, the online softwares, ProtParam and ProtScale, were used to predict the physicochemical properties; NetPhos3.1 and CD-search to predict the phosphorylation sites and conserved domains; SOMPA and SWISS-MODEL to predict the secondary and tertiary structures; the STRING database to analyze the PPIs; and the IEDB, ABCpred, SVMTrip, and SYFPEITHI databases to predict the B- and T-cell epitopes. L7/L12 were docked to TLR4, BCR, MHC Ⅰ-TCR and MHC Ⅱ-TCR complexes, respectively, and the binding ability of L7/L12 to the targeted receptors was tested. Results: L7/L12, consisting of 124 amino acids, was determined to be a stable, intracellular, hydrophilic protein containing 11 phosphorylation sites and ribosomal protein-related conserved domains. α-helices accounted for 70.16%, β-turns for 2.42%, extended strands for 8.87%, and irregular coils for 18.55% of the secondary structure. The PPIs indicated that L7/L12 was involved in the constitution of ribosomes and regulating the accuracy of the translation process. Three B-cell, two CTL and three HTL epitopes were finally screened by comparing multiple databases. L7/L12 binds to TLR4, BCR, MHC Ⅰ-TCR and MHC Ⅱ-TCR complexes and forms stable hydrogen bonds, respectively. Conclusions: L7/L12, which governs the ac translation curate of proteins, possesses several potentially advantageous epitopes, laying a theoretical foundation for designing multiepitope vaccines.
Apramycin has high in vitro activity against Mycobacterium tuberculosis
Authors: Sun Qing , Yan Jun , Long Sibo , Shi Yiheng , Jiang Guanglu , Li Hao , Huang Hairong , Wang Guirong
Published: July 2024

Introduction. Aminoglycoside antibiotics such as amikacin and kanamycin are important components in the treatment of Mycobacterium tuberculosis (Mtb) infection. However, more and more clinical strains are found to be aminoglycoside antibiotic-resistant. Apramycin is another kind of aminoglycoside antibiotic that is commonly used to treat infections in animals.

Hypothesis. Apramycin may have in vitro activity against Mtb.

Aim. This study aims to evaluate the efficacy of apramycin against Mtb in vitro and determine its epidemiological cut-off (ECOFF) value.

Methodology. One hundred Mtb isolates, including 17 pansusceptible and 83 drug-resistant tuberculosis (DR-TB) strains, were analysed for apramycin resistance using the MIC assay.

Results. Apramycin exhibited significant inhibitory activity against Mtb clinical isolates, with an MIC50 of 0.5 μg ml−1 and an MIC90 of 1 μg ml−1. We determined the tentative ECOFF value as 1 µg ml−1 for apramycin. The resistant rates of multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant (pre-XDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains were 12.12 % (4/33), 20.69 % (6/29) and 66.67 % (14/21), respectively. The rrs gene A1401G is associated with apramycin resistance, as well as the cross-resistance between apramycin and other aminoglycosides.

Conclusion. Apramycin shows high in vitro activity against the Mtb clinical isolates, especially the MDR-TB clinical isolates. This encouraging discovery calls for more research on the functions of apramycin in vivo and as a possible antibiotic for the treatment of drug-resistant TB.
SPArrOW: a flexible, interactive and scalable pipeline for spatial transcriptomics analysis
Authors: Pollaris Lotte , Vanneste Bavo , Rombaut Benjamin , Defauw Arne , Vernaillen Frank , Mortier Julien , Vanhenden Wout , Martens Liesbet , Thoné Tinne , Hastir Jean-Francois , Bujko Anna , Saelens Wouter , Marine Jean-Christophe , Nelissen Hilde , Van Hamme Evelien , Seurinck Ruth , Scott Charlotte L. , Guilliams Martin , Saeys Yvan
Published: July 2024

Current spatial transcriptomics technologies are increasingly able to measure large gene panels at subcellular resolution, but a major bottleneck in this rapidly advancing field is the computational analysis and interpretation of the data. To bridge this gap, here we present SPArrOW, a flexible, modular and scalable pipeline for processing spatial transcriptomics data. SPArrOW improves cell segmentation and leads to better overall data quality, resulting in more accurate cell annotations at the single-cell level. Furthermore, it provides the users with numerous visual quality checks that are crucial for the correct interpretation of the data, offering users more control in processing their data. Our workflow is designed to accommodate the various available spatial transcriptomics platforms. Finally, SPArrOW offers interactive visualization and data exploration, enabling sample-specific pipeline optimization by various tuneable parameters and an efficient comparison of different staining and gene allocation strategies.
A probabilistic view of forbidden links: their prevalence and their consequences for the robustness of plant-hummingbird communities
Authors: Duchenne François , Barreto Elisa , Guevara Esteban A. , Beck Holger , Bello Carolina , Bobato Rafaela , Bôlla Daniela , Brenes Emanuel , Büttner Nicole , Caron Ana P. , Chaves-Elizondo Nelson , Gavilanes María J. , Restrepo-González Alejandro , Castro Jose Alejandro , Kaehler Miriam , Machado-de-Souza Tiago , Machnicki-Reis Miguel , Marcayata Andrés Sebastián F. , de Menezes Cauã G. , Nieto Andrea , de Oliveira Rafael , de Oliveira Ricardo A. C. , Richter Friederike , Rojas Bryan G. , Romanowski Luciele L. , L.de Souza Wellinton , Veluza Danila S. , Weinstein Ben , Wüest Rafael , Zanata Thais B. , Zuniga Krystal , Maglianesi María A. , Santander Tatiana , Varassin Isabella G. , Graham Catherine H.
Published: July 2024

The presence in ecological communities of unfeasible species interactions, termed forbidden links, due to physiological or morphological exploitation barriers has been long debated, but little direct evidence has been found. Forbidden links are likely to make ecological communities less robust to species extinctions, stressing the need to assess their prevalence. Here, we used a dataset of plant-hummingbird interactions, coupled with a Bayesian hierarchical model, to assess the importance of exploitation barriers in determining species interactions. We found evidence for exploitation barriers between flowers and hummingbirds across the 32 studied communities, however, the proportion of forbidden links changed drastically among communities, because of changes in trait distributions. The higher the proportion of forbidden links, the more they decreased network robustness, because of constraints on interaction rewiring. Our results suggest that exploitation barriers are not rare in plant-hummingbird communities and have the potential to limit the rescue of species experiencing partner extinction.
TRPML1 gating modulation by allosteric mutations and lipids
Authors: Gan Ninghai , Han Yan , Zeng Weizhong , Jiang Youxing
Published: July 2024

Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible to agonist or antagonist modulation, making them better targets for screening potent TRPML1 activators and inhibitors. We also determined the high-resolution structure of TRPML1 in complex with the PI(4,5)P2inhibitor, revealing the structural basis underlying this lipid inhibition. In addition, an endogenous phospholipid likely from sphingomyelin is identified in the PI(4,5)P2-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation.
Understanding Cu+2binding with DNA: A molecular dynamics study comparing Cu2+and Mg2+binding to the Dickerson DNA
Authors: Sharma Angad , Yadav Hari O. S. , Bandyopadhyay Pradipta
Published: July 2024

Cu2+ions led DNA damage by reactive oxygen species (ROS) is widely known biological phenomena. The ionic radii of Cu2+and Mg2+being similar, the binding of Cu2+ions to DNA is expected to be similar to that of the Mg2+ions. However, little is known how Cu2+ions bind in different parts (phosphate, major and minor grooves) of a double-strand (ds) DNA, especially at atomic level. In the present study, we employ molecular dynamic (MD) simulations to investigate the binding of Cu2+ions with the Dickerson DNA, a B-type dodecamer double stranded (ds) DNA. The binding characteristics of Cu2+and Mg2+ions with this dsDNA are compared to get an insight into the differences and similarities in binding behavior of both ions. Unlike Mg2+ions, the first hydration shell of Cu2+is found to be labile, thus it shows both direct and indirect binding with the dsDNA, i.e., binding through displacement of water from the hydration shell or through the hydration shell. Though the binding propensity of Cu2+ions with dsDNA is observed relatively stronger, the binding order to phosphates, major groove, and minor groove is found qualitatively similar (phosphates > major groove > minor groove) for both ions. The study gives a deep understanding of Cu2+binding to DNA, which could be helpful in rationalizing the Cu2+led ROS-mediated DNA damage.
Glioma-associated tertiary lymphoid structures are sites of lymphocyte clonal expansion and plasma cell formation
Authors: Cakmak Pinar , Lun Jennifer H. , Singh Aakanksha , Macas Jadranka , Schupp Jonathan , Köhler Miriam , Starzetz Tatjana , Burger Michael C. , Steidl Eike , Hasse Lucie Marie , Hattingen Elke , Plate Karl H. , Reiss Yvonne , Imkeller Katharina
Published: July 2024

Adult-type diffuse gliomas, the most common primary brain tumors, pose significant clinical challenges due to limited treatment options, restricted anti-tumor immune response and dismal patient prognosis. In this study, we elucidate the immunological function and clinical relevance of intra-tumoral tertiary lymphoid structures (TLS) in adaptive anti-glioma immunity. We conducted a comprehensive, unbiased analysis of lymphoid aggregation in 642 gliomas using a multi-modal approach that combines RNA sequencing with spatial transcriptome and proteome profiling. Our findings reveal that TLS are present in 15% of tumors and correlate with improved overall survival. Gliomas with TLS exhibit a remodeled perivascular space, marked by transcriptional upregulation and spatial redistribution of collagens associated with barrier functions. Furthermore, we demonstrate that TLS maturation into sites of dynamic adaptive immune responses, characterized by clonal T and B cell expansion and IgA+ and IgG+ plasma-cell formation, is driven by efficient early T cell recruitment to the perivascular space.
Physical constraints on the positions and dimensions of the zebrafish swim bladder by surrounding bones
Authors: Satoh Koumi , Maeno Akiteru , Adachi Urara , Ishizaka Mizuki , Yamada Kazuya , Koita Rina , Nakazawa Hidemichi , Oikawa Sae , Fujii Renka , Furudate Hiroyuki , Kawamura Akinori
Published: July 2024

Precise regulation of organ size and position is crucial for optimal organ function. Since the swim bladder is primarily responsible for buoyancy in teleosts, early development and subsequent inflation of the swim bladder should be appropriately controlled with the body growth. However, the underlying mechanism remains unclear. In this study, we show that the size and position of the swim bladder are physically constrained by the surrounding bones in zebrafish. Non-invasive micro-CT scanning revealed that the anterior edge of the swim bladder is largely attached to the os suspensorium, which is an ossicle extending medioventrally from the 4th vertebra. Additionally, we observed thathoxc6amutants, which lack the os suspensorium, exhibited an anterior projection of the swim bladder beyond the 4th vertebra. During the swim bladder development, we found that the counterclockwise rotation of the os suspensorium correlates with posterior regression of the swim bladder, suggesting that the os suspensorium pushes the swim bladder posteriorly into its proper position. Furthermore, our results revealed a close association between the posterior region of the swim bladder and the pleural ribs. Inhoxaacluster mutants with additional ribs, the swim bladder expanded posteriorly, accompanied by an enlarged body cavity. Taken together, our results demonstrate the importance of the surrounding bones in the robust regulation of swim bladder size and position in zebrafish.
Methamphetamine-induced adaptation of learning rate dynamics depend on baseline performance
Authors: Kirschner Hans , Molla Hanna M. , Nassar Matthew R. , de Wit Harriet , Ullsperger Markus
Published: July 2024

The ability to calibrate learning according to new information is a fundamental component of an organism’s ability to adapt to changing conditions. Yet, the exact neural mechanisms guiding dynamic learning rate adjustments remain unclear. Catecholamines appear to play a critical role in adjusting the degree to which we use new information over time, but individuals vary widely in the manner in which they adjust to changes. Here, we studied the effects of a low dose of methamphetamine (MA), and individual differences in these effects, on probabilistic reversal learning dynamics in a within-subject, double-blind, randomized design. Participants first completed a reversal learning task during a drug-free baseline session to provide a measure of baseline performance. Then they completed the task during two sessions, one with MA (20 mg oral) and one with placebo (PL). First, we showed that, relative to PL, MA modulates the ability to dynamically adjust learning from prediction errors. Second, this effect was more pronounced in participants who performed poorly at baseline. These results present novel evidence for the involvement of catecholaminergic transmission on learning flexibility and highlights that baseline performance modulates the effect of the drug.
Implementing a Behaviour Change Communication interaction for enhancing male involvement in maternity care among the Saharia Tribes in Gwalior District, Madhya Pradesh: a feasibility study
Authors: Adhikari Tulsi , Nair Saritha , Grover Ashpinder kaur
Published: July 2024

Background

The Indian tribal population is diverse, with a wide range of customs, ways of life, and cultural practices. However, there is one thing that all Indian tribal communities have in common: they have worse health indicators, a higher rate of illness and mortality, and very restricted access to medical care. Their health issues require extra consideration in the right setting.[1] Growth in the utilization of reproductive and maternal health services will not only curtail down the reproductive morbidities, but it will also reduce the child mortality.[2] Men’s participation in prenatal care, delivery and postpartum period is rarely found, especially among tribal communities, due to their economic instabilities and priorities. Also our health system does not promote the involvement of men in the maternal and child health care. Hence, there was a need felt for development of gender and community sensitive interventions package that could address the individual and the community health care facility level barriers of male involvement in utilisation of the maternal care services. Our study was an endeavour to determine the feasibility of implementing a behaviour Change Communication Interaction developed for improvement in utilisation of maternity care services through male participation among the Saharia Tribes in Gwalior District, Madhya Pradesh.

Methods

The Study utilised a qualitative approach. Various activities were organised as a part of BCC, viz, Community mobilization, Campaign/Rallies, Interpersonal Communication-Drama & Mock Sessions, Face to Face counselling and Quiz etc. Action technique called Transect was used in order to know more about the environment and living of the people of Saharia Tribes in Gwalior District, Madhya Pradesh. Feasibility of the model was assessed by focusing on three main principles i.e., acceptability, integration and limited-efficacy testing.

Result

Acceptability testing study reveal that BCC intervention was successfully accepted by intended individual-both targeted individuals and those involved in implementing programs. Integration approach reveal that no major change in infrastructure of Govt. Programmes and facilities is required; only the participation of key people in society and workers local health services is required. Limited-efficacy testing reveals that there is a behavioural change in men’s perception of accompanying their spouse to the health centre; same was observed on the vaccination day in the village.

Conclusions

The BCC intervention proved to be feasible to implement. The Proposed BCC interaction is feasible and accepted by both Programme stake holders and beneficiaries.
MIST: an interpretable and flexible deep learning framework for single-T cell transcriptome and receptor analysis
Authors: Lai Wenpu , Li Yangqiu , Luo Oscar Junhong
Published: July 2024

Joint analysis of transcriptomic and T cell receptor (TCR) features at single-cell resolution provides a powerful approach for in-depth T cell immune function research. Here, we introduce a deep learning framework for single-T cell transcriptome and receptor analysis, MIST (Multi-Insight for T cell). MIST features three latent spaces: gene expression, TCR, and a joint latent space. Through analyses of antigen- specific T cells and T cells related to lung cancer immunotherapy, we demonstrate MIST’s interpretability and flexibility. MIST easily and accurately resolves cell function and antigen-specificity by vectorizing and integrating transcriptome and TCR data of T cells. In addition, using MIST, we identified the heterogeneity of CXCL13+subsets in lung cancer infiltrating CD8+T cells and their association with immunotherapy, providing additional insights into the functional transition of CXCL13+T cells related to anti-PD-1 therapy that were not reported in the original study. MIST is available athttps://github.com/aapupu/MIST.
Cell sorting based on single nucleotide variation enables characterization of mutation-dependent transcriptome and chromatin states
Authors: Salatino Roberto , Franco Marianna , Romero-Toledo Arantxa , Wang Yi , Tsuda Shanel , Szentirmai Oszkar , Janiszewska Michalina
Published: July 2024

Single nucleotide variants (SNVs) contribute to cancer by altering the coding and the non-coding regions of the genome. Connecting SNVs to transcriptomic and epigenetic changes at the single-cell level remains challenging. To enable studies of rare cell populations harboring specific point mutations, we developed STAR-FACS, Specific-To-Allele PCR-FACS, to sort cells based on genomic allele alterations. We show that STAR-FACS can separate cells based on TERT promoter mutation status and is compatible with bulk and single-cell transcriptomic and epigenetic profiling. We demonstrate that glioblastoma cell lines derived from the same tumor but harboring distinct TERT promoter SNVs have different transcriptional programs.
Insights into non-crossover recombination from long-read sperm sequencing
Authors: Schweiger Regev , Lee Sangjin , Zhou Chenxi , Yang Tsun-Po , Smith Katie , Li Stacy , Sanghvi Rashesh , Neville Matthew , Mitchell Emily , Nessa Ayrun , Wadge Sam , Small Kerrin S , Campbell Peter J , Sudmant Peter H , Rahbari Raheleh , Durbin Richard
Published: July 2024

Meiotic recombination is a fundamental process that generates genetic diversity by creating new combinations of existing alleles. Although human crossovers have been studied at the pedigree, population and single-cell level, the more frequent non-crossover events that lead to gene conversion are harder to study, particularly at the individual level. Here we show that single high-fidelity long sequencing reads from sperm can capture both crossovers and non-crossovers, allowing effectively arbitrary sample sizes for analysis from one male. Using fifteen sperm samples from thirteen donors we demonstrate variation between and within donors for the rates of different types of recombination. Intriguingly, we observe a tendency for non-crossover gene conversions to occur upstream of nearby PRDM9 binding sites, whereas crossover locations have a slight downstream bias. We further provide evidence for two distinct non-crossover processes. One gives rise to the vast majority of non-crossovers with mean conversion tract length under 50bp, which we suggest is an outcome of standard PRDM9-induced meiotic recombination. In contrast ~2% of non-crossovers have much longer mean tract length, and potentially originate from the same process as complex events with more than two haplotype switches, which is not associated with PRDM9 binding sites and is also seen in somatic cells.
Development and Characterization of 50 nanometer diameter Genetically Encoded Multimeric Nanoparticles
Authors: Hernandez Cindy M. , Duran-Chaparro David C. , van Eeuwen Trevor , Rout Michael P. , Holt Liam J.
Published: July 2024

The mechanisms that regulate the physical properties of the cell interior remain poorly understood, especially at the mesoscale (10nm-100nm). Changes in these properties have been suggested to be crucial for both normal physiology and disease. Many crucial macromolecules and molecular assemblies such as ribosomes, RNA polymerase, and biomolecular condensates span the mesoscale size range. Therefore, we need better tools to study the cellular environment at this scale. A recent approach has been to use genetically encoded multimeric nanoparticles (GEMs), which consist of self-assembling scaffold proteins fused to fluorescent tags. After translation of the fusion protein, the monomers self-assemble into bright and stable nanoparticles of defined geometry that can be visualized by fluorescence microscopy. Physical properties of the cell can then be inferred through analysis of the motion of these particles, an approach called nanorheology. Previously, 40nm-GEMs elucidated TORC1 kinase as a regulator of cytoplasmic crowding. However, extremely sensitive microscopes were required. Here, we describe the development and characterization of a 50 nm diameter GEM that is brighter and probes a larger length scale. 50nm-GEMs will make high-throughput nanorheology accessible to a broader range of researchers and reveal new insights into the biophysical properties of cells.
Shikimate pathway-Dependent Catabolism: enabling near-to-maximum production yield of aromatics
Authors: Bruinsma Lyon , Batianis Christos , Moreno Paz Sara , Kurnia Kesi , Dirkmaat Job. J , Müller Alexandra , Juncosa Nunez Jose , Weusthuis Ruud A. , Martins dos Santos Vitor A. P.
Published: July 2024

Catabolism is a complex network of tightly regulated metabolic reactions that provides energy and carbon to fuel anabolism in all living organisms. Rewiring catabolism is essential for harnessing industrial biotechnology but remains a substantial metabolic engineering challenge due to its high genetic stability and tight regulation acquired through evolution. In this study, by combining metabolic modeling, rational engineering, and adaptive laboratory evolution, we fundamentally redesigned bacterial catabolism. We created a new-to-nature shikimate pathway-dependent catabolism (SDC) inPseudomonas putidaby reprogramming the shikimate pathway as the primary catabolic route. SDC supports growth by supplying the glycerol catabolic end-product pyruvate, enabling superior production of shikimate pathway-derived molecules. Through SDC, aromatics production reached over 89% of the pathway’s maximum theoretical yield, setting a new benchmark for their microbial synthesis. Our study successfully repurposed an anabolic pathway for catabolism, exemplifying the high metabolic plasticity of microbes and providing a bacterial chassis for the efficient production of high-added value compounds.
Integrative genomic reconstruction of carbohydrate utilization networks in bifidobacteria: global trends, local variability, and dietary adaptation
Authors: Arzamasov Aleksandr A. , Rodionov Dmitry A. , Hibberd Matthew Charles , Guruge Janaki L. , Kazanov Marat D. , Leyn Semen A. , Kent James Edward D , Sejane Kristija , Bode Lars , Barratt Michael J. , Gordon Jeffrey , Osterman Andrei
Published: July 2024

Bifidobacteria are among the earliest colonizers of the human gut, conferring numerous health benefits. While multiple Bifidobacterium strains are used as probiotics, accumulating evidence suggests that the individual responses to probiotic supplementation may vary, likely due to a variety of factors, including strain type(s), gut community composition, dietary habits of the consumer, and other health/lifestyle conditions. Given the saccharolytic nature of bifidobacteria, the carbohydrate composition of the diet is one of the primary factors dictating the colonization efficiency of Bifidobacterium strains. Therefore, a comprehensive understanding of bifidobacterial glycan metabolism at the strain level is necessary to rationally design probiotic or synbiotic formulations that combine bacterial strains with glycans that match their nutrient preferences. In this study, we systematically reconstructed 66 pathways involved in the utilization of mono-, di-, oligo-, and polysaccharides by analyzing the representation of 565 curated metabolic functional roles (catabolic enzymes, transporters, transcriptional regulators) in 2973 non-redundant cultured Bifidobacterium isolates and metagenome-assembled genomes (MAGs). Our analysis uncovered substantial heterogeneity in the predicted glycan utilization capabilities at the species and strain level and revealed the presence of a yet undescribed phenotypically distinct subspecies-level clade within the Bifidobacterium longum species. We also identified Bangladeshi isolates harboring unique gene clusters tentatively implicated in the breakdown of xyloglucan and human milk oligosaccharides. Predicted carbohydrate utilization phenotypes were experimentally characterized and validated. Our large-scale genomic analysis considerably expands the knowledge of carbohydrate metabolism in bifidobacteria and provides a foundation for rationally designing single- or multi-strain probiotic formulations of a given bifidobacterial species as well as synbiotic combinations of bifidobacterial strains matched with their preferred carbohydrate substrates.
Low coverage whole genome sequencing of low-grade dysplasia strongly predicts colorectal cancer risk in ulcerative colitis
Authors: Bakir Ibrahim Al , Curtius Kit , Cresswell George D , Grant Heather E , Nasreddin Nadia , Smith Kane , Nowinski Salpie , Guo Qingli , Belnoue-Davis Hayley L , Fisher Jennifer , Clarke Theo , Kimberley Christopher , Mossner Maximilian , Dunne Philip D , Loughrey Maurice B , Speight Ally , East James E , Wright Nicholas A , Rodriguez-Justo Manuel , Jansen Marnix , Moorghen Morgan , Baker Ann-Marie , Leedham Simon J , Hart Ailsa L , Graham Trevor A
Published: July 2024

Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC), and this risk increases dramatically in those who develop low-grade dysplasia (LGD). However, there is currently no accurate way to risk-stratify patients with LGD, leading to both over- and under-treatment of cancer risk. Here we show that the burden of somatic copy number alterations (CNAs) within resected LGD lesions strongly predicts future cancer development. We performed a retrospective multi-centre validated case-control study of n=122 patients (40 progressors, 82 non-progressors, 270 LGD regions). Low coverage whole genome sequencing revealed CNA burden was significantly higher in progressors than non-progressors (p=2x10-6in discovery cohort) and was a very significant predictor of CRC risk in univariate analysis (odds ratio = 36; p=9x10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. The measurement of CNAs in LGD lesions is a robust, low-cost and rapidly translatable predictor of CRC risk in IBD that can be used to direct management and so prevent CRC in high-risk individuals whilst sparing those at low-risk from unnecessary intervention.
Exposure to and engagement with digital psychoeducational content and community related to maternal mental health by perinatal persons and mothers: design of an online survey with optional follow-up and participant characteristics
Authors: Waring Molly E. , McManus-Shipp Katherine E. , Field Christiana M. , Bhusal Sandesh , Perez Asley , Shapiro Olivia , Gaspard Sophia A. , Dennis Cindy-Lee
Published: July 2024

Background

Leveraging digital platforms may be an effective strategy for connecting perinatal persons and mothers with evidence-based information and support related to maternal mental health and peers. Momwell is a mom-centered model of care that provides psychoeducational content through several digital platforms including social media, podcasts, and blog posts.

Objective

To describe the design of a study of perinatal persons and mothers who are exposed to or engage with psychoeducation content and community related to maternal mental health on social media or other digital platforms (Momwell), and to describe characteristics of the sample.

Methods

Adults who engaged with Momwell on any of their digital platforms were recruited to participate in an online survey study in summer/fall 2023. Participants completed either a longer or shorter survey. Two to 3 months after completing this survey, participants who provided permission to be re-contacted were invited to complete a second survey. The surveys included validated psychological measures, study-specific quantitative questions, and open-ended questions that assessed participant demographics, exposure to and engagement with Momwell psychoeducation content and community, maternal mental health, parenting relationships, parenting self-efficacy, and additional psychosocial and health measures.

Results

Participants (N=584; n=298 longer survey, n=286 shorter survey) were >99% mothers, 46% perinatal (10% pregnant, 36% post-partum), and on average 32.4 (SD: 3.9) years old. Fifty-nine percent were from the United States, 36% from Canada, and 5% from other countries. The vast majority (95%) followed Momwell on Instagram, 44% listened to the Momwell podcast and 41% received their newsletter. Most participants had been exposed to Momwell’s psychoeducation content for at least 6 months across the different platforms (range: 40% TikTok to 87% Instagram). Two to 3 months later, 246 participants completed a second survey (n=149 longer survey, n=97 shorter survey).

Conclusions

Data from this study will provide insights into how perinatal persons and mothers leverage digital psychoeducational content and peer communities to support their mental health across the perinatal period and into the early years of motherhood. Leveraging digital platforms to disseminate evidence-based digital psychoeducational content related to maternal mental health and connect peers has the potential to change how we care for perinatal persons and mothers.
The WAVE complex forms linear arrays at negative membrane curvature to instruct lamellipodia formation
Authors: Wu Muziyue , Marchando Paul , Meyer Kirstin , Tang Ziqi , Woolfson Derek N. , Weiner Orion D.
Published: July 2024

Cells generate a wide range of actin-based membrane protrusions for various cell behaviors. These protrusions are organized by different actin nucleation promoting factors. For example, N-WASP controls finger-like filopodia, whereas the WAVE complex controls sheet-like lamellipodia. These different membrane morphologies likely reflect different patterns of nucleator self-organization. N-WASP phase separation has been successfully studied through biochemical reconstitutions, but how the WAVE complex self-organizes to instruct lamellipodia is unknown. Because WAVE complex self-organization has proven refractory to cell-free studies, we leveragein vivobiochemical approaches to investigate WAVE complex organization within its native cellular context. With single molecule tracking and molecular counting, we show that the WAVE complex forms highly regular multi-layered linear arrays at the plasma membrane that are rem-iniscent of a microtubule-like organization. Similar to the organization of microtubule protofilaments in a curved array, membrane curvature is both necessary and sufficient for formation of these WAVE complex linear arrays, though actin polymerization is not. This dependency on negative membrane curvature could explain both the templating of lamellipodia and their emergent behaviors, including barrier avoidance. Our data uncover the key biophysical properties of mesoscale WAVE complex patterning and highlight an integral relationship between NPF self-organization and cell morphogenesis.
Enhanced MC1R-signalling and pH modulation facilitate melanogenesis within late endosomes of BLOC-1-deficient melanocytes
Authors: Goff Philip S. , Patel Shyamal , Carter Tom , Marks Michael S. , Sviderskaya Elena V.
Published: July 2024

Photoprotective melanins in the skin are synthesised by epidermal melanocytes within specialised lysosome-related organelles called melanosomes. Melanosomes coexist with lysosomes; thus, melanocytes employ specific trafficking machineries to ensure correct cargo delivery to either the endolysosomal system or maturing melanosomes. Mutations in some of the protein complexes required for melanogenic cargo delivery, such as biogenesis of lysosome-related organelles complex 1 (BLOC-1), result in hypopigmentation due to mistrafficking of cargo to endolysosomes. We show that hypopigmented BLOC-1-deficient melanocytes retain melanogenic capacity that can be enhanced by treatment with cAMP elevating agents despite the mislocalisation of melanogenic proteins. The melanin formed in BLOC-1-deficient melanocytes is not generated in melanosomes but rather within late endosomes/lysosomes to which some cargoes mislocalise. Although these organelles generally are acidic, a cohort of late endosomes/lysosomes have a sufficiently neutral pH to facilitate melanogenesis, perhaps due to mislocalised melanosomal transporters and melanogenic enzymes. Modulation of the pH of late endosomes/lysosomes by genetic manipulation or via treatment with lysosomotropic agents significantly enhances the melanin content of BLOC-1-deficient melanocytes. Our data suggest that upregulation of mistargeted cargoes can facilitate reprogramming of a subset of endolysosomes to generate some functions of lysosome-related organelles.
Block Lanczos method for excited states on a quantum computer
Authors: Baker Thomas E.
Published: July 2024

The method of quantum Lanczos recursion is extended to solve for multiple excitations on the quantum computer. While quantum Lanczos recursion is, in principle, capable of obtaining excitations, the extension to a block Lanczos routine can resolve degeneracies with better precision and only costs O(d2) for d excitations on top of the previously introduced quantum Lanczos recursion method. Extension to non-Hermitian operators is also discussed.

Published by the American Physical Society
2024
Shock-wave generation and propagation in dissipative and nonlocal nonlinear Rydberg media
Authors: Qin Lu , Hang Chao , Huang Guoxiang , Li Weibin
Published: July 2024

We investigate the generation of optical shock waves in strongly interacting Rydberg atomic gases with a spatially homogeneous dissipative potential. The Rydberg atom interaction induces an optical nonlocal nonlinearity. We focus on local nonlinear (Rb≪R0) and nonlocal nonlinear (Rb∼R0) regimes, where Rb and R0 are the characteristic length of the Rydberg nonlinearity and beam width, respectively. In the local regime, we show spatial width and contrast of the shock wave change monotonically when increasing strength of the dissipative potential and optical intensity. In the nonlocal regime, the characteristic quantity of the shock wave depends on Rb/R0 and dissipative potential nontrivially and on the intensity monotonically. We find that formation of shock waves dominantly takes place when Rb is smaller than R0, while the propagation dynamics is largely linear when Rb is comparable to or larger than R0. Our results reveal nontrivial roles played by dissipation and nonlocality in the generation of shock waves, and provide a route to manipulate their profiles and stability. Our study furthermore opens new avenues to explore non-Hermitian physics and nonlinear wave generation and propagation by controlling dissipation and nonlocality in the Rydberg media.

Published by the American Physical Society
2024
Bulk medium properties of heavy-ion collisions from the beam energy scan with a multistage hydrodynamic model
Authors: Du Lipei
Published: July 2024

I introduce a method to reconstruct full rapidity distributions of charged particle multiplicity and net proton yields, crucial for constraining the longitudinal dynamics of nuclear matter created in the beam energy scan program. Employing rapidity distributions within a multistage hydrodynamic model calibrated for Au+Au collisions at sNN=7.7–200GeV, I estimate the total energy and baryon number deposited into the collision fireball, offering insights into initial dynamics and the identification of nuclear remnants. I explore the potential of rapidity-dependent measurements in probing equations of state at finite chemical potentials. Furthermore, I compare the freeze-out parameters derived from both hydrodynamics and thermal models, highlighting that the parameters extracted via thermal models represent averaged properties across rapidities.

Published by the American Physical Society
2024
Amplitude analysis of
B0→KS0K+K−
decays in a quasi-two-body QCD factorization approach
Authors: Dedonder J.-P. , Kamiński R. , Leśniak L. , Loiseau B. , Żenczykowski P.
Published: July 2024

The B0→KS0K+K− decay amplitude is derived within a quasi-two-body QCD factorization framework in terms of kaon form factors and B0 to two-kaon-transition functions. The final state kaon-kaon interactions in the S, P, and D waves are taken into account. The unitarity constraints are satisfied for the two kaons in scalar states. It is shown that with few terms of the full decay amplitude one may reach a fair agreement with the total branching fraction and Dalitz-plot projections published in 2010 by the Belle Collaboration and in 2012 by the Collaboration. With 13 free parameters, our model fits the corresponding 422 data with a χ2 of 583.6 which leads to a χ2 per degree of freedom equal to 1.43. The dominant branching fraction arises from the

f

0

(

K

+

K

−

)

K

S

0

mode with 83.0% of the total branching. The next important mode is dominated by ϕKS0 plus small ωKS0 and ρ0KS0 modes with 18.3% of the total. Then follows the a0±K∓ mode with 6.2%. Adding the other smaller modes, the total percentage sum is 107.7% which indicates a small interference contribution. In most regions of the Dalitz plot, our model gives rather small CP asymmetry, but in some parts its values can be large and positive or negative. Its predicted total value is equal to −0.11%. The calculated time dependent CP-asymmetry parameters agree, within errors, with those obtained by the analysis. Our model amplitude can be the basis for a parametrization in experimental Dalitz plot analyses of LHCb and Belle II Collaborations.

Published by the American Physical Society
2024