bluuebunny/crossref_metadata_2025 huggingface dataset:
Corneal Transplantation for Infectious Keratitis: A Prospective Dutch Registry Study
Authors: Veugen Judith M. J. , Dunker Suryan L. , Wolffs Petra F. G. , Savelkoul Paul H. M. , Winkens Bjorn , van den Biggelaar Frank J. H. M. , Nuijts Rudy M. M. A. , Dickman Mor M. ,   on behalf of the Netherlands Cornea Transplant Network (NCTN)
Published: February 2023

Purpose:

The aim of this study was to analyze real-world practice patterns and graft survival after corneal transplantation for infectious keratitis in the Netherlands.

Methods:

All consecutive keratoplasties for infectious keratitis registered in the Netherlands Organ Transplant Registry were included. Graft survival was analyzed using Kaplan–Meier survival curves with Cox regression to compare the 3 most common pathogens with subgroup analysis for type and reason of transplantation, sex, and graft size. Multivariable analysis was performed using the same explanatory factors.

Results:

Between 2007 and 2017, 1111 keratoplasties for infectious keratitis were registered in the Netherlands Organ Transplant Registry. The most common pathogens were viruses (n = 437), bacteria (n = 271), and Acanthamoeba (n = 121). Human leukocyte antigen (HLA) matching did not provide a significant survival benefit, whereas emergency procedures showed worse graft survival [hazard ratio (HR) = 0.40, P = 0.120; HR = 2.73, P < 0.001, respectively]. Graft size >8.5 mm was significantly worse than graft size 8.5 mm (HR = 2.062, P = 0.010). In therapeutic keratoplasty, graft survival was significantly worse for Acanthamoeba than viral keratitis (HR = 2.36, P = 0.008). In the multivariable model, adjusting for graft size, type, and reason for transplantation, viral and bacterial keratitis did not differ significantly in graft survival, and Acanthamoeba showed a significantly worse prognosis (vs. viral keratitis, HR = 2.30, P < 0.001; bacterial keratitis, HR = 2.65, P < 0.001).

Conclusions:

Viral keratitis was the most common indication for transplantation, followed by bacterial and Acanthamoeba keratitis. HLA matching did not offer protection over elective non-HLA–matched procedures, whereas emergency procedures and grafts sized >8.5 mm showed poor survival. In optical keratoplasty, survival is high for all pathogens, whereas in therapeutic keratoplasty Acanthamoeba shows poor outcome.
Cultural Adaptation of the Younger Women’s Wellness After Cancer Program for Younger Chinese Women With Breast Cancer
Authors: Chan Dorothy Ngo Sheung , Chow Ka Ming , Anderson Debra Jane , Porter-Steele Janine , Laing Bobbi , Ling Wai Man , Lam Carol Choi Hung , Choi Kai Chow , Chan Carmen Wing Han , So Winnie Kwok Wei , McCarthy Alexandra Leigh
Published: February 2023

Background

The incidence of breast cancer in younger women, that is, aged 50 years or younger, in Hong Kong is increasing. The Internet-based Younger Women’s Wellness After Cancer Program (YWWACP) is a whole-lifestyle intervention that can help young women to manage their health and risks of chronic diseases.

Objectives

The study aimed to test the acceptability and feasibility of the culturally adapted YWWACP in Hong Kong (YWWACPHK) and to evaluate its preliminary effects in improving health-related quality of life, distress, sexual function, menopausal symptoms, dietary intake, physical activity, and sleep among younger Chinese women with breast cancer.

Intervention/Methods

Women aged 18 to 50 years with breast cancer were recruited from an oncology outpatient department. The participants in the intervention group received the 12-week YWWACPHK, whereas the control group received standard care.

Results

Sixty women consented to participate. At 12 weeks after intervention completion, the intervention group showed a significant increase in the pain subscale scores of sexual function and more improvement in the level of physical activity than the control group, with Hedge g effect sizes 0.66 and 0.65, respectively. Nineteen intervention group participants reported that they were satisfied with the program and suggestions for improvement were provided.

Conclusion

The implementation of YWWACPHK is feasible. The preliminary findings suggest that YWWACPHK could increase the level of physical activity among the participants.

Implications for Practice

Nurses could utilize YWWACPHK to support younger Chinese patients with breast cancer to maintain a healthy lifestyle, subject to wider confirmation of these results through a larger study.
TQIP mortality reporting system case reports: Unanticipated mortality due to inadequate preoperative ICU “clearance”
Authors: Ross Samuel W. , Jacobs David G. ,   the ACS TQIP Mortality Reporting System Writing Group
Published: February 2023

The Trauma Quality Improvement Program Mortality Reporting System is an online anonymous case reporting system designed to share experiences from rare events that may have contributed to unanticipated mortality at contributing trauma centers. The Trauma Quality Improvement Program Mortality Reporting System Working Group monitors submitted cases and organizes them into emblematic themes. This report summarizes unanticipated mortality from a case of inadequate clearance by the intensive care unit service before surgical intervention in an injured patient and presents strategies to mitigate these events locally with the hope of decreasing unanticipated mortality nationwide.
TQIP mortality reporting system case reports: Unanticipated mortality due to communication and handoff failures
Authors: Williams Regan F. , Mandell Samuel P. ,   the ACS TQIP Mortality Reporting System Writing Group
Published: February 2023

The TQIP Mortality Reporting System is an online anonymous case reporting system designed to share experiences from rare events that may have contributed to unanticipated mortality at contributing trauma centers. The TQIP Mortality Reporting System Working group monitors submitted cases and organizes them into emblematic themes. This report summarizes unanticipated mortality from two cases of failure of communication and handoff, and presents strategies to mitigate these events locally with the hope of decreasing unanticipated mortality nationwide.
TQIP mortality reporting system case reports: Unanticipated mortality due to airway loss
Authors: Scott John W. , Cole Frederic J. ,   the ACS TQIP Mortality Reporting System Writing Group
Published: February 2023

The Trauma Quality Improvement Program Mortality Reporting System is an online anonymous case reporting system designed to share experiences from rare events that may have contributed to unanticipated mortality at contributing trauma centers. The Trauma Quality Improvement Program Mortality Reporting System Working Group monitors submitted cases and organizes them into emblematic themes. This report summarizes unanticipated mortality from 3 cases of airway loss in injured patients and presents strategies to mitigate these events locally, with the hope of decreasing unanticipated mortality nationwide.
Inferring condition in wild mammals: body condition indices confer no benefit over measuring body mass across ecological contexts
Authors: Wishart Andrea E. , Guerrero-Chacón Adriana L. , Smith Rebecca , Hawkshaw Deborah M. , McAdam Andrew G. , Dantzer Ben , Boutin Stan , Lane Jeffrey E.
Published: February 2023

Many studies assume that it is beneficial for individuals of a species to be heavier, or have a higher body condition index (BCI), without accounting for the physiological relevance of variation in the composition of different body tissues. We hypothesized that the relationship between BCI and masses of physiologically important tissues (fat and lean) would be conditional on annual patterns of energy acquisition and expenditure. We studied three species with contrasting ecologies in their respective natural ranges: an obligate hibernator (Columbian ground squirrel,Urocitellus columbianus), a facultative hibernator (black-tailed prairie dog,Cynomys ludovicianus), and a food-caching non-hibernator (North American red squirrel,Tamiasciurus hudsonicus). We measured fat and lean mass in adults of both sexes using quantitative magnetic resonance (QMR). We measured body mass and two measures of skeletal structure (zygomatic width and right hind foot length) to develop sex- and species-specific BCIs, and tested the utility of BCI to predict body composition in each species. Body condition indices were more consistently, and more strongly correlated, with lean mass than fat mass. The indices were most positively correlated with fat when fat was expected to be very high (pre-hibernation prairie dogs). In all cases, however, BCI was never better than body mass alone in predicting fat or lean mass. While the accuracy of BCI in estimating fat varied across the natural histories and annual energetic patterns of the species considered, measuring body mass alone was as effective, or superior in capturing sufficient variation in fat and lean in most cases.
ΔF508-Cftrmutation in genetically diverse Collaborative Cross mice yields novel disease-relevant phenotypes for cystic fibrosis
Authors: Sipione Barbara , Lorè Nicola Ivan , Sanvito Francesca , Rossi Giacomo , Neri Alessia , Gianferro Fabrizio , Tascini Anna Sofia , Livraghi-Butrico Alessandra , Cigana Cristina , Bragonzi Alessandra
Published: February 2023

Mutations ofCystic Fibrosis Transmembrane conductance Regulator(CFTR) lead to Cystic Fibrosis (CF), but the substantial phenotypic variations are determined by non-CFTRallelic diversity. To map novel disease phenotypes in a CF mouse model, we used Collaborative Cross (CC) mice, a highly genetically diverse mouse resource population.ΔF508-Cftrhomozygosity produced a fully penetrant lethal phenotype by eight weeks in two CC lines. The lethality of CC006ΔF508/ΔF508was fully prenatal while CC037ΔF508/ΔF508showed either prenatal or postnatal lethality. Novel phenotypes of CC037ΔF508/ΔF508were revealed early in life including respiratory and systemic inflammatory profiles, and blood, bone marrow, pancreas, heart, and reproductive tract pathologies. Severe intestinal blockage was observed as common in other CF mouse models. These results suggest that the exploration of CF disease phenotypes in a mouse population with diverse genetic profiles is needed to map the genetic origin of currently unidentified disease traits and their potential translation to humans.
Theoretical model of membrane protrusions driven by curved active proteins
Authors: Ravid Yoav , Penic Samo , Mimori-Kiyosue Yuko , Suetsugu Shiro , Iglic Ales , Gov Nir
Published: February 2023

Eukaryotic cells intrinsically change their shape, by changing the composition of their membrane and by restructuring their underlying cytoskeleton. We present here further studies and extensions of a minimal physical model, describing a closed vesicle with mobile curved membrane protein complexes. The cytoskeletal forces describe the protrusive force due to actin polymerization which is recruited to the membrane by the curved protein complexes. We characterize the phase diagrams of this model, as function of the magnitude of the active forces, nearest-neighbor protein interactions and the proteins spontaneous curvature. It was previously shown that this model can explain the formation of lamellipodia-like flat protrusions, and here we explore the regimes where the model can also give rise to filopodia-like tubular protrusions. We extend the simulation with curved components of both convex and concave species, where we find the formation of complex ruffled clusters, as well as internalized invaginations that resemble the process of endocytosis and macropinocytosis. We alter the force model representing the cytoskeleton to simulate the effects of bundled instead of branched structure, resulting in shapes which resemble filopodia.
Transcriptional survey of ovarian bacteriomes in the cereal weevil,Sitophilus oryzae, shows down-regulation of immune effectors at the onset of sexual maturity
Authors: Ferrarini Mariana Galvão , Vallier Agnès , Dell’Aglio Elisa , Balmand Séverine , Vincent-Monégat Carole , Debbache Mériem , Maire Justin , Parisot Nicolas , Zaidman-Rémy Anna , Heddi Abdelaziz , Rebollo Rita
Published: February 2023

Insects often establish long-term relationships with intracellular symbiotic bacteria,i.e. endosymbionts, that provide them with essential nutrients such as amino acids and vitamins. Endosymbionts are typically confined within specialized host cells called bacteriocytes that may form an organ, the bacteriome. Compartmentalization within host cells is paramount for protecting the endosymbionts and also avoiding chronic activation of the host immune system. In the cereal weevilSitophilus oryzae, bacteriomes are present as a single organ at the larval foregut-midgut junction, and in adults, at the apex of midgut mesenteric caeca and at the apex of the four ovarioles. While the adult midgut endosymbionts experience a drastic proliferation during early adulthood followed by complete elimination through apoptosis and autophagy, ovarian endosymbionts are maintained throughout the weevil lifetime by unknown mechanisms. Bacteria present in ovarian bacteriomes are thought to be involved in the maternal transmission of endosymbionts through infection of the female germline, but the exact mode of transmission is not fully understood. Here, we show that endosymbionts are able to colonize the germarium in one-week-old females, pinpointing a potential infection route of oocytes. To identify potential immune regulators of ovarian endosymbionts, we have analyzed the transcriptomes of the ovarian bacteriomes through young adult development, from one-day-old adults to sexually mature ones. In contrast with midgut bacteriomes, immune effectors are downregulated in ovarian bacteriomes at the onset of sexual maturation. We hypothesize that relaxation of endosymbiont control by antimicrobial peptides might allow bacterial migration and potential oocyte infection, ensuring endosymbiont transmission.
Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics
Authors: Yoshitake Ryohei , Mori Hitomi , Ha Desiree , Wu Xiwei , Wang Jinhui , Wang Xiaoqiang , Saeki Kohei , Chang Gregory , Shim Hyun Jeong , Chan Yin , Chen Shiuan
Published: February 2023

Background

Intratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive (ER+) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth.

Methods

Spatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of “ER-high” metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80–100% ER) and estrogen-stimulated SC31 (30–75% ER) models. The analyses included samples treated with and without 17β-estradiol. The findings were validated via scRNA-seq analyses on “ER-low” estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts.

Results

Our novel space-gene-function study revealed a “proliferative” cell population in addition to three major spatially distinct compartments within ER+metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The “proliferative (MKI67+)” population, not “estrogen-responsive” compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such asPGRwere not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67+proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression.

Conclusions

For the first time, our study elucidated a “proliferative” cell population distinctly distributed in ER+metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the “proliferative” compartment is an important determinant of luminal cancer subtypes.
Sterile triggers drive joint inflammation in TNF and IL-1β dependent mouse arthritis models
Authors: Thiran Alexandra , Petta Ioanna , Blancke Gillian , Thorp Marie , Plankaert Guillaume , Jans Maude , Andries Vanessa , Barbry Korneel , Hochepied Tino , Vanhove Christian , Gracey Eric , Dumas Emilie , Manuelo Teddy , Josipovic Ivan , van Loo Geert , Elewaut Dirk , Vereecke Lars
Published: February 2023

Arthritis is the most common extra-intestinal complication in inflammatory bowel disease (IBD). Conversely, arthritis patients are at risk for developing IBD and often display subclinical gut inflammation. These observations suggest a shared disease etiology, commonly termed ‘the gut-joint-axis’. The clinical association between gut and joint inflammation is further supported by the success of common therapeutic strategies and microbiota dysbiosis in both conditions. Most data however support a correlative relationship between gut & joint inflammation, while causative evidence is lacking. Using two independent transgenic mouse arthritis models, either TNF or IL1β dependent, we demonstrate that arthritis develops independently of the microbiota and intestinal inflammation, since both lines develop full-blown articular inflammation under germ-free conditions. In contrast, TNF-driven gut inflammation is fully rescued in germ-free conditions indicating that the microbiota is driving TNF-induced gut inflammation. Together, our study demonstrates that, although common inflammatory pathways may drive both gut and joint inflammation, the molecular triggers initiating such pathways are distinct in these tissues.
Epigenetic Regulation Explains The Functionality Behind Colon Cancer Specific Biomarker Septin9
Authors: Vizkeleti Laura , Kiss Csaba , Tisza Viktoria , Szigeti Aniko , Gellert Akos , Csabai Istvan , Pongor Lorinc S. , Spisak Sandor
Published: February 2023

Despite advancements in early cancer detection and prevention methods, colorectal cancer (CRC) remains a significant global health problem. It is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Additionally, there has been a marked increase of incidence in young adults, and the reasons for this tendency are not fully understood. Therefore, the need for more effective diagnostic methods of assessing disease risk at early stage is crucial.

One of the newly developed blood-based circulating biomarkers with promising potential is the short hypermethylated region located at the Septin9 intronic region. Several clinical studies have proven its performance and applicability. However, the molecular mechanism behind this consistent and recurrent feature present in most of the CRC and related precancerous stages and why it is specific and advantageous for CRC development are poorly understood.

Here, we used comprehensive epigenetic and gene expression profile analyses from different sources of human clinical samples and cell line data to link specific hypermethylation events at the Septin9 intronic loci, which initiate alternative transcription of the Septin9 gene.

Through our investigation of TCGA-COAD RNA-seq samples (n=287), we found that there was no significant difference in global Septin9 levels between normal and tumor samples. However, we did observe a significant alteration in the transcript variant ratio between v1 and v2, suggesting the use of an alternative promoter. Our findings were further supported by our analysis of ATAC-seq data, which revealed that the v2 promoter conferred higher chromatin accessibility, which correlated with the expression of the v2 isoform. However, this was not supported by promoter or enhancer activity as measured by H3K27ac signals. Hypermethylation at the v2 promoter was confirmed in tumor samples, providing a possible explanation for the switch in variants.

Protein sequence analysis confirmed small differences between Septin9 variant ‘A’(v1) and ‘B’(v2). However, AlphaFold2 indicates a substantial difference at the N terminus, which could impact protein phosphorylation. We hypothesize, that variant ‘A’ (v1) and variant ‘B’ (v2) are required for normal cell functions but shifting the balance towards v1 is more favourable for the tumor.

Although very little is known about Septin9 and its function in CRC biology, we are confident that our study will help to emphasize the importance of understanding regulatory mechanisms behind tumor-specific biomarkers and helps to improve the application.
Analysis of AlphaFold and molecular dynamics structure predictions of mutations in serpins
Authors: Garrido-Rodríguez Pedro , Carmena-Bargueño Miguel , de la Morena-Barrio María Eugenia , Bravo-Pérez Carlos , de la Morena-Barrio Belén , Cifuentes-Riquelme Rosa , Lozano María Luisa , Pérez-Sánchez Horacio , Corral Javier
Published: February 2023

Serine protease inhibitors (serpins) include thousands of structurally conserved proteins playing key roles in many organisms. Mutations affecting serpins may disturb their conformation, leading to inactive forms. Unfortunately, conformational consequences of mutations affecting serpins are difficult to predict. In this study we integrate experimental data of patients with mutations affecting one serpin with the predictions obtained by AlphaFold and molecular dynamics. FiveSERPINC1mutations causing antithrombin deficiency, the strongest congenital thrombophilia, (p.Arg79Cys; p.Pro112Ser, p.Met283Val; p.Pro352insValPheLeuPro, and p.Glu241_Leu242delinsValLeuValLeuValAsnThrArgThr-Ser) were selected from a cohort of 350 unrelated patients based on functional, biochemical, and crystallographic evidence supporting a folding defect. AlphaFold gave an accurate prediction for the wild-type antithrombin structure. However, it only produced native structures for all variants, regardless of its complexity andin-vivoconformational consequences. Similarly, molecular dynamics of up to 1000 ns at temperatures that caused conformational transitions did not show significant changes in the native structure of wild-type or variants. In conclusion, one predictive tool of protein folding, AlphaFold, and a simulation method for analyzing the physical movements of atoms and molecules, molecular dynamics, force predictions into the native stressed conformation at conditions with experimental evidence supporting a conformational change to relaxed structures. It is necessary to improve predictive strategies for serpins that consider the conformational sensitivity of these molecules.
Cell-free multi-omics analysis reveals tumor status-informative signatures in gastrointestinal cancer patients’ plasma
Authors: Tao Yuhuan , Xing Shaozhen , Zuo Shuai , Bao Pengfei , Jin Yunfan , Li Yu , Wu Yingchao , Chen Shanwen , Wang Xiaojuan , Zhu Yumin , Feng Ying , Zhang Xiaohua , Wang Xianbo , Xi Qiaoran , Lu Qian , Wang Pengyuan , Lu Zhi John
Published: February 2023

During cancer development, host’s tumorigenesis and immune signals are released to and informed by circulating molecules, like cell-free DNA (cfDNA) and RNA (cfRNA) in blood. However, these two kinds of molecules are still not systematically compared in gastrointestinal cancer. Here, we profiled 4 types of cell-free omics data from colorectal and stomach cancer patients, and assayed 15 types of genomic, epi-genomic, and transcriptomic variations. First, we demonstrated that the multi-omics data were more capable of detecting cancer genes than the single-omics data, where cfRNAs were more sensitive and informative than cfDNAs in terms of detection ratio, variation type, altered number, and enriched functional pathway. Moreover, we revealed several peripheral immune signatures that were suppressed in cancer patients and originated from specific circulating and tumor-microenvironment cells. Particularly, we defined a γδ-T-cell score and a cancer-associated-fibroblast (CAF) score using the cfRNA-seq data of 143 cancer patients. They were informative of clinical status like cancer stage, tumor size, and survival. In summary, our work reveals the cell-free multi-molecular landscape of colorectal and stomach cancer, and provides a potential monitoring utility in blood for the personalized cancer treatment.
Hmrbase2: A comprehensive database of hormones and their receptors
Authors: Kaur Dashleen , Arora Akanksha , Patiyal Sumeet , Raghava Gajendra Pal Singh
Published: February 2023

Background and objective

Hormones are essential for cell communication and hence regulate various physiological processes. The discrepancies in the hormones or their receptors can break this communication and cause major endocrinological disorders. It is, therefore, indispensable for the therapeutics and diagnostics of hormonal diseases.

Methods

We collected widespread information on peptide and non-peptide hormones and hormone receptors. The information was collected from HMDB, UniProt, HORDB, ENDONET, PubChem and literature.

Results

Hmrbase2 is an updated version of Hmrbase. The current version contains a total of 12056 entries which is more than twice the entries in the previous version. These include 7406, 753, and 3897 entries for peptide hormones, non-peptide hormones and hormone receptors, respectively, from 803 organisms compared to the 562 organisms in the previous version. The database also hosts 5662 hormone receptor pairs. The source organism, function, and subcellular location are provided for peptide hormones and receptors and properties like melting point; water solubility is provided for non-peptide hormones. Besides browsing and keyword search, an advanced search option has also been provided. Additionally, a similarity search module has been incorporated, enabling users to run similarity searches against peptide hormone sequences using BLAST and Smith-Waterman.

Conclusions

To make the database accessible to various users, we designed a user-friendly, responsive website that can be easily used on smartphones, tablets, and desktop computers. The updated database version, Hmrbase2, offers improved data content compared to the previous version. Homebase 2.0 is freely available athttps://webs.iiitd.edu.in/raghava/hmrbase2.
A cortical mechanism linking saliency detection and motor reactivity in rhesus monkeys
Authors: Novembre Giacomo , Lacal Irene , Benusiglio Diego , Quarta Eros , Schito Andrea , Grasso Stefano , Caratelli Ludovica , Caminiti Roberto , Mayer Alexandra Battaglia , Iannetti Gian Domenico
Published: February 2023

Sudden and surprising sensory events trigger neural processes that swiftly adjust behavior. To study the phylogenesis and the mechanism of this phenomenon, we trained two rhesus monkeys to keep a cursor inside a visual target by exerting force on an isometric joystick. We examined the effect of surprising auditory stimuli on exerted force, scalp electroencephalographic (EEG) activity, and local field potentials (LFP) recorded from the dorso-lateral prefrontal cortex. Auditory stimuli elicited (1) a biphasic modulation of isometric force: a transient decrease followed by a corrective tonic increase, and (2) EEG and LFP deflections dominated by two large negative-positive waves (N70 and P130). The EEG potential was maximal at the scalp vertex, in all respects similar to the human ‘vertex potential’. Electrocortical potentials and force were tightly coupled: the P130 amplitude predicted the magnitude of the corrective force increase, particularly in the EEG electrodes contralateral to the limb exerting force, and in the LFP recorded from deep rather than superficial cortical layers, suggesting a direct effect of the vertex potential on the motor output determining the behavior. These results disclose a phylogenetically-preserved cortico-motor mechanism supporting adaptive behavior in response to salient sensory events.
Capturing the mechanosensitivity of cell proliferation in models of epithelium
Authors: Höllring Kevin , Nuić Lovro , Rogić Luka , Kaliman Sara , Gehrer Simone , Wollnik Carina , Rehfeldt Florian , Hubert Maxime , Smith Ana-Sunčana
Published: February 2023

Despite the primary role of cell proliferation in tissue development and homeostatic maintenance, the interplay between cell density, cell mechanoresponse, and cell growth and division is not yet understood. In this article we address this issue by reporting on an experimental investigation of cell proliferation on all time- and length-scales of the development of a model tissue, grown on collagen-coated glass or deformable substrates. Through extensive data analysis, we demonstrate the relation between mechanoresponse and probability for cell division, as a function of the local cell density. Motivated by these results, we construct a minimal model of cell proliferation that can recover the data. By parametrizing the growth and the dividing phases of the cell cycle, and introducing such a proliferation model in dissipative particle dynamics simulations, we recover the mechanoresponsive, time-dependent density profiles in 2D tissues growing to macroscopic scales. The importance of separating the cell population into growing and dividing cells, each characterized by a particular time scale, is further emphasized by calculations of density profiles based on adapted Fisher-Kolmogorov equations. Together, these results show that the mechanoresponse on the level of a constitutive cell and its proliferation results in a matrix-sensitive active pressure. The latter evokes massive cooperative displacement of cells in the invading tissue and is a key factor for developing large-scale structures in the steady state.
scDecouple: Decoupling cellular response from infected proportion bias in scCRISPR-seq
Authors: Meng Qiuchen , Wei Lei , Ma Kun , Shi Ming , Lin Xinyi , Ho Joshua W. K. , Li Yinqing , Zhang Xuegong
Published: February 2023

Motivation

scCRISPR-seq is an emerging high-throughput CRISPR screening technology that combines CRISPR screening with single-cell sequencing technologies. It provides rich information on the mechanism of gene regulation. However, when scCRISPR-seq is applied in a population of heterogeneous cells, the true cellular response to perturbation is coupled with infected proportion bias of guide RNAs (gRNAs) across different cell clusters. The mixing of these effects introduces noise into scCRISPR-seq data analysis and thus obstacles to relevant studies.

Results

We developed scDecouple to decouple true cellular response of perturbation from the influence of infected proportion bias. scDecouple first models the distribution of gene expression profiles in perturbed cells and then iteratively finds the maximum likelihood of cell cluster proportions as well as the cellular response for each gRNA. We demonstrated its performance in a series of simulation experiments. By applying scDecouple to real scCRISPR-seq data, we found that scDecouple enhances the identification of biologically perturbation-related genes. scDecouple can benefit scCRISPR-seq data analysis, especially in the case of heterogeneous samples or complex gRNA libraries.

Availability

scDecouple is freely available athttps://github.com/MengQiuchen/scDecouple.

Contact

weilei92@tsinghua.edu.cn,yinqingl@tsinghua.edu.cn
Pro-myelinating Clemastine administration improves recording performance of chronically implanted microelectrodes and nearby neuronal health
Authors: Chen Keying , Cambi Franca , Kozai Takashi D.Y.
Published: February 2023

Intracortical microelectrodes have become a useful tool in neuroprosthetic applications in the clinic and to understand neurological disorders in basic neurosciences. Many of these brain-machine interface technology applications require successful long-term implantation with high stability and sensitivity. However, the intrinsic tissue reaction caused by implantation remains a major failure mechanism causing loss of recorded signal quality over time. Oligodendrocytes remain an underappreciated intervention target to improve chronic recording performance. These cells can accelerate action potential propagation and provides direct metabolic support for neuronal health and functionality. However, implantation injury causes oligodendrocyte degeneration and leads to progressive demyelination in surrounding brain tissue. Previous work highlighted that healthy oligodendrocytes are necessary for greater electrophysiological recording performance and the prevention of neuronal silencing around implanted microelectrodes over chronic implantation. Thus, we hypothesize that enhancing oligodendrocyte activity with a pharmaceutical drug, Clemastine, will prevent the chronic decline of microelectrode recording performance. Electrophysiological evaluation showed that the promyelination Clemastine treatment significantly elevated the signal detectability and quality, rescued the loss of multi-unit activity, and increased functional interlaminar connectivity over 16-weeks of implantation. Additionally, post-mortem immunohistochemistry showed that increased oligodendrocyte density and myelination coincided with increased survival of both excitatory and inhibitory neurons near the implant. Overall, we showed a positive relationship between enhanced oligodendrocyte activity and neuronal health and functionality near the chronically implanted microelectrode. This study shows that therapeutic strategy that enhance oligodendrocyte activity is effective for integrating the functional device interface with brain tissue over chronic implantation period.

Abstract Figure
Serial Capture Affinity Purification and Integrated Structural Modeling of the H3K4me3 Binding and DNA Damage Related WDR76:SPIN1 Complex
Authors: Liu Xingyu , Zhang Ying , Wen Zhihui , Hao Yan , Banks Charles A.S. , Lange Jeffrey J. , Cesare Joseph , Bhattacharya Saikat , Slaughter Brian D. , Unruh Jay R. , Florens Laurence , Workman Jerry L. , Washburn Michael P.
Published: February 2023

WDR76 is a multifunctional protein involved in many cellular functions. With a diverse and complicated protein interaction network, dissecting the structure and function of specific WDR76 complexes is needed. We previously demonstrated the ability of the Serial Capture Affinity Purification (SCAP) method to isolate specific complexes by introducing two proteins of interest as baits at the same time. Here, we applied SCAP to dissect a subpopulation of WDR76 in complex with SPIN1, a histone marker reader that specifically recognizes trimethylated histone H3 lysine4 (H3K4me3). In contrast to the SCAP analysis of the SPIN1:SPINDOC complex, H3K4me3 was copurified with the WDR76:SPIN1 complex. In combination with crosslinking mass spectrometry, we built an integrated structural model of the complex which revealed that SPIN1 recognized the H3K4me3 epigenetic mark while interacting with WDR76. Lastly, interaction network analysis of copurifying proteins revealed the potential role of the WDR76:SPIN1 complex in the DNA damage response.

Teaser

In contrast to the SPINDOC/SPIN1 complex, analyses reveal that the WDR76/SPIN1 complex interacts with core histones and is involved in DNA damage.
Liquid spherical shells are a non-equilibrium steady state
Authors: Bergmann Alexander M. , Bauermann Jonathan , Bartolucci Giacomo , Donau Carsten , Stasi Michele , Holtmannspötter Anna-Lena , Jülicher Frank , Weber Christoph A. , Boekhoven Job
Published: February 2023

Liquid-liquid phase separation is the process in which two immiscible liquids demix. This spontaneous phenomenon yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, nonequilibrium reaction cycle. Chemically fueled phase separation yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can transition into a new morphology—a liquid, spherical shell of droplet material. A spherical shell would be highly unstable at equilibrium. Only by continuously converting chemical energy, this dissipative structure can be sustained. We demonstrate the transition mechanism, which is related to the activation of a product outside of the droplet, and the deactivation within the droplets leading to gradients of droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests new avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.
Molecular simulations reveal the free energy landscape and transition state of membrane electroporation
Authors: Kasparyan Gari , Hub Jochen S.
Published: February 2023

The formation of pores over lipid membranes by the application of electric fields, termed membrane electroporation, is widely used in biotechnology and medicine to deliver drugs, vaccines, or genes into living cells. Continuum models for describing the free energy landscape of membrane electroporation have been proposed decades ago, but they have never been tested against spatially detailed atomistic models. Using molecular dynamics (MD) simulations with a recently proposed reaction coordinate, we computed potentials of mean force of pore nucleation and pore expansion in lipid membranes at various transmembrane potentials. Whereas the free energies of pore expansion are compatible with previous continuum models, the experimentally important free energy barrier of pore nucleation is at variance with established models. We trace the discrepancy to previously incorrect assumptions on the geometry of the transition state; previous continuum models assumed the presence of a membrane-spanning defect throughout the process whereas, according to the MD simulations, the transition state of pore nucleation is typically passed before a transmembrane defect has formed. A modified continuum model is presented that qualitatively agrees with the MD simulations. Using kinetics of pore opening together with transition state theory, our free energies of pore nucleation are in excellent agreement with previous experimental data.
Narratives engage brain and body: bidirectional interactions during natural story listening
Authors: Madsen Jens , Parra Lucas C.
Published: February 2023

It is often said that the body and the mind are connected. Yet, direct evidence of a bidirectional link is elusive. We hypothesized a top-down effect of cognition on arousal, and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size and heart rate were all associated with anterior-central brain signals. Together this suggests bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.

Highlights

Listening to narratives modulates eye movements.

Heart rate fluctuations precede fluctuations in pupil size and anterior-central neural activity.

Breathing modulates pupil size suggesting causal effect on central arousal.

Rhythmic saccades can entrain heart beats.

eTOC

When we listen to a story our body is integrally involved in the experience. We provide evidence for a bidirectional and causal link between body and mind by analyzing brain signals, pupil size, heart rate and eye movements, while subjects listen to narratives and during interventions that control autonomic signals.
LCP1 Regulates Cell Motility in Chondrosarcoma and Correlates with Metastatic Potential and Poor Patient Outcomes
Authors: Watson Caleb , Martin John T. , Nakagawa Makoto , Guardino Nicholas , Zou Trudy , Peairs Emily , Krez Alexandra , Nadesan Puvi , Huang ZeYu , Ou Jianhong , Somarelli Jason A. , Alman Benjamin , Visgauss Julia D.
Published: February 2023

Chondrosarcoma (CSA) is the second most common primary malignancy of bone, whose aggressive potential and chemo-resistant nature result in extremely poor outcomes in patients with advanced disease. Grading and prognostication of these tumors remain a significant challenge for pathologists, and medical oncologists have no effective therapies to prevent or treat metastatic disease. In the present study, we sought to explore the pathogenesis and aggressive progression of chondrosarcoma by comparing gene expression differences from metastasizing and non-metastasizing CSA tumors. We hypothesized that metastasizing tumors have inherent differences that may be attributed to the dysregulation of specific oncogenic cell signaling pathways. RNA-Seq analysis from patient-derived low-passage cell lines of metastasizing and non-metastasizing tumors pinpointed the geneLCP1(lymphocyte cytosolic protein 1) as upregulated in CSA cells from metastasizing tumors. Analysis of a large clinical cohort of CSA demonstrated that increased expression ofLCP1correlated with poor patient survival.In vitroanalyses confirmed the ability of LCP1 to promote migration and invasion of CSA cells. These data support the key role of LCP1 on metastatic potential and poor prognosis in CSA. In conclusion, we confirm the ability of LCP1 to drive metastatic behavior and correlate with poor outcomes in patients.
Co-Evolving Dynamics and Topology in a Coupled Oscillator Model of Resting Brain Function
Authors: Pope Maria , Seguin Caio , Varley Thomas F. , Faskowitz Joshua , Sporns Olaf
Published: February 2023

Dynamic models of ongoing BOLD fMRI brain dynamics and models of communication strategies have been two important approaches to understanding how brain network structure constrains function. However, dynamic models have yet to widely incorporate one of the most important insights from communication models: the brain may not use all of its connections in the same way or at the same time. Here we present a variation of a phase delayed Kuramoto coupled oscillator model that dynamically limits communication between nodes on each time step. An active subgraph of the empirically derived anatomical brain network is chosen in accordance with the local dynamic state on every time step, thus coupling dynamics and network structure in a novel way. We analyze this model with respect to its fit to empirical time-averaged functional connectivity, finding that it significantly outperforms standard Kuramoto models with phase delays. We also perform analyses on the novel structural edge time series it produces, demonstrating a slowly evolving topology moving through intermittent episodes of integration and segregation. We hope to demonstrate that the exploration of novel modeling mechanisms and the investigation of dynamicsofnetworks in addition to dynamicsonnetworks may advance our understanding of the relationship between brain structure and function.
Anabolic phenotype in cartilage-specific Mitogen-inducible gene-6 knockout mice is independent of Transforming growth factor-α
Authors: Hadzic Ermina , To Bethia , Pest Michael A. , Qin Ling , Beier Frank
Published: February 2023

Background/Objective

Osteoarthritis (OA) is a whole joint disorder with no disease modifying treatment currently available. The Epidermal Growth Factor Receptor (EGFR) signaling pathway plays an important role in cartilage/bone development and its ligand transforming growth factor-α(TGl·α) is upregulated in OA. In contrast, Mitogen-inducible gene 6 (Mig6) is a negative regulator of EGFR, and our studies demonstrate that cartilage-specific Mig-6 deletion results in anabolic effects on cartilage and formation of chondro-osseus nodules (CON). We aimed to attenuate EGFR signaling by inhibiting TGFαproduction in cartilage-specific Mig6 deficient mice, to test whether this would prevent the formation of CONs.

Methods

We generated double knockout mice by crossing cartilage-specificMig-6fl/flCol2a1-Cre+/-and whole-bodyTgfa+/-mice to generate experimental and control wild-type mice. Knee and elbow sections were stained with toluidine blue to examine articular cartilage thickness and cell density, and tartrate-resistant acid phosphatase for osteoclast activity. Additionally, immunohistochemistry was completed to analyze phospho-EGFR and SOX9.

Results

Mig-6 deficient mice display cartilage thickening and CONs at 12 weeks in both the elbow and knee joints, which is independent of TGFαligand presence. Similarly, articular cartilage cell density is increased inMig-6fl/flCol2a1-Cre+/-Tgfa-/-andMig-6fl/flCol2al-Cre+/-mice, but notTgfa-/-mice, and displays increased SOX9 and phospho-EGFR staining.

Conclusion

The articular cartilage displays increased thickness, increased cell density, and CON formation independent of the presence of TGFα, suggesting the anabolic phenotype in the Mig6-deficient mice is independent of TGFα/EGFR binding. The anabolic phenotype may be due to an alternative EGFR ligand activation, or perhaps due to other non-EGFR specific mechanism. More research is required to elucidate the exact pathway responsible for the anabolic effects.