Nagoya J Med Sci. 2023 Feb;85(1):50-58. doi: 10.18999/nagjms.85.1.50.

ABSTRACT

In the neuroendovascular field, the training of operators has become an important issue. Recently, eye-tracking technology has been introduced into various fields of medical education. This study aimed to apply eye-tracking technology to the training of neuroendovascular therapy. Six neurosurgeons, including three neuroendovascular specialists and three trainees, at our institution and related facilities participated in the study. Eye movement was recorded by the eye-tracking device during the microcatheter navigation and coil placement into the silastic aneurysm model under biplane X-ray fluoroscopy. Eye-tracking analysis during neuroendovascular therapy was feasible in all six subjects. In microcatheter navigation, specialists tended to more frequently switch their attention between frontal and lateral images than trainees. In coil embolization, the overall gaze frequency tended to increase, and the average fixation duration tended to decrease as the number of experienced cases increased. Inexperienced operators tend to fix their gaze when they are operators than when they are assistants. More experienced operators tended to look at the microcatheter longer in the coil insertion task. The eye-tracking analysis may be useful for operator training in neuroendovascular therapy. Experts may have moved their eyes more frequently than trainees to gaze at the right place. In the future, it will be necessary to collect gaze data for more operators in various tasks.

PMID:36923614 | PMC:PMC10009636 | DOI:10.18999/nagjms.85.1.50

Front Oncol. 2023 Feb 27;13:1129405. doi: 10.3389/fonc.2023.1129405. eCollection 2023.

ABSTRACT

INTRODUCTION: Hematologic malignancies are currently underrepresented in multidisciplinary molecular-tumor-boards (MTB). This study assesses the potential of precision-oncology in primary-refractory plasmablastic-lymphoma (prPBL), a highly lethal blood cancer.

METHODS: We evaluated clinicopathological and molecular-genetic data of 14 clinically annotated prPBL-patients from initial diagnosis. For this proof-of-concept study, we employed our certified institutional MTB-pipeline (University-Cancer-Center-Schleswig-Holstein, UCCSH) to annotate a comprehensive dataset within the scope of a virtual MTB-setting, ultimately recommending molecularly stratified therapies. Evidence-levels for MTB-recommendations were defined in accordance with the NCT/DKTK and ESCAT criteria.

RESULTS: Median age in the cohort was 76.5 years (range 56-91), 78.6% of patients were male, 50% were HIV-positive and clinical outcome was dismal. Comprehensive genomic/transcriptomic analysis revealed potential recommendations of a molecularly stratified treatment option with evidence-levels according to NCT/DKTK of at least m2B/ESCAT of at least IIIA were detected for all 14 prPBL-cases. In addition, immunohistochemical-assessment (CD19/CD30/CD38/CD79B) revealed targeted treatment-recommendations in all 14 cases. Genetic alterations were classified by treatment-baskets proposed by Horak et al. Hereby, we identified tyrosine-kinases (TK; n=4), PI3K-MTOR-AKT-pathway (PAM; n=3), cell-cycle-alterations (CC; n=2), RAF-MEK-ERK-cascade (RME; n=2), immune-evasion (IE; n=2), B-cell-targets (BCT; n=25) and others (OTH; n=4) for targeted treatment-recommendations. The minimum requirement for consideration of a drug within the scope of the study was FDA-fast-track development.

DISCUSSION: The presented proof-of-concept study demonstrates the clinical potential of precision-oncology, even in prPBL-patients. Due to the aggressive course of the disease, there is an urgent medical-need for personalized treatment approaches, and this population should be considered for MTB inclusion at the earliest time.

PMID:36923431 | PMC:PMC10008852 | DOI:10.3389/fonc.2023.1129405

Int J STD AIDS. 2023 Mar 15:9564624231162180. doi: 10.1177/09564624231162180. Online ahead of print.

ABSTRACT

BACKGROUND: The re-emergence of Monkeypox (MPX) and its related ophthalmic disease represent a clinical challenge in the initial stages because of the presence of lesions like those caused by varicella zoster, syphilis, and other infections due to other poxviruses. Human Immunodeficiency Virus (HIV) infection and secondary immunodepression raise the risk of severe and prolonged disease.

PURPOSE: We present the case of a young immunosuppressed male patient with MPX, who presented with multiple skin lesions, also including risky ophthalmological manifestations due to extensive eyelid involvement.

CONCLUSIONS: We describe a novel form of late-onset conjunctivitis and eyelid lesions, without active extraocular disease, highlighting the heterogeneous behavior of the new clinical form of MPX, that exhibits a wide spectrum of lesions in different stages of evolution.

PMID:36922742 | DOI:10.1177/09564624231162180

Nat Rev Immunol. 2023 Mar 15. doi: 10.1038/s41577-023-00848-y. Online ahead of print.

ABSTRACT

Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules - such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.

PMID:36922638 | DOI:10.1038/s41577-023-00848-y

Nature. 2023 Mar 15. doi: 10.1038/s41586-023-05824-z. Online ahead of print.

ABSTRACT

Engineering the genetic code of an organism has been proposed to provide a firewall from natural ecosystems by preventing viral infections and gene transfer1-6. However, numerous viruses and mobile genetic elements encode parts of the translational apparatus7-9, potentially rendering a genetic-code-based firewall ineffective. Here we show that such mobile transfer RNAs (tRNAs) enable gene transfer and allow viral replication in Escherichia coli despite the genome-wide removal of 3 of the 64 codons and the previously essential cognate tRNA and release factor genes. We then establish a genetic firewall by discovering viral tRNAs that provide exceptionally efficient codon reassignment allowing us to develop cells bearing an amino acid-swapped genetic code that reassigns two of the six serine codons to leucine during translation. This amino acid-swapped genetic code renders cells resistant to viral infections by mistranslating viral proteomes and prevents the escape of synthetic genetic information by engineered reliance on serine codons to produce leucine-requiring proteins. As these cells may have a selective advantage over wild organisms due to virus resistance, we also repurpose a third codon to biocontain this virus-resistant host through dependence on an amino acid not found in nature10. Our results may provide the basis for a general strategy to make any organism safely resistant to all natural viruses and prevent genetic information flow into and out of genetically modified organisms.

PMID:36922599 | DOI:10.1038/s41586-023-05824-z

Nature. 2023 Mar 15. doi: 10.1038/s41586-023-05755-9. Online ahead of print.

ABSTRACT

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

PMID:36922589 | DOI:10.1038/s41586-023-05755-9

Nature. 2023 Mar 15. doi: 10.1038/s41586-023-05795-1. Online ahead of print.

ABSTRACT

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1-5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.

PMID:36922587 | DOI:10.1038/s41586-023-05795-1

Expert Rev Pharmacoecon Outcomes Res. 2023 Mar 15. doi: 10.1080/14737167.2023.2192482. Online ahead of print.

ABSTRACT

BACKGROUND: There is evidence suggesting that exaggerated reliance on pulse oximetry (SpO2) and the use of arbitrary/inadequate thresholds of SpO2 might drive unnecessary hospitalizations for viral bronchiolitis, especially among high-altitude residents. The aim of the present study was to compare the cost-effectiveness of two oxygen SpO2 thresholds for deciding whether infants with viral bronchiolitis living at high altitudes need hospital admission or can be discharged to home.

METHODS: : A cost-effectiveness study was performed to compare the cost and clinical outcomes of two oxygen SpO2 thresholds, adjusted or not, to the altitude above the sea level of Bogota, Colombia (2640m), for deciding whether infants with viral bronchiolitis need hospitalization or can be discharged to home. The principal outcome was avoidance of hospital admission.

RESULTS: Compared to the use of an SpO2 threshold of 90%, using an SpO2 threshold of 85% in infants with viral bronchiolitis was associated with lower overall costs (US$130.4 vs. US$194.0 average cost per patient) and a higher probability of hospitalization avoided (0.7500 vs. 0.5900), thus leading to dominance.

CONCLUSIONS: The use of an SpO2 threshold below 90% for deciding on hospitalization in infants with viral bronchiolitis living at high altitudes appear to be logical, secure, and cost-effective.

PMID:36922366 | DOI:10.1080/14737167.2023.2192482

J Neurophysiol. 2023 Mar 15. doi: 10.1152/jn.00227.2022. Online ahead of print.

ABSTRACT

According to the theory of coordinated reset (CR) stimulation, multifocal bursts of stimuli delivered in a random order with a specific interval may reduce the resonance power of the oscillatory generator in the epicenter. We develop a noninvasive coordinated multifocal burst stimulation (COMBS) with three repetitive transcranial stimulation machines based on CR theory to modulate the target frequency in the primary motor cortex and to assess its effect on motor cortical excitability in separate experiments. Electroencephalography and electromyography were recorded in 16 healthy participants during a finger-tapping task, both before and after the intervention. The resting oscillatory power at the targeted frequency was not changed by COMBS. α- band power was increased in both preparation and movement stages and the low β-band power was increased in the movement stage of the finger tapping task. The extent of low β-band event related desynchronization was reduced by COMBS. There were no changes in reaction time, but there was a trend for a reduced error rate after COMBS. In another 14 healthy participants, there were no significant change in cortical excitability before and after COMBS measured by rest motor threshold, short interval intracortical inhibition, short interval intracortical facilitation and cortical silent period. The result indicate that COMBS may modify the cortical oscillatory power and its perturbation within specific movement stage.

PMID:36922160 | DOI:10.1152/jn.00227.2022

SLAS Discov. 2023 Mar 13:S2472-5552(23)00023-0. doi: 10.1016/j.slasd.2023.03.001. Online ahead of print.

ABSTRACT

With over 39,000 students, and research expenditures in excess of $200 million, George Mason University (GMU) is the largest R1 (Carnegie Classification of very high research activity) university in Virginia. Mason scientists have been involved in the discovery and development of novel diagnostics and therapeutics in areas as diverse as infectious diseases and cancer. Below are highlights of the efforts being led by Mason researchers in the drug discovery arena. To enable targeted cellular delivery, and non-biomedical applications, Veneziano and colleagues have developed a synthesis strategy that enables the design of self-assembling DNA nanoparticles (DNA origami) with prescribed shape and size in the 10 to 100 nm range. The nanoparticles can be loaded with molecules of interest such as drugs, proteins and peptides, and are a promising new addition to the drug delivery platforms currently in use. The investigators also recently used the DNA origami nanoparticles to fine tune the spatial presentation of immunogens to study the impact on B cell activation. These studies are an important step towards the rational design of vaccines for a variety of infectious agents. To elucidate the parameters for optimizing the delivery efficiency of lipid nanoparticles (LNPs), Buschmann, Paige and colleagues have devised methods for predicting and experimentally validating the pKa of LNPs based on the structure of the ionizable lipids used to formulate the LNPs. These studies may pave the way for the development of new LNP delivery vehicles that have reduced systemic distribution and improved endosomal release of their cargo post administration. To better understand protein-protein interactions and identify potential drug targets that disrupt such interactions, Luchini and colleagues have developed a methodology that identifies contact points between proteins using small molecule dyes. The dye molecules noncovalently bind to the accessible surfaces of a protein complex with very high affinity, but are excluded from contact regions. When the complex is denatured and digested with trypsin, the exposed regions covered by the dye do not get cleaved by the enzyme, whereas the contact points are digested. The resulting fragments can then be identified using mass spectrometry. The data generated can serve as the basis for designing small molecules and peptides that can disrupt the formation of protein complexes involved in disease processes. For example, using peptides based on the interleukin 1 receptor accessory protein (IL-1RAcP), Luchini, Liotta, Paige and colleagues disrupted the formation of IL-1/IL-R/IL-1RAcP complex and demonstrated that the inhibition of complex formation reduced the inflammatory response to IL-1B. Working on the discovery of novel antimicrobial agents, Bishop, van Hoek and colleagues have discovered a number of antimicrobial peptides from reptiles and other species. DRGN-1, is a synthetic peptide based on a histone H1-derived peptide that they had identified from Komodo Dragon plasma. DRGN-1 was shown to disrupt bacterial biofilms and promote wound healing in an animal model. The peptide, along with others, is being developed and tested in preclinical studies. Other research by van Hoek and colleagues focuses on in silico antimicrobial peptide discovery, screening of small molecules for antibacterial properties, as well as assessment of diffusible signal factors (DFS) as future therapeutics. The above examples provide insight into the cutting-edge studies undertaken by GMU scientists to develop novel methodologies and platform technologies important to drug discovery.

PMID:36921802 | DOI:10.1016/j.slasd.2023.03.001

Biosystems. 2023 Mar 13:104872. doi: 10.1016/j.biosystems.2023.104872. Online ahead of print.

ABSTRACT

Formalization of autopoiesis is an ongoing effort among theoretical biologists. In this field, Letelier and co-authors proposed that Robert Rosen's (M,R)-systems theory be used as a formalism for autopoiesis. In (M,R)-systems theory, Rosen proposes that one solve a set of functional closure equations (FCEs) which account for all of the components of the system as coming from within the system itself. A key part of the functional closure equations is the repair of the metabolism component of the system. Rosen's theory gives the organizational closure of the components as well as their products, as found in autopoiesis. However, according to Razeto-Barry (M,R)-systems leaves out some of the messiness and approximation that we find in autopoiesis as he reformulates it. A related problem is that though FCEs have a long history, they are difficult in practice to solve due to their mathematical formulation. In this paper we give a novel exact solution for the FCEs for continuous real vector-valued functions which is nevertheless difficult to compute. In addition we propose an extended form of FCEs which both captures more of the messiness of autopoiesis and also helps to make the FCEs more solvable. Finally, we use our solution for the extended FCEs to give an extended repair function for a metabolism taken from a representative class of biological dynamics for gene expression (the repressilator). More generally we show that one can use our solution for the extended FCEs to get an extended repair function for continuous real vector-valued functions.

PMID:36921792 | DOI:10.1016/j.biosystems.2023.104872

Gastroenterology. 2023 Mar 13:S0016-5085(23)00262-7. doi: 10.1053/j.gastro.2023.03.008. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Gastric cancer (GC) is a major cancer type characterized by high heterogeneity in both tumor cells and the tumor immune microenvironment (TIME). One intractable GC subtype is gastric signet-ring cell carcinoma (GSRCC), which is associated with poor prognosis. However, it remains unclear what the GSRCC TIME characteristics are and how these characteristics may contribute to clinical outcomes.

METHODS: We enrolled 32 patients with advanced GC of diverse subtypes and profiled their TIME using an immune-targeted single-cell profiling strategy, including (i) immune-targeted single-cell RNA sequencing (scRNA-seq, n = 20 patients) and (ii) protein expression profiling by a targeted antibody panel for mass cytometry (CyTOF, n = 12 patients). We also generated matched V(D)J sequencing of T and B cells along CD45+ immunocytes.

RESULTS: We find that compared to non-GSRCC, the GSRCC TIME appears to be quiescent where both CD4+ and CD8+ T cells are difficult to be mobilized, which further impairs the proper functions of B cells. CXCL13, mainly produced by Tfh, Th17, and exhausted CD8+ T cells, is a central coordinator of this transformation. We show that CXCL13 expression can predict the response to immune checkpoint blockade in GC patients, which may be related to its effects on tertiary lymphoid structures.

CONCLUSIONS: Our study provides a comprehensive molecular portrait of immune cell compositions and cell states in advanced GC patients, highlighting adaptive immune irresponsiveness in GSRCC and a mediator role of CXCL13 in TIME. Our targeted single-cell transcriptomic and proteomic profiling represents a powerful approach for TIME-oriented translational research.

PMID:36921674 | DOI:10.1053/j.gastro.2023.03.008

Nature. 2023 Mar 15. doi: 10.1038/s41586-023-05939-3. Online ahead of print.

ABSTRACT

Lactate is abundant in rapidly dividing cells due to the requirement for elevated glucose catabolism to support proliferation1-6. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodeling and can overcome anti-mitotic pharmacology via mitotic slippage. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

PMID:36921622 | DOI:10.1038/s41586-023-05939-3

Cell Rep Med. 2023 Mar 8:100977. doi: 10.1016/j.xcrm.2023.100977. Online ahead of print.

ABSTRACT

Although breast cancer mortality is largely caused by metastasis, clinical decisions are based on analysis of the primary tumor and on lymph node involvement but not on the phenotype of disseminated cells. Here, we use multiplex imaging mass cytometry to compare single-cell phenotypes of primary breast tumors and matched lymph node metastases in 205 patients. We observe extensive phenotypic variability between primary and metastatic sites and that disseminated cell phenotypes frequently deviate from the clinical disease subtype. We identify single-cell phenotypes and spatial organizations of disseminated tumor cells that are associated with patient survival and a weaker survival association for high-risk phenotypes in the primary tumor. We show that p53 and GATA3 in lymph node metastases provide prognostic information beyond clinical classifiers and can be measured with standard methods. Molecular characterization of disseminated tumor cells is an untapped source of clinically applicable prognostic information for breast cancer.

PMID:36921599 | DOI:10.1016/j.xcrm.2023.100977

Sci Transl Med. 2023 Mar 15;15(687):eadd6137. doi: 10.1126/scitranslmed.add6137. Epub 2023 Mar 15.

ABSTRACT

GM-CSF in glomerulonephritisDespite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust et al. characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis. -CM.

PMID:36921033 | DOI:10.1126/scitranslmed.add6137

PLoS One. 2023 Mar 15;18(3):e0282580. doi: 10.1371/journal.pone.0282580. eCollection 2023.

ABSTRACT

Nipah virus (NiV) is an emerging zoonotic virus that caused several serious outbreaks in the south asian region with high mortality rates ranging from 40 to 90% since 2001. NiV infection causes lethal encephalitis and respiratory disease with the symptom of endothelial cell-cell fusion. No specific and effective vaccine has yet been reported against NiV. To address the urgent need for a specific and effective vaccine against NiV infection, in the present study, we have designed two Multi-Epitope Vaccines (MEVs) composed of 33 Cytotoxic T lymphocyte (CTL) epitopes and 38 Helper T lymphocyte (HTL) epitopes. Out of those CTL and HTL combined 71 epitopes, 61 novel epitopes targeting nine different NiV proteins were not used before for vaccine design. Codon optimization for the cDNA of both the designed MEVs might ensure high expression potential in the human cell line as stable proteins. Both MEVs carry potential B cell linear epitope overlapping regions, B cell discontinuous epitopes as well as IFN-γ inducing epitopes. Additional criteria such as sequence consensus amongst CTL, HTL and B Cell epitopes was implemented for the design of final constructs constituting MEVs. Hence, the designed MEVs carry the potential to elicit cell-mediated as well as humoral immune response. Selected overlapping CTL and HTL epitopes were validated for their stable molecular interactions with HLA class I and II alleles and in case of CTL epitopes with human Transporter Associated with antigen Processing (TAP) cavity. The structure based epitope cross validation for interaction with TAP cavity was used as another criteria choosing final epitopes for NiV MEVs. Finally, human Beta-defensin 2 and Beta-defensin 3 were used as adjuvants to enhance the immune response of both the MEVs. Molecular dynamics simulation studies of MEVs-TLR3 ectodomain (Human Toll-Like Receptor 3) complex indicated the stable molecular interaction. We conclude that the MEVs designed and in silico validated here could be highly potential vaccine candidates to combat NiV infections, with great effectiveness, high specificity and large human population coverage worldwide.

PMID:36920996 | DOI:10.1371/journal.pone.0282580

STAR Protoc. 2023 Mar 13;4(2):102162. doi: 10.1016/j.xpro.2023.102162. Online ahead of print.

ABSTRACT

GlyCompareCT is a portable command-line tool to facilitate downstream glycomic data analyses, by addressing data inherent sparsity and non-independence. Inputting glycan abundances, users can run GlyCompareCT with one line of code to obtain the abundances of a minimal substructure set, named glycomotif, thereby quantifying hidden biosynthetic relationships between measured glycans. Optional parameters tuning and annotation are supported for personal preference. For complete details on the use and execution of this protocol, please refer to Bao et al. (2021).1.

PMID:36920914 | DOI:10.1016/j.xpro.2023.102162

Cell Rep. 2023 Mar 14;42(3):112252. doi: 10.1016/j.celrep.2023.112252. Online ahead of print.

ABSTRACT

Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.

PMID:36920903 | DOI:10.1016/j.celrep.2023.112252

Expert Rev Hematol. 2023 Mar;16(sup1):55-70. doi: 10.1080/17474086.2023.2175661.

ABSTRACT

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life.

RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities.

RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection.

CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

PMID:36920862 | DOI:10.1080/17474086.2023.2175661

Mol Biol Rep. 2023 Mar 15. doi: 10.1007/s11033-023-08345-0. Online ahead of print.

ABSTRACT

Interactomics is a branch of systems biology that deals with the study of protein-protein interactions and how these interactions influence phenotypes. Identifying the interactomes involved during host-pathogen interaction events may bring us a step closer to deciphering the molecular mechanisms underlying plant defence. Here, we conducted a systematic review of plant interactomics studies over the last two decades and found that while a substantial progress has been made in the field, plant-pathogen interactomics remains a less-travelled route. As an effort to facilitate the progress in this field, we provide here a comprehensive research pipeline for an in planta plant-pathogen interactomics study that encompasses the in silico prediction step to the validation step, unconfined to model plants. We also highlight four challenges in plant-pathogen interactomics with plausible solution(s) for each.

PMID:36920596 | DOI:10.1007/s11033-023-08345-0