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Acknowledgements: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service (NHS) England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. GS was performed by Illumina at Illumina Laboratory Services and was overseen by Genomics England. We thank all NHS clinicians who have contributed clinical phenotype data to the 100,000 Genomes Rare Diseases Programme and all staff at Genomics England who have contributed to the sequencing, maintenance of the research environment and assembly of the standard bioinformatic files that were required for our analyses. We thank the participants of the rare diseases program who made this research possible. We are grateful to V. Keeley for providing access to paternal DNA (ERG), F. Elmslie for inviting a patient to the clinic (ERG) and T. Jaworek for technical assistance (GPR156). D.G. was supported by the Cambridge British Heart Foundation (BHF) Centre of Research Excellence (RE/18/1/34212) and the Wellcome Collaborative (219506/Z/19/Z). V.H. was supported by an Medical Research Council (MRC)/National Institute for Health and Care Research Clinical Academic Research Partnership (MR/V037617/1). G.M.B. and K. Frudd were funded by BHF (PG/17/33/32990). G.M.B. and D.P. were funded by BHF (PG/20/16/35047). E.S. was supported by the Swiss Federal National Fund for Scientific Research (CRSII5_177191/1). S.M. and P.O. were supported by the MRC (MR/P011543/1) and BHF (RG/17/7/33217). K. Freson was supported by Katholieke Universiteit (KU) Leuven Special Research Fund (BOF) (C14/19/096) and Research Foundation – Flanders (G072921N). Work at the University of Maryland, Baltimore was supported by the National Institute on Deafness and Other Communication Disorders/National Institutes of Health (R01DC016295 to Z.M.A.). M.A.-O., F.I. and K.R. were supported by the King Salman Center for Disability Research (85722). E.T. was supported by the Mindich Child Health and Development Institute, the Charles Bronfman Institute for Personalized Medicine and the Lowy Foundation USA., Funder: Cambridge BHF Centre of Research Excellence [RE/18/1/34212] and Wellcome Collaborative Award 219506/Z/19/Z, Funder: BHF Project grant PG/17/33/32990, Funder: Swiss National Science Foundation grant CRSII5_177191, Funder: King Salman Center for Disability Research # 85722, Funder: MRC/NIHR Clinical Academic Research Partnership MR/V037617/1, Funder: Medical Research Council grant MR/P011543/1 and British Heart Foundation grant RG/17/7/33217, Funder: NIDCD/NIH R01DC016295, Funder: BHF Project grants PG/20/16/35047 & PG/17/33/32990, Funder: KULeuven BOF grant C14/19/096, FWO grant G072921N, The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.

Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity.

A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) to a target adenine N1, and recently, high-resolution crystal structures have become available. We use a combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) and alchemical free energy (AFE) simulations to elucidate the atomic-level solution mechanism of MTR1. Simulations identify an active reactant state involving protonation of C10 that hydrogen bonds with O6mG:N1. The deduced mechanism involves a stepwise mechanism with two transition states corresponding to proton transfer from C10:N3 to O6mG:N1 and rate-controlling methyl transfer (19.4 kcal·mol−1 barrier). AFE simulations predict the pKa for C10 to be 6.3, close to the experimental apparent pKa of 6.2, further implicating it as a critical general acid. The intrinsic rate derived from QM/MM simulations, together with pKa calculations, enables us to predict an activity–pH profile that agrees well with experiment. The insights gained provide further support for a putative RNA world and establish new design principles for RNA-based biochemical tools.

Der Cyberspace ist ein ständig wachsendes und modernisiertes Umfeld, das angesichts der Interkonnektivität Chancen für die digitale Transformation bietet. Aus der Integration der physischen Umgebung mit der virtuellen Welt entstehen jedoch auch Herausforderungen, die im Ökosystem der Industrie 4.0 gelöst werden müssen. So führen Konnektivität, Virtualisierung und Digitalisierung sowie Charakteristika des Engineerings (E4.0) zu Herausforderungen in Bezug auf die Cybersicherheit in einem Ökosystem, das Cyber-physische Systeme (CPS) und Digitale Zwillinge (DZ) integriert. Die Verwendung digitaler Geräte durch Konnektivität im Product Lifecycle Management (PLM) kann die Angriffsfläche für Cyber-Attacken erhöhen. Daher soll in diesem Beitrag ein Ansatz für die wichtigsten Cybersicherheitsrisiken vorgestellt werden, die durch die Integration von I4.0-Technologien in Produktionsumgebungen entstehen können. Zudem wird ein spezifischer Fahrplan für die PLM-Cybersicherheit vorgestellt und Beiträge zur Cybersicherheit im DZ erörtert.

The objective of this study is to assess the efficiency of flood control measures implemented in the Audi-União District, located on the Iguaçu River floodplain in the city of Curitiba, Brazil, by the application of hydrological-hydraulic modeling using HEC-HMS and HEC-RAS software packages. The scenarios of the years of 2014, 2024 and 2034 with return periods of 10, 25, 50 and 100 years were analyzed. It was observed that the set of hydraulic structures located upstream of Audi-União District can reduce the peak flow at the beginning of the Iguaçu River by 31.4% and the flood area by 35.1%, considering the period of return of 100 years and the land use of 2014. Regarding the measures implemented directly by the Audi-União District, it was observed that the built levee can control floods in the area, except for a small area that is not protected by the levee, in both 2014 and future scenarios. The creation of the Iguaçu Environmental Protection Area and the relocation of families, which were non-structural measures implemented in the region, also proved to be efficient, considering that these areas would suffer from flooding even for rainfall events with a period of return of 10 years. Keywords: Flood control, HEC-HMS, HEC-RAS.

Background: Metaplastic breast cancer (MpBC) is a rare, lethal, and highly chemoresistant breast cancer subtype, with no FDA-approved therapeutic options. Most MpBCs are triple-negative, yet have a worse prognosis than non-metaplastic triple-negative breast cancer (non-MpTNBC). MpBC tumors are enriched for markers of epithelial-to-mesenchymal transition (EMT)/cancer stem cells (CSC), produce high nitric oxide (NO) levels, and have a hyperactive phosphoinositide 3-kinase (PI3K) signaling pathway. Increased PI3K and inducible nitric oxide synthase (iNOS) activity are poor prognostic indicators in MpBC. NO can activate multiple oncogenic pathways spatially and temporally, such as PI3K and transforming growth factor beta (TGFβ), a critical regulator of EMT. Therefore, our study evaluates whether pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) augments the efficacy of alpha isoform-specific PI3K inhibitor alpelisib in MpBC in vitro and in vivo models. Methods: MpBC cell lines (SUM159, BT549, Hs578T, HCC1806) and Patient-Derived Xenograft (PDX) models were used in our studies. Droplet digital polymerase chain reaction (ddPCR) was conducted to evaluate the iNOS-associated mutation (RPL39 A14V) and PIK3CA hotspot mutation rates in PDX models. Cell viability (SRB/Cell Titer-Glo), combination index (CI), immunoblotting, and immunofluorescence of treated MpBC cell lines and tumor tissues were evaluated. Results: Immunostaining analysis revealed that MpBC PDX tumors had elevated co-expression of iNOS and pAkt (60% vs 23%, p=0.0495) relative to non-MpTNBC PDX tumors. MpBC PDX tumors had higher RPL39 A14V (66% vs 4.7%, p< 0.0006) and PIK3CA hotspot mutation rates (50% vs 19.1%, p=0.1247) than non-MpTNBC PDX tumors. Combining L-NMMA with alpelisib was synergistic in MpBC cell lines harboring PIK3CA/PIK3R1 mutations (CI< 1) and antagonistic in PIK3CA-wild type and PTEN-deleted models (CI>1). In vivo evaluation using MpBC PDX tumors found that L-NMMA significantly augmented the efficacy of alpelisib in reducing tumor volume in PIK3CA-mutated MpBC PDX models. Transcriptomic analysis found gene sets associated with EMT reversal, such as the formation of cornified envelope (Padj = 0.0254) and keratinization pathway (Padj = 0.048) were enriched pathways in MpBC PDX tumors that responded to combination therapy. Pharmacological and genomic inhibition of iNOS reversed EMT in MpBC cells, as shown by decreased expression of Zeb1, TGFβ, Snail, Vimentin, and increased expression of E-cadherin and ZO-1 in immunoblotting analysis. MpBC cells with NOS2 knockout acquired an epithelial-like cellular morphology and this reversal of EMT rendered MpBC cells more sensitive to alpelisib and taxane-chemotherapy. MpBC PDX tumors that responded to combination therapy also exhibited a reversal in EMT, with an associated decrease in aldehyde dehydrogenase (ALDH1), a CSC marker. L-NMMA and alpelisib therapy also resulted in the loss of tumor-initiating ability, enhanced chemosensitivity, and improved overall survival in MpBC PDX models. These studies paralleled results from a phase 1b/2 clinical trial with L-NMMA combined with taxane chemotherapy in a cohort of anthracycline-refractory MpBC patients (n=15, NCT02834403). The clinical benefit rate was 40% (6/15), the overall response rate was 20% (3/15), and one patient achieved a pathologic complete response. Relative to baseline tumors, the responder end-of-treatment tumors had undergone reversal of EMT, with enhanced expression of E-cadherin, and decreased expression of iNOS, Zeb1, and ALDH1. Conclusion: Our findings suggest that combining L-NMMA and alpelisib is a novel therapeutic strategy to treat MpBC by reversing EMT and decreasing CSCs, rendering MpBC tumors more chemosensitive. This combination therapy is being tested in a first multicenter phase 2 study targeting this orphan disease. Citation Format: Tejaswini Reddy, Akshjot Puri, Liliana Guzman, Wei Qian, Jianying Zhou, Roberto Rosato, Hong Zhao, Christoforos Thomas, Xiaoxian Li, Bijan Mahboubi, Adrian Oo, Young-Jae Cho, Baek Kim, Jose Thaiparambil, Camila Ayerbe, Noah Giese, Stacy Moulder, Helen Piwnica-Worms, Funda Meric-Bernstam, Jenny Chang. NOS inhibition reverses epithelial-to-mesenchymal transition and synergizes with alpelisib in metaplastic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-05.

Background (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients. Patients and methods Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients. Results PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients. Conclusion Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.

We develop a framework for the design of optimized alchemical transformation pathways in free energy simulations using nonlinear mixing and a new functional form for so-called "softcore" potentials. We describe the implementation and testing of this framework in the GPU-accelerated AMBER software suite. The new optimized alchemical transformation pathways integrate a number of important features, including (1) the use of smoothstep functions to stabilize behavior near the transformation end points, (2) consistent power scaling of Coulomb and Lennard-Jones (LJ) interactions with unitless control parameters to maintain balance of electrostatic attractions and exchange repulsions, (3) pairwise form based on the LJ contact radius for the effective interaction distance with separation-shifted scaling, and (4) rigorous smoothing of the potential at the nonbonded cutoff boundary. The new softcore potential form is combined with smoothly transforming nonlinear λ weights for mixing specific potential energy terms, along with flexible λ-scheduling features, to enable robust and stable alchemical transformation pathways. The resulting pathways are demonstrated and tested, and shown to be superior to the traditional methods in terms of numerical stability and minimal variance of the free energy estimates for all cases considered. The framework presented here can be used to design new alchemical enhanced sampling methods, and leveraged in robust free energy workflows for large ligand data sets.

Background: Normative motor skill assessments occupy a privileged position in physical education scholarship and practice. So much so, in fact, they manifest as commonsense cultural arrangements in most movement contexts, including adapted physical education. The proliferation of such tools has generally been uncontested, until now. Purpose: We argue that normative motor skill assessments have ableist underpinnings and consequently may do more to subordinate, rather than empower disabled children. More specifically, we suggest that normative motor assessment tools and criteria, perhaps unintentionally, highlight what is perceived to be wrong, bad, and faulty about the ways disabled bodies look and move, thus reinforcing ableist norms and values relating to ability. Conclusions: We end by encouraging adapted physical education scholars and practitioners to critically reflect on ableist notions of ability, particularly as they relate to movement competence, and to work with disabled children because of their embodied experiences to co-design assessments that are more meaningful to disabled children.

Nematode larvae can cause damage to fish and diseases to consumers. In this paper we record the first occurrence of Hysterothylacium sp. in Hoplias malabaricus captured by artisanal fishers in the Poti River, State of Piauí, northeast Brazil. In the laboratory the fish were investigated for the collection of helminths. Sixteen hosts (63.3%) were parasitized by 94 nematodes larvae that were morphologically identified as Hysterothylacium sp. parasitizing the liver, intestine, stomach, pyloric cecum, abdominal cavity and swim bladder. The parasitic diversity in H. malabaricus is composed of thirty-two taxa, with the larvae of Contracaecum being dominant. This work records the parasitological inventory of nematodes in H. malabaricus and we add morphological and morphometric data for Hysterothylacium sp. in the state of Piauí, parasitizing fish of commercial importance.

Green chemistry developed historically from twelve industrial principles for research chemists. Recently, interest has grown to begin introducing these principles in science classrooms even at the secondary and pre-secondary school levels. However, teachers must do significant work to adapt and translate green chemistry from the industrial or manufacturing perspective into one more appropriate to students at younger ages. This research project explores how a group of current teachers in the US and Canada have been developing their language and understanding of green chemistry through Beyond Benign's Lead Teacher Program. Transcripts from phone interviews with program participants are analyzed to propose a classroom-based definition of green chemistry and its justification as an approach at the secondary and pre-secondary school levels. This pedagogical understanding provides a foundation to solidify green chemistry as a standard practice in science education. Then classroom observations and case studies of four teachers are developed into a framework for green chemistry education at the K-12 level.

Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaption to hypoxia and are considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared to WT mice. In Phd3 -/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages (TAMs) in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin ( Ereg) in macrophages, and (iii) augmented signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic ( Vav:Cre-Phd2f/f) but not in intestinal epithelial cells ( Villin:Cre-Phd2f/f) increased CAC growth. In conclusion, the three different PHD isoenzymes have distinct and non-redundant, either promoting (PHD1), diminishing (PHD2), or neutral effects (PHD3) on CAC growth. KBK received funding from the German Cancer Aid. MJS. received funding from the German Research Foundation (DFG; STR 1570/1-1) and the Braun Foundation (Braun®; BBST-D-18-00018). MSch received funding from the German Federal Ministry of Education and Research (BMBF; 031L0084). JMH received funding from the Heidelberg Stiftung Chirurgie. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The 6TM family of K channels comprises the voltage-gated KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+-activated Slo subfamily (actually with 7TM, termed BK) and the Ca2+-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. Kv1.1 with Kv1.2; Kv7.2 with Kv7.3). The pharmacology largely reflects the subunit composition of the functional channel.

Background/Aim: The solitary fibrous tumor (SFT) is a mesenchymal neoplasm and belongs to the group of soft tissue sarcomas. The SFT is characterized by indolent, slowly progressive growth and manifests itself clinically by compression of neighboring structures. The treatment of choice is surgical removal of the tumor. In advanced stages, there is also the possibility of chemotherapy, systemic therapy, or immunotherapy, as well as radiotherapy. Depending on their location and severity, SFTs show different recurrence rates and survival functions. Case Report: The present case report shows an extremely rare localization of a low-risk SFT in the floor of the mouth. Despite complete surgical removal of the SFT, the patient showed a metastasis of the SFT in the mandible two years postoperatively. Therefore, this case report shows that even a low-risk SFT in the localized stage can metastasize despite of total surgical removal. Consequently, SFTs of the head and neck region require close clinical and imaging follow-up. Conclusion: Although the localization of the SFT in the oral cavity is a rarity, this entity should be included in the differential diagnosis in the case of long-term space-occupying processes in the head and neck region. This report is the first regarding metastasis of a SFT to the mandible.

At present, national competitiveness is presented as a means of fighting for a place in the world economic system. The issue of formation, ensuring and increasing the competitiveness of the national economy of the Republic of Kazakhstan is the main issue in the development of the Strategy "Kazakhstan–2050", "Strategy "Kazakhstan–2030", the Strategic Development Plan of the Republic of Kazakhstan until 2025 and other government programs aimed at modernizing the economy of the state [1].The purpose of this article is to investigate the impact of human capital on economic development. Transnationalization of economic relations and globalization of markets intensify competition between countries and large corporations for influence and markets, which in turn leads to new methods and means of competition. The development of human capital makes it possible to introduce innovations, adapt the economy to the conditions of globalization, and achieve high competitiveness. In the conditions of globalization of the world economy the country faces acute problems, such as: general technical and technological backwardness of enterprises, raw material orientation of economy, underdevelopment of production infrastructure, low integration into the world economy, underdevelopment of social infrastructure. Lack of effective communication between science and production, low costs of R&D, design work, etc. To solve these problems it will be necessary to create in Kazakhstan a competitive knowledge-intensive economy, which can become the basis of public welfare. In the future, Kazakhstan needs to create an innovative, post-crisis economy, i.e. knowledge-based economy, which creates opportunities for practical use of human intellectual capital in the development of areas requiring knowledge, provides the transition to the sixth economic paradigm, takes the features of the intellectual economy.

Background Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinical significance in GC patients. Methods Using GC cell lines and patient-derived xenografts, we evaluated CD44+ and CD44v3+ GC cells molecular signature and their tumorigenic, chemoresistance, invasive and metastatic properties, and expression in patients-derived tissues. Results CD44v3+ cells, which represented a subpopulation of CD44+ cells, were detected in advanced preneoplastic lesions and presented CSCs chemoresistance and tumorigenic properties in vitro and in vivo. Molecular and functional analyses revealed two subpopulations of gastric CSCs: CD44v3+ CSCs with an epithelial-mesenchymal transition (EMT)-like signature, and CD44+/v3– CSCs with an epithelial-like signature; both were tumorigenic but CD44v3+ cells showed higher invasive and metastatic properties in vivo. CD44v3+ cells detected in the primary tumours of GC patients were associated with a worse prognosis. Conclusion CD44v3 is a marker of a subpopulation of CSCs with metastatic properties in GC. The identification of metastasis-initiating cells in GC represents a major advance for further development of anti-metastatic therapeutic strategies.

Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.

Background and ObjectivesWhile chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological “brain age.” We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes.MethodsWe extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input.ResultsWe reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years,r= 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; allp-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes.DiscussionT2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Blue phases (BPs), a unique manifestation of chirality in the liquid crystalline state, have gained considerable attention due to the unusual combination of properties such as sub-millisecond response times to electrical fields and Bragg reflection of circularly polarised light. Initially they were regarded as promising materials for the development of the next-level display technologies. However, in recent years, they have gained increasing attention as responsive photonic materials with sensing or optoelectronics properties (photonic mirrors and filters). A major limitation so far has been their narrow temperature range in which they usually exist. The aim of the present review is to summarise the recent efforts made to stabilise BPs by employing specific non-covalent bonds and the principles of supramolecular chemistry.1 Introduction2 Stabilisation of Blue Phases by Supramolecular Methods2.1 Doping Approach2.2 Design Approach3 Conclusions and Outlook

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC.Experimental Design: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems.Results: PDAC overproduced several T-cell-active chemokines, but their levels were not correlated with intratumoral T-cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a β1-integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters.Conclusion: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell–directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cell–based immunotherapies. Clin Cancer Res; 20(13); 3422–33. ©2014 AACR.

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PDF file - 53KB, Phenotype of non-activated and activated T cells, representative FACS data of CD45RO/CCR7 (A) and CRs expression (B). Activated PBT displayed an effector/memory CD45RO+ CCR7- phenotype (A) and mainly expressed CXCR4 and CXCR3 (B).

Purpose: To enhance T-cell responsiveness toward cancer cells, we overexpressed TRAIL in lymphocytes, as this death ligand induces tumor-specific apoptosis. To increase contact time of lymphocytes with tumor cells and thereby of TRAIL with its death receptors, lymphocytes were linked to the CD3 arm of bispecific antibody EpCAMxCD3, to guide the lymphocytes to tumor cells positive for the cancer stem cell marker EpCAM/ESA.Experimental Design: Lymphocytes were transduced with TRAIL lentivirus and the antitumor effect in presence and absence of EpCAMxCD3 was evaluated in vitro and in xenograft studies using epithelial cell adhesion molecule (EpCAM)–positive pancreatic and prostate cancer cells.Results: Compared with control lymphocytes, TRAIL-lymphocytes increased cytotoxicity and further induced expression of several apoptosis-related molecules. Cotransplantation of TRAIL-lymphocytes and tumor cells in mice or peritumoral injection of TRAIL-lymphocytes in larger xenografts retarded growth and induced apoptosis. Combination of TRAIL-lymphocytes with EpCAMxCD3 potentiated tumor eradication by enhancing antiapoptotic and antiproliferative signaling and by decreasing tumor vasculature. Intratumoral cyst formation was involved and associated with enhanced chemokine secretion and infiltration of mouse macrophages, suggesting contribution of an inflammatory host response. Most importantly, tumorigenicity of pancreatic cancer cells with cancer stem cell features resistant to conventional chemotherapy was strongly reduced.Conclusions: This gene-immunotherapeutic approach may be a new tool to support endogenous immune responses toward cancer even in its advanced stages. Clin Cancer Res; 18(4); 1028–38. ©2012 AACR.

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PDF file - 44KB, T cell migration in response to SDF-1 and IP-10 in collagen matrix of different densities with and without beta1-integrin blockade. Migration of activated PBTs in a collagen type I matrix was not changed through the uniform chemokine concentration and was independent of beta1-integrin blockade.

The purpose of this work is to study the process of telemedicine implementation in the context of digitalization of Kazakhstan to identify problems. Development of recommendations for solving these problems, both in the public and in the private sectors of medical services. The scientific significance of the work lies in the contribution of new knowledge on the issue of telemedicine in the example of Kazakhstan, since this issue has been underxplored. The results of this study can be used to further develop the digitalization process of healthcare in the Republic of Kazakhstan. A qualitative method is used, a semi-structured interview with experts in the field of telemedicine implementation was conducted. Atlas.ti software is used for data processing. As a result of the analysis of the interviews, the limitations and problems of the implementation of telemedicine in the country were identified, such as high costs for the provision of IT services and the quality of the Internet, as well as the government’s weak interest in cooperation with the private sector. However, despite these obstacles, the private sector is interested in implementing telemedicine. Analysis of world official data showed that the telemedicine market is growing rapidly, and there is a demand for consultations using telemedicine in the Kazakhstani market. Therefore, there is a need to develop this direction. Recommendations were offered to solve the problems of telemedicine implementation in Kazakhstan. Eliminating the identified problems can accelerate the process of healthcare digitalization, which is a contribution to the development of this area.

4D Flow MRI is a quantitative imaging technique to evaluate blood flow patterns; however, it is unclear how compressed sensing (CS) acceleration would impact aortic hemodynamic quantification in type B aortic dissection (TBAD).To investigate CS-accelerated 4D Flow MRI performance compared to GRAPP-accelerated 4D Flow MRI (GRAPPA) to evaluate aortic hemodynamics in TBAD.Prospective.Twelve TBAD patients, two volunteers.1.5T, 3D time-resolved cine phase-contrast gradient echo sequence.GRAPPA (acceleration factor [R] = 2) and two CS-accelerated (R = 7.7 [CS7.7] and 10.2 [CS10.2]) 4D Flow MRI scans were acquired twice for interscan reproducibility assessment. Voxelwise kinetic energy (KE), peak velocity (PV), forward flow (FF), reverse flow (RF), and stasis were calculated. Plane-based mid-lumen flows were quantified. Imaging times were recorded.Repeated measures analysis of variance, Pearson correlation coefficients (r), intraclass correlation coefficients (ICC). P 0.05 indicated statistical significance.The KE and FF in true lumen (TL) and PV in false lumen (FL) did not show difference among three acquisition types (P = 0.818, 0.065, 0.284 respectively). The PV and stasis in TL were higher, KE, FF, and RF in FL were lower, and stasis was higher in GRAPPA compared to CS7.7 and CS10.2. The RF was lower in GRAPPA compared to CS10.2. The correlation coefficients were strong in TL (r = [0.781-0.986]), and low to strong in FL (r = [0.347-0.948]). The ICC levels demonstrated moderate to excellent interscan reproducibility (0.732-0.989). The FF and net flow in mid-descending aorta TL were significantly different between CS7.7 and CS10.2.CS-accelerated 4D Flow MRI has potential for clinical utilization with shorter scan times in TBAD. Our results suggest similar hemodynamic trends between acceleration types, but CS-acceleration impacts KE, FF, RF, and stasis more in FL.1 Technical Efficacy: Stage 2.

A história recente, com o advento da pandemia, tem requerido reflexões profundas sobre formas de viver socialmente, com impactos na gestão do tempo e na organização do espaço. Na educação, o ensino on-line tornou-se fundamental, e pensar atividades práticas de projeto a distância, um desafio. O objetivo desse trabalho é apresentar e discutir oficinas criativas como instrumentos metodológicos para análise do entendimento dos ingressantes em curso de Arquitetura e Urbanismo acerca da percepção sobre o mobiliário urbano. A partir de referenciais teóricos que perpassam os campos do Design, da Arquitetura e da Educação, a metodologia adotada para dinamização das oficinas apresentou um panorama geral sobre os temas e propôs o croqui como meio de expressão de ideias para intervenção na cidade através do mobiliário urbano. Como resultado, pré-selecionamos 54 desenhos confeccionados pelos estudantes, dentre os quais 14 são destacados como categorias temáticas para discussão sobre o espaço público da cidade contemporânea. Conclui-se que a estruturação das oficinas apoiada no uso de croquis sobre os temas destacados mostrou-se efetiva para reflexão sobre o momento vivido e como atividade agregadora para alunos em ambiente remoto.

Sleep-related infant death is a major cause of infant mortality in the United States. In the District of Columbia, infant mortality varies widely among regions (2 to 14 per 1000 live births). The study objectives were to analyze the patient characteristics and related variables to sudden unexpected infant deaths at 2 pediatric emergency department (ED) sites and the geographic patterns of infant deaths and their relationship to social vulnerability. This retrospective cohort study examined infants under 1 year of age presenting with cardiac arrest at 2 ED sites from 2010 to 2020. Analysis showed 81 deaths with a median population age of 75 days (SD, 46 days). The most frequent demographics of deceased patients were African American Black (89%) with Medicaid insurance (63%), born at term gestation (66%), and without comorbidity (60%). The cause of death was most frequently undetermined (32%) and asphyxia (31%). Most cases involved bed-sharing (63%), despite more than half of those cases having a known safe sleep surface available. Infant death location showed that most deaths occurred in areas with the highest social vulnerability index, including near a community ED location. Understanding the etiologies of this geographic variability may enhance sleep-related infant death prevention strategies.

Objective In Cushing’s disease (CD), detection of an adenoma by MRI is challenging. The aim of this study is to compare real-life MRI in the initial diagnostic workup of CD with high-quality MRI performed in a tertiary center for pituitary diseases. Design and methods We retrospectively analyzed 139 patients with CD who underwent primary transsphenoidal surgery (TSS) in our department and had both an MRI conducted at a different institution (external MRI; extMRI) and an MRI conducted at our institution (internal MRI; intMRI). Preoperative interpretation of MRI was performed independently by an external radiologist (extRAD), an internal neuroradiologist (intRAD) and a pituitary surgeon (SURG). Intraoperative detection of an adenoma and endocrinological remission provided proof of the true adenoma localization in 105 patients. Results Interpretation of extMRI by extRAD and SURG was concordant in only 64% (89/139) of cases, while 74.1% (103/139) concordance was observed for interpretation of intMRI by intRAD and SURG. Based on extMRI, the true localization of the adenoma was correctly predicted in only 46.7% of the patients by extRAD and in 65.7% by SURG. In contrast, the sensitivity to correctly identify the adenoma on intMRI was 80.0% for intRAD and 94.3% for SURG. Conclusion Both the quality of MRI and the reader’s experience are paramount for detection of microadenomas in CD. Every effort should be made to perform high-quality initial MRI according to current standards and to ensure rating by an expert in pituitary imaging.

To evaluate hemodynamic markers obtained by accelerated GRAPPA (R = 2, 3, 4) and compressed sensing (R = 7.6) 4D flow MRI sequences under complex flow conditions.The accelerated 4D flow MRI scans were performed on a pulsatile flow phantom, along with a nonaccelerated fully sampled k-space acquisition. Computational fluid dynamics simulations based on the experimentally measured flow fields were conducted for additional comparison. Voxel-wise comparisons (Bland-Altman analysis,mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:semanticsmml:mrowmml:msubmml:miL/mml:mimml:mn2/mml:mn/mml:msub/mml:mrowmml:annotation$$ {L}_2 $$/mml:annotation/mml:semantics/mml:math-norm metric), as well as nonderived quantities (velocity profiles, flow rates, and peak velocities), were used to compare the velocity fields obtained from the different modalities.4D flow acquisitions and computational fluid dynamics depicted similar hemodynamic patterns. Voxel-wise comparisons between the MRI scans highlighted larger discrepancies at the voxels located near the phantom's boundary walls. A trend for all MR scans to overestimate velocity profiles and peak velocities as compared to computational fluid dynamics was noticed in regions associated with high velocity or acceleration. However, good agreement for the flow rates was observed, and eddy-current correction appeared essential for consistency of the flow rates measurements with respect to the principle of mass conservation.GRAPPA (R = 2, 3) and highly accelerated compressed sensing showed good agreement with the fully sampled acquisition. Yet, all 4D flow MRI scans were hampered by artifacts inherent to the phase-contrast acquisition procedure. Computational fluid dynamics simulations are an interesting tool to assess these differences but are sensitive to modeling parameters.