bluuebunny/crossref_metadata_2025 huggingface dataset:
Freely acting orbifolds of type IIB string theory on T5
Authors: Gkountoumis George , Hull Chris , Stemerdink Koen , Vandoren Stefan
Published: August 2023

Abstract

We study freely acting orbifolds of type IIB string theory on T5 that spontaneously break supersymmetry from $$ \mathcal{N} $$
N
= 8 to $$ \mathcal{N} $$
N
= 6, 4, 2 or 0 in five dimensions. We focus on orbifolds that are a ℤp quotient by a T-duality acting on T4 and a shift on the remaining S1. Modular invariant partition functions are constructed and detailed examples of both symmetric and asymmetric orbifolds are presented, including new examples of five-dimensional non-supersymmetric string theories with no tachyons. The orbifolds we consider arise at special points in the moduli space of string theory compactifications with a duality twist. The supergravity limit of these are Scherk-Schwarz reductions which generate gauged supergravities with positive definite classical potentials on the moduli space in five dimensions. Both symmetric and asymmetric freely acting orbifolds give a landscape of Minkowski vacua. For gauged supergravities to belong to this landscape, we find a number of constraints and conditions. Firstly, the scalar potential should lead to a massive spectrum with masses that obey quantization conditions arising from a string theory orbifold, which we discuss in detail. Secondly, we find constraints on the massless sector, e.g. in the examples of orbifolds preserving sixteen supersymmetries in five dimensions that we consider, only an odd number of vector multiplets arises. Lastly, we present new examples of candidate asymmetric orbifolds with modular invariant partition functions, but with non-integral coefficients in the $$ q\overline{q} $$
q

q
¯

-expansion in the twisted sectors.
Heart rate variability as a predictor of successful catheter-guided pulmonary vein isolation for atrial fibrillation
Authors: Drexler M. , Blum T. , Heinroth K. M. , Hartkopf T. , Plehn A. , Schirdewahn P. , Sedding D. G.
Published: August 2023

Background

This retrospective observational study investigated the relationship between heart rate variability (HRV) and atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) by cryoballoon or radiofrequency ablation (RF).

Methods

We enrolled 497 patients who underwent PVI using first-generation cryoballoon (CB1), second-generation cryoballoon (CB2), or RF. We analyzed HRV as a surrogate for modulation of the intrinsic autonomic nervous system using 24‑h Holter recordings 1 or 2 days after the procedure and compared the recurrence and non-recurrence group with regard to ablation methods. Furthermore, we calculated recurrence-free survival (RFS) below/over HRV cut-off values for the whole study population and separately for each ablation method.

Results

All except one of the five time-based HRV parameters analyzed were significantly lower in the non-recurrence group than in the recurrence group after CB2. Only a trend toward lower HRV for the non-recurrence group was found after RF and no remarkable differences were detected after CB1. The HRV parameters below their calculated cut-off were associated with a significantly higher RFS rate 2 years after CB2. This also applied to root mean sum of squared distance (rMSSD) and the percentage of adjacent NN interval differences greater than 50 ms (pNN50) after RF. No differences were found regarding CB1. Concerning rMSSD, the sensitivity, specificity, and difference in RFS increased when using cut-offs that were calculated including only CB2 patients. Multivariate cox regression analysis showed that low rMSSD values could independently predict AF recurrence after adjusting for covariates (hazard ratio: 0.50;p < 0.001).

Conclusion

Low values of rMSSD early after a PVI could independently predict AF recurrence, especially after CB2.
Time-Asymptotic Expansion with Pointwise Remainder Estimates for 1D Viscous Compressible Flow
Authors: Koike Kai
Published: August 2023

We construct a time-asymptotic expansion with pointwise remainder estimates for solutions to 1D compressible Navier–Stokes equations. The leading-order term is the well-known diffusion wave and the higher-order terms are a newly introduced family of waves which we call higher-order diffusion waves. In particular, these provide an accurate description of the power-law asymptotics of the solution around the origin $$x=0$$

x
=
0

, where the diffusion wave decays exponentially. The expansion is valid locally and also globally in the $$L^p({\mathbb {R}})$$

L
p

(
R
)

-norm for all $$1\le p\le \infty $$

1
≤
p
≤
∞

. The proof is based on pointwise estimates of Green’s function.
Analytical factors for eight short-chain fatty acid analyses in mouse feces through headspace solid-phase microextraction–triple quadrupole gas chromatography tandem mass spectrometry
Authors: Kang Sunhee , Yun Jeonghyun , Park Ho-Young , Lee Jang-Eun
Published: August 2023

This study developed a method for quantifying eight short-chain fatty acids (SCFAs) in mouse fecal samples using solid-phase microextraction (SPME) coupled with triple quadrupole gas chromatography tandem mass spectrometry. Furthermore, significant factors affecting SCFA analysis, including SPME fiber selection, pH, salting-out agent, and sample collection time, were investigated. Contrary to previous studies, we found that the CAR/PDMS fiber had the highest extraction efficiency for all SCFAs. The optimal extraction efficiency was observed at pH 2.0, particularly for low-molecular-weight SCFAs. NaH2PO4 showed a more effective extraction efficiency than NaCl, owing to its pH stability and less interference with the solvent matrix. Additionally, our results showed that the SCFA concentration increased over collection time. The composition ratio of the eight SCFAs was maintained for up to 24 h; thus, we concluded that samples should be collected within four hours to obtain reliable results. Our findings may improve laboratory methods for SCFA extraction and mouse fecal sample analysis.

Graphical Abstract
Step away from depression—results from a multicenter randomized clinical trial with a pedometer intervention during and after inpatient treatment of depression
Authors: Große Julia , Huppertz Charlotte , Röh Astrid , Oertel Viola , Andresen Sara , Schade Niklas , Goerke-Arndt Franziska , Kastinger Anna , Schoofs Nikola , Thomann Philipp Arthur , Henkel Karsten , Malchow Berend , Plag Jens , Terziska Aleksandra , Brand Ralf , Helmig Frank , Schorb Alexander , Wedekind Dirk , Jockers-Scherübl Maria , Schneider Frank , Petzold Moritz Bruno , Ströhle Andreas
Published: August 2023

Evidence for the effectiveness of physical activity (PA) in the treatment of depression prevails for outpatients with mild and moderate symptom levels. For inpatient treatment of severe depression, evidence-based effectiveness exists only for structured and supervised group PA interventions. The Step Away from Depression (SAD) study investigated the effectiveness of an individual pedometer intervention (PI) combined with an activity diary added to inpatient treatment as usual (TAU). In this multicenter randomized controlled trial, 192 patients were randomized to TAU or TAU plus PI. The two primary outcomes at discharge were depression—blindly rated with the Montgomery–Åsberg Depression Rating Scale (MADRS)—and average number of daily steps measured by accelerometers. Secondary outcomes were self-rated depression and PA, anxiety, remission and response rates. Multivariate analysis of variance (MANOVA) revealed no significant difference between both groups for depression and daily steps. Mean MADRS scores at baseline were 29.5 (SD = 8.3) for PI + TAU and 28.8 (SD = 8.1) for TAU and 16.4 (SD = 10.3) and 17.2 (SD = 9.9) at discharge, respectively. Daily steps rose from 6285 (SD = 2321) for PI + TAU and 6182 (SD = 2290) for TAU to 7248 (SD = 2939) and 7325 (SD = 3357). No differences emerged between groups in secondary outcomes. For severely depressed inpatients, a PI without supervision or further psychological interventions is not effective. Monitoring, social reinforcement and motivational strategies should be incorporated in PA interventions for this population to reach effectiveness.
Bio-inspired, task-free continual learning through activity regularization
Authors: Lässig Francesco , Aceituno Pau Vilimelis , Sorbaro Martino , Grewe Benjamin F.
Published: August 2023

The ability to sequentially learn multiple tasks without forgetting is a key skill of biological brains, whereas it represents a major challenge to the field of deep learning. To avoid catastrophic forgetting, various continual learning (CL) approaches have been devised. However, these usually require discrete task boundaries. This requirement seems biologically implausible and often limits the application of CL methods in the real world where tasks are not always well defined. Here, we take inspiration from neuroscience, where sparse, non-overlapping neuronal representations have been suggested to prevent catastrophic forgetting. As in the brain, we argue that these sparse representations should be chosen on the basis of feed forward (stimulus-specific) as well as top-down (context-specific) information. To implement such selective sparsity, we use a bio-plausible form of hierarchical credit assignment known as Deep Feedback Control (DFC) and combine it with a winner-take-all sparsity mechanism. In addition to sparsity, we introduce lateral recurrent connections within each layer to further protect previously learned representations. We evaluate the new sparse-recurrent version of DFC on the split-MNIST computer vision benchmark and show that only the combination of sparsity and intra-layer recurrent connections improves CL performance with respect to standard backpropagation. Our method achieves similar performance to well-known CL methods, such as Elastic Weight Consolidation and Synaptic Intelligence, without requiring information about task boundaries. Overall, we showcase the idea of adopting computational principles from the brain to derive new, task-free learning algorithms for CL.
The immune microenvironment after neoadjuvant therapy compared to upfront surgery in patients with pancreatic cancer
Authors: Zwart Eline S. , van Ee Thomas , Doppenberg Deesje , Farina Arantza , Wilmink Johanna W. , Versteijne Eva , Busch Olivier R. , Besselink Marc G. , Meijer Laura L. , van Kooyk Yvette , Mebius Reina E. , Kazemier Geert
Published: August 2023

Background

Patients with resectable and borderline resectable pancreatic ductal adenocarcinoma increasingly receive neoadjuvant therapy prior to surgery. However, the effect of neoadjuvant therapy on the immune microenvironment remains largely unknown. We analyzed the immune microenvironment in pancreatic cancer tumor tissue samples from patients treated with neoadjuvant therapy compared to patients after upfront surgery to gain knowledge about the immunological environment after therapy.

Methods

Multispectral imaging was performed on tissue from resected specimens from patients with PDAC who underwent upfront surgery (n = 10), neoadjuvant FOLFIRINOX (n = 10) or gemcitabine + radiotherapy (gem-RT) (n = 9) followed by surgery. The samples were selected by a dedicated pancreas pathologist from both the central part and the invasive front of the tumor (by the resected vein or venous surface) and subsequently analyzed using the Vectra Polaris.

Results

Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile, with less regulatory T cells and more CD8 T cells in the tumor tissue compared to patients receiving neoadjuvant gem-RTgem-RT or undergoing upfront surgery. Furthermore, CD163+ macrophages were decreased, and a higher CD163− macrophages versus CD163+ macrophages ratio was found in patients with neoadjuvant FOLFIRINOX. In all treatment groups, percentage of FoxP3+ B cells was significantly higher in tumor tissue compared to adjacent tissue. Furthermore, an increase in regulatory T cells in the tumor tissue was found in patients undergoing upfront surgery or receiving neoadjuvant gem-RT. In the gem-RT group, less CD8 T cells and a higher CD163+ macrophages to CD8 ratio were noted in the tumor tissue, suggesting a more immune suppressive profile in the tumor tissue.

Conclusion

Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile compared to patients receiving neoadjuvant gem-RT or undergoing upfront surgery. Furthermore, in all treatment groups, a more immune suppressive microenvironment was found in the tumor tissue compared to the adjacent non-tumorous tissue.
Cumulative incidence of type 1 diabetes in two cohorts of children with different national gluten recommendations in infancy
Authors: Lindgren Marie , Palmkvist Elsa , Norström Fredrik , Cerqueiro Bybrant Mara , Myleus Anna , Samuelsson Ulf , Ludvigsson Johnny , Carlsson Annelie
Published: August 2023

Aims

Between 1985 and 1996, Sweden experienced an “epidemic” of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this “epidemic”. We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the “epidemic” compared to children born after.

Methods

This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0–17 years old born 1992–1993, during the “epidemic”, and 179 530 children born 1997–1998, after the “epidemic”. Children diagnosed with type 1 diabetes were identified using three national registers.

Results

The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the “epidemic” 0.77% than in those born during the “epidemic” 0.68% (p < 0.001).

Conclusion

The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.
Family and literature analysis demonstrates phenotypic effect of two variants in the calpain-3 gene
Authors: Tomforde Maike , Steinbach Meike , Haack Tobias B. , Kuhlenbäumer Gregor
Published: August 2023

Both, recessive (LGMD R1) and dominant (LGMD D4) inheritance occur in calpain 3-related muscular dystrophy. We report a family with calpain-related muscular dystrophy caused by two known variants in the calpain 3 gene (CAPN3, NM_000070.3; (I) c.700G>A, p.Gly234Arg and (II) c.1746-20C>G, p.?). Three family members are compound heterozygous and exhibit a relatively homogeneous phenotype characterized by progressive proximal weakness starting in the third to fourth decade of life in the shoulder girdle and spreading to the legs. Two family members affected only by the p.Gly234Arg heterozygous missense variants show a different phenotype characterized by severe exertional myalgia without overt pareses. We conclude that in our family, the missense variant causes a severe myalgic phenotype without pareses that is aggravated by the second intronic variant and put these findings in the context of previous studies of the same variants.
Professionalisierung Sozialer Arbeit – internationale Perspektiven
Authors: Gredig Daniel , Scherr Albert
Published: August 2023

Die Diskussion um Professionalität und Professionalisierung Sozialer Arbeit ist im deutschen Sprachraum mit einem Fokus auf Merkmale professionellen Handelns geführt worden. In international vergleichender Perspektive wird dagegen deutlich, dass Möglichkeiten und Schwierigkeiten von Professionalisierung von gesellschaftlichen Rahmenbedingungen sowie davon abhängig sind, welchen Einfluss die Selbstorganisationsstrukturen der Sozialen Arbeit auf Ausbildung, Zulassung zum Beruf und die Einhaltung fachlicher Standards haben.
Experimental and analytical investigations of the removal of spatters by various process gases during the powder bed fusion of metals using a laser beam
Authors: Baehr Siegfried , Klecker Tobias , Pielmeier Sebastian , Ammann Thomas , Zaeh Michael F.
Published: August 2023

The powder bed fusion of metals using a laser beam (PBF-LB/M) is increasingly being utilized in industrial applications. This is due to several advantages over conventional manufacturing processes when it comes to the fabrication of complex part designs. However, the process still poses various challenges that have to be overcome. One of these challenges is the formation of a significant amount of spatters and fumes. These could attenuate the laser beam or decrease the powder reusability. To lower their negative impact on the process and the mechanical properties of the parts, a process gas flow is used in PBF-LB/M to remove these by-products from the processing zone. This study was, therefore, dedicated to investigating the potential of various gases on the removal of spatters. The focus was placed on argon, helium, and their mixtures. After theoretical considerations determining the range of applicable gas flow velocities, the experimental results unveiled the real spread of spatters over the powder bed and their characteristics. Whilst the removal of spatters was found to be worse for an argon–helium gas mixture at comparable gas flow velocities, increasing the velocity turned out to be a proper measure to enhance the removal for low-density gases. At this flow condition, the use of the argon–helium gas mixture led to a similar removal of spatters and the creation of a lower spatter mass in total (reduced to 40%) compared to argon.
Falsch-positive – falsch-negative Befunde – Stellenwert der PSMA-PET/CT beim Staging von Patienten mit Prostatakarzinom
Authors: Lenart Sebastian , Maurer Tobias
Published: August 2023

Die PSMA-Positronenemissionstomographie (PET) findet seit über 10 Jahren Anwendung im Staging von Prostatakrebspatienten und stellt die Bildgebung mit der höchsten Sensitivität in der Ausbreitungsdiagnostik dar. Zahlreiche Studien aber zeigten, dass das prostataspezifische Membranantigen (PSMA) nicht nur auf Prostata- und Prostatakrebszellen vorkommt, sondern Anreicherungen des Tracers auch in anderen Organen, unabhängig vom Prostatakarzinom, stattfinden. Dies kann zu falsch-positiven Befunden führen, mit Beeinflussung der Therapieplanung. Aber auch falsch-negative Befunde können Therapieplanveränderungen bedeuten. Während die PSMA-PET/CT in der Primärdiagnostik (noch) einen eingeschränkten Stellenwert hat, ist sie in der Rezidivdiagnostik das bildgebende Verfahren der ersten Wahl.
Stanley Cavell's Democratic Perfectionism
Authors: Havercroft Jonathan
Published: August 2023

Post-truth politics is both a result of a democratic culture in which each person is encouraged to voice their opinion, and a threat to the continuation of democracy as partisans seek to deny political standing to those with incommensurate world views. Are there resources within political theory for overcoming this tension? This book argues that Stanley Cavell's philosophy provides a conceptual framework for responding to post-truth politics. Jonathan Havercroft develops an original interpretation of Stanley Cavell as a theorist of democratic perfectionism. By placing Cavell's writings in conversation with political theorists on debates about the social contract, interpretive methods, democratic theory and political aesthetics, Stanley Cavell's Democratic Perfectionism cultivates modes of responsiveness that strengthen our democratic culture and help us resist the contemporary crisis of democratic backsliding. Each chapter diagnoses a sceptical crisis in contemporary politics and a mode of responsiveness in Cavell's thought that can respond to that crisis.
Truth and Transparency
Authors: Chen Alan K. , Marceau Justin
Published: August 2023

While undercover investigators have been celebrated as critical conduits of political speech, they have also been derided as intrusive and spy-like, inconsistent with private property rights, and morally or ethically questionable. In Truth and Transparency, Alan Chen and Justin Marceau examine this distinction and provide clarity that has until now been lacking. The book concretely defines undercover investigations, distinguishes the practice from investigative journalism and whistleblowing, and provides a comprehensive legal history. Chapters explores the public need for investigations and the rights of investigators, paying close attention to the types of investigations that fall beyond the scope of constitutional protection. The book also provides concrete empirical evidence of the broad, bipartisan support for undercover investigations and champions the practice as an essential component of the transparency our democracy needs to thrive.
Milk coagulation properties are moderately heritable in dairy cows: a meta-analysis using the random-effects model
Authors: Ghavi Hossein-Zadeh Navid
Published: August 2023

This study aimed to conduct a meta-analysis using the random-effects model to merge published genetic parameter estimates for milk coagulation properties (MCP: comprising rennet coagulation time (RCT), curd-firming time (k20), curd firmness 30 min after rennet addition (a30), titrable acidity (TA) and milk acidity or pH) in dairy cows. Overall, 80 heritability estimates and 157 genetic correlations from 23 papers published between 1999 and 2020 were used. The heritability estimates for RCT, a30, k20, TA, and pH were 0.273, 0.303, 0.278, 0.189 and 0.276, respectively. The genetic correlation estimates between RCT-a30, RCT-pH, and RCT-TA were 0.842, 0.549 and −0.565, respectively. Genetic correlation estimates between RCT and production traits were generally low and ranged from −0.142 (between RCT and casein content) to 0.094 (between RCT and somatic cell score). Moderate and significant genetic correlations were observed between a30-pH (−0.396) and a30-TA (0.662). Also, the genetic correlation estimates between a30 and production traits were low to moderate and varied from −0.165 (between a30 and milk yield) to 0.481 (between a30 and casein content). Genetic correlation estimates between pH and production traits were low and varied from −0.190 (between pH and milk protein percentage) to 0.254 (between pH and somatic cell score). The results of this meta-analysis indicated the existence of additive genetic variation for MCP that could be used in genetic selection programs for dairy cows. Because of the moderate heritability of MCP and small genetic correlations with production traits, it could be possible to improve MCP with negligible correlated effects on production traits.
The role of a mobile hearing application in secondary care ENT (HAppENT)
Authors: Thompson G , Abdelhamid A , Khudan A , Dobbs S , Suleman M T , Salem O M , Khwaja S
Published: August 2023

Objective

Sudden hearing loss is a common presentation to ENT. In the authors’ practice, patients often wait many weeks for formal hearing testing. This study aimed to assess whether a tablet-based hearing test, hearTest, could aid clinical decision-making within secondary care ENT.

Method

This was a multi-centre, prospective, non-randomised study to assess the feasibility, usability and accuracy of hearTest.

Results

In the sample, hearTest was shown to be an acceptable method of testing for hearing loss by both patients and clinicians. The 0.5–4 kHz range had an average clinical agreement rate of 95.1 per cent when compared with formal pure tone audiometry, deeming it an accurate test to diagnose hearing loss.

Conclusion

The authors propose that hearTest can be used within ENT as a clinical decision support tool when manual audiometry is not immediately available. Within the authors’ practice, hearTest is used to aid diagnosis and management of sudden sensorineural hearing loss.
Shang dynasty's “nine generations chaos” and the reign of Wu Ding: towards a unilineal line of transmission of royal power
Authors: Boileau Gilles
Published: August 2023

This article explores the political crisis before Wu Ding. The accession of king Wu Ding to the throne was not a given but the result of a political move by his father Xiao Yi. It must be seen as one of the consequences of an earlier political crisis named the “nine generations chaos” by Sima Qian, during which an attempt to share royal power between two royal lines finally collapsed and led to a move by Pan Geng to a new capital. This new city has recently been discovered north of the Huai river. The political crisis of the time led Shang kings to try to implement a unilineal system of succession. Other steps, ritual in particular, were involved after the reign of the king Zu Jia, one of the reigning sons of Wu Ding, in order to ensure the primacy of the unilineal system of royal succession.
Understanding household healthcare expenditure can promote health policy reform
Authors: Best Rohan , Tuncay Berna
Published: August 2023

Studies of health care expenditure often exclude explanatory variables measuring wealth, despite the intuitive importance and policy relevance. We use the Household, Income and Labour Dynamics in Australia Survey to assess impacts of income and wealth on health expenditure. We investigate four different dependent variables related to health expenditure and use three main methodological approaches. These approaches include a first difference model and introduction of a lagged dependent variable into a cross-sectional context. The key findings include that wealth tends to be more important than income in identifying variation in health expenditure. This applies for health variables which are not directly linked to means testing, such as spending on health practitioners and for being unable to afford required medical treatment. In contrast, the paper includes no evidence of different impacts of income and wealth on spending on medicines, prescriptions or pharmaceuticals. The results motivate two novel policy innovations. One is the introduction of an asset test for determining rebate eligibility for private health insurance. The second is greater focus on asset testing, rather than income tests, for a wide range of general welfare payments that can be used for health expenditure. Australia's world-leading use of means testing can provide a test case for many countries.
Circulating tumor cell-derived preclinical models: current status and future perspectives
Authors: Kahounová Zuzana , Pícková Markéta , Drápela Stanislav , Bouchal Jan , Szczyrbová Eva , Navrátil Jiří , Souček Karel
Published: August 2023

Despite the advancements made in the diagnosis and treatment of cancer, the stages associated with metastasis remain largely incurable and represent the primary cause of cancer-related deaths. The dissemination of cancer is facilitated by circulating tumor cells (CTCs), which originate from the primary tumor or metastatic sites and enter the bloodstream, subsequently spreading to distant parts of the body. CTCs have garnered significant attention in research due to their accessibility in peripheral blood, despite their low abundance. They are being extensively studied to gain a deeper understanding of the mechanisms underlying cancer dissemination and to identify effective therapeutic strategies for advanced stages of the disease. Therefore, substantial efforts have been directed towards establishing and characterizing relevant experimental models derived from CTCs, aiming to provide relevant tools for research. In this review, we provide an overview of recent progress in the establishment of preclinical CTC-derived models, such as CTC-derived xenografts (CDX) and cell cultures, which show promise for the study of CTCs. We discuss the advantages and limitations of these models and conclude by summarizing the potential future use of CTCs and CTC-derived models in cancer treatment decisions and their utility as precision medicine tools.
Impaired renal autoregulation and pressure-natriuresis: any role in the development of heart failure in normotensive and angiotensin II-dependent hypertensive rats?
Authors: Honetschlägerová Zuzana , Sadowski Janusz , Kompanowska-Jezierska Elzbieta , Maxová Hana , Táborský Miloš , Kujal Petr , Červenka Luděk
Published: August 2023

The aim of the present study was to assess the autoregulatory capacity of renal blood flow (RBF) and of the pressure-natriuresis characteristics in the early phase of heart failure (HF) in rats, normotensive and with angiotensin II (ANG II)-dependent hypertension. Ren-2 transgenic rats (TGR) were employed as a model of ANG II-dependent hypertension. HF was induced by creating the aorto-caval fistula (ACF). One week after ACF creation or sham-operation, the animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and the pressure-natriuresis characteristics after stepwise changes in renal arterial pressure (RAP) induced by aortic clamping. In ACF TGR the basal mean arterial pressure, RBF, urine flow (UF), and absolute sodium excretion (UNaV) were all significantly lower tha n in sham-operated TGR. In the latter, reductions in renal arterial pressure (RAP) significantly decreased RBF whereas in ACF TGR they did not change. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Our data show that compared with sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and improved slope of the pressure-natriuresis relationship. Thus, even though in the very early HF stage renal dysfunction was demonstrable, in the HF model of ANG II-dependent hypertensive rat such dysfunction and the subsequent HF decompensation cannot be simply ascribed to impaired renal autoregulation and pressure-natriuresis relationship.
Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells
Authors: Rattigan Kevin M. , Brabcova Zuzana , Sarnello Daniele , Zarou Martha M. , Roy Kiron , Kwan Ryan , de Beauchamp Lucie , Dawson Amy , Ianniciello Angela , Khalaf Ahmed , Kalkman Eric R. , Scott Mary T. , Dunn Karen , Sumpton David , Michie Alison M. , Copland Mhairi , Tardito Saverio , Gottlieb Eyal , Vignir Helgason G.
Published: August 2023

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples.
A RAD51–ADP double filament structure unveils the mechanism of filament dynamics in homologous recombination
Authors: Luo Shih-Chi , Yeh Min-Chi , Lien Yu-Hsiang , Yeh Hsin-Yi , Siao Huei-Lun , Tu I-Ping , Chi Peter , Ho Meng-Chiao
Published: August 2023

ATP-dependent RAD51 recombinases play an essential role in eukaryotic homologous recombination by catalyzing a four-step process: 1) formation of a RAD51 single-filament assembly on ssDNA in the presence of ATP, 2) complementary DNA strand-exchange, 3) ATP hydrolysis transforming the RAD51 filament into an ADP-bound disassembly-competent state, and 4) RAD51 disassembly to provide access for DNA repairing enzymes. Of these steps, filament dynamics between the ATP- and ADP-bound states, and the RAD51 disassembly mechanism, are poorly understood due to the lack of near-atomic-resolution information of the ADP-bound RAD51–DNA filament structure. We report the cryo-EM structure of ADP-bound RAD51–DNA filaments at 3.1 Å resolution, revealing a unique RAD51 double-filament that wraps around ssDNA. Structural analysis, supported by ATP-chase and time-resolved cryo-EM experiments, reveals a collapsing mechanism involving two four-protomer movements along ssDNA for mechanical transition between RAD51 single- and double-filament without RAD51 dissociation. This mechanism enables elastic change of RAD51 filament length during structural transitions between ATP- and ADP-states.
Molecular rearrangement of bicyclic peroxy radicals is a key route to aerosol from aromatics
Authors: Iyer Siddharth , Kumar Avinash , Savolainen Anni , Barua Shawon , Daub Christopher , Pichelstorfer Lukas , Roldin Pontus , Garmash Olga , Seal Prasenjit , Kurtén Theo , Rissanen Matti
Published: August 2023

The oxidation of aromatics contributes significantly to the formation of atmospheric aerosol. Using toluene as an example, we demonstrate the existence of a molecular rearrangement channel in the oxidation mechanism. Based on both flow reactor experiments and quantum chemical calculations, we show that the bicyclic peroxy radicals (BPRs) formed in OH-initiated aromatic oxidation are much less stable than previously thought, and in the case of the toluene derived ipso-BPRs, lead to aerosol-forming low-volatility products with up to 9 oxygen atoms on sub-second timescales. Similar results are predicted for ipso-BPRs formed from many other aromatic compounds. This reaction class is likely a key route for atmospheric aerosol formation, and including the molecular rearrangement of BPRs may be vital for accurate chemical modeling of the atmosphere.
Machine learning the microscopic form of nematic order in twisted double-bilayer graphene
Authors: Sobral João Augusto , Obernauer Stefan , Turkel Simon , Pasupathy Abhay N. , Scheurer Mathias S.
Published: August 2023

Modern scanning probe techniques, such as scanning tunneling microscopy, provide access to a large amount of data encoding the underlying physics of quantum matter. In this work, we show how convolutional neural networks can be used to learn effective theoretical models from scanning tunneling microscopy data on correlated moiré superlattices. Moiré systems are particularly well suited for this task as their increased lattice constant provides access to intra-unit-cell physics, while their tunability allows for the collection of high-dimensional data sets from a single sample. Using electronic nematic order in twisted double-bilayer graphene as an example, we show that incorporating correlations between the local density of states at different energies allows convolutional neural networks not only to learn the microscopic nematic order parameter, but also to distinguish it from heterostrain. These results demonstrate that neural networks are a powerful method for investigating the microscopic details of correlated phenomena in moiré systems and beyond.
One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids
Authors: Geurts Maarten H. , Gandhi Shashank , Boretto Matteo G. , Akkerman Ninouk , Derks Lucca L. M. , van Son Gijs , Celotti Martina , Harshuk-Shabso Sarina , Peci Flavia , Begthel Harry , Hendriks Delilah , Schürmann Paul , Andersson-Rolf Amanda , Chuva de Sousa Lopes Susana M. , van Es Johan H. , van Boxtel Ruben , Clevers Hans
Published: August 2023

Optimization of CRISPR/Cas9-mediated genome engineering has resulted in base editors that hold promise for mutation repair and disease modeling. Here, we demonstrate the application of base editors for the generation of complex tumor models in human ASC-derived organoids. First we show efficacy of cytosine and adenine base editors in modelingCTNNB1hot-spot mutations in hepatocyte organoids. Next, we use C > T base editors to insert nonsense mutations inPTENin endometrial organoids and demonstrate tumorigenicity even in the heterozygous state. Moreover, drug sensitivity assays on organoids harboring eitherPTENorPTENandPIK3CAmutations reveal the mechanism underlying the initial stages of endometrial tumorigenesis. To further increase the scope of base editing we combine SpCas9 and SaCas9 for simultaneous C > T and A > G editing at individual target sites. Finally, we show that base editor multiplexing allow modeling of colorectal tumorigenesis in a single step by simultaneously transfecting sgRNAs targeting five cancer genes.
Ligand recognition and G protein coupling of the human itch receptor MRGPRX1
Authors: Guo Lulu , Zhang Yumu , Fang Guoxing , Tie Lu , Zhuang Yuming , Xue Chenyang , Liu Qi , Zhang Minghui , Zhu Kongkai , You Chongzhao , Xu Peiyu , Yuan Qingning , Zhang Chao , Liu Lei , Rong Naikang , Peng Shengxuan , Liu Yuan , Wang Chuanzheng , Luo Xin , Lv Zongyao , Kang Dongwei , Yu Xiao , Zhang Cheng , Jiang Yi , Dong Xinzhong , Zhou Jiuyao , Liu Zhongmin , Yang Fan , Eric Xu H. , Sun Jin-Peng
Published: August 2023

MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal “RF/RY” motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the G6.48XP6.50F6.51G6.52X(2)F/W6.55 motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling.
Machine learning force fields for molecular liquids: Ethylene Carbonate/Ethyl Methyl Carbonate binary solvent
Authors: Magdău Ioan-Bogdan , Arismendi-Arrieta Daniel J. , Smith Holly E. , Grey Clare P. , Hermansson Kersti , Csányi Gábor
Published: August 2023

Highly accurate ab initio molecular dynamics (MD) methods are the gold standard for studying molecular mechanisms in the condensed phase, however, they are too expensive to capture many key properties that converge slowly with respect to simulation length and time scales. Machine learning (ML) approaches which reach the accuracy of ab initio simulation, and which are, at the same time, sufficiently affordable hold the key to bridging this gap. In this work we present a robust ML potential for the EC:EMC binary solvent, a key component of liquid electrolytes in rechargeable Li-ion batteries. We identify the necessary ingredients needed to successfully model this liquid mixture of organic molecules. In particular, we address the challenge posed by the separation of scale between intra- and inter-molecular interactions, which is a general issue in all condensed phase molecular systems.
Cardiovascular disease behavioural risk factors in rural interventions: cross-sectional study
Authors: Akinosun Adewale Samuel , Kamya Sylvia , Watt Jonathan , Johnston William , Leslie Stephen J. , Grindle Mark
Published: August 2023

This study aims to (1) assess the distribution of variables within the population and the prevalence of cardiovascular disease (CVD) behavioural risk factors in patients, (2) identify target risk factor(s) for behaviour modification intervention, and (3) develop an analytical model to define cluster(s) of risk factors which could help make any generic intervention more targeted to the local patient population. Study patients with at least one CVD behavioural risk factor living in a rural region of the Scottish Highlands. The study used the STROBE methodology for cross-sectional studies. Demographic and clinical data of patients (n = 2025) in NHS Highlands hospital were collected at the point of admission for PCI between 04.01.2016 and 31.12.2019. Collected data distributions were analysed by CVD behavioural risk factors for prevalence, associations, and direction of associations. Cluster definition was measured by assignment of a unit score each for the overall level of prevalence and significance of associations, and general logistics modelling for direction and significance of the risk. The mean (SD) age was 69.47(± 10.93) years [95% CI (68.99–69.94)]. The key risk factors were hyperlipidaemia, hypertension, and elevated body mass index (BMI). Approximately 40% of the population have multiple risk factor counts of two. Analytical measures revealed a population risk factor cluster with elevated BMI [77.5% (1570/2025)] that is mostly either hyperlipidaemic [9.43%, co-eff. (17), P = 0.007] or hypertensive [22.72%, co-eff. (17), P = 0.99] as key risk factor clusters. Carefully modelled analyses revealed clustered risk associated with elevated BMI. This information would support a strategy for targeting risk factor clusters in novel interventions to improve implementation efficiency. Exposure to and outcome of an elevated BMI is linked more to the population’s socio-economic outcomes rather than to regional rurality or urbanity.
Optical monitoring of hemodialysis using noninvasive measurement of uric acid in the dialysate
Authors: Żyłka Wojciech , Tęcza Krystyna , Szemela Krzysztof , Prach Piotr , Żyłka Marta , Jakubczyk Dorota , Błądziński Maciej , Gala-Błądzińska Agnieszka , Jakubczyk Paweł
Published: August 2023

The aim of this study was to present a methodology for predicting changes in uric acid concentrations in the blood of chronically hemodialyzed patients based on an optical measurement of the intensity of selected wavelengths in the dialysate. Blood samples were taken from the arterial line every 30 min throughout the hemodialysis period, to measure uric acid levels. Simultaneously, optical measurements were made on dialysate flowing from the dialyzer. Uric acid concentration can be measured either directly from the blood or from dialyzer outflow with acceptable error. In addition, both methods reveal any increased dynamics in uric acid concentration in the initial phase of hemodialysis. The wavelength of the light was adjusted for optimal uric acid particle detection. Comparing the uric acid concentration measured in the blood of patients with the intensity of wave absorption in the dialysate, the functional relationship between the uric acid concentration levels was determined. Using the optical method for measuring uric acid concentration in the dialysate, the concentration of uric acid in the blood during hemodialysis can be non-invasively and accurately estimated. This method can be used to assess the adequacy of hemodialysis by computer acquisition of uric acid concentrations determined in on-line dialysate.
Multispectral sensor fusion in SmartWatch for in situ continuous monitoring of human skin hydration and body sweat loss
Authors: Volkova Elena , Perchik Alexey , Pavlov Konstantin , Nikolaev Evgenii , Ayuev Alexey , Park Jaehyuck , Chang Namseok , Lee Wonseok , Kim Justin Younghyun , Doronin Alexander , Vilenskii Maksim
Published: August 2023

Post-pandemic health operations have become a near-term reality, discussions around wearables are on the rise. How do wearable health solutions effectively deploy and use this opportunity to fill the gap between wellness and healthcare? In this paper, we will talk about wearable healthcare diagnosis, with a particular focus on monitoring skin hydration using optical multi-wavelength sensor fusion. Continuous monitoring of human skin hydration is a task of paramount importance for maintaining water loss dynamics for fitness lovers as well as for skin beauty, integrity and the health of the entire body. Preserving the appropriate levels of hydration ensures consistency of weight, positively affects psychological state, and proven to result in a decrease in blood pressure as well as the levels of “bad” cholesterol while slowing down the aging processes. Traditional methods for determining the state of water content in the skin do not allow continuous and non-invasive monitoring, which is required for variety of consumer, clinical and cosmetic applications. We present novel sensing technology and a pipeline for capturing, modeling and analysis of the skin hydration phenomena and associated changes therein. By expanding sensing capabilities built into the SmartWatch sensor and combining them with advanced modeling and Machine Learning (ML) algorithms, we identified several important characteristics of photoplethysmography (PPG) signal and spectral sensitivity corresponding to dynamics of skin water content. In a hardware aspect, we newly propose the expansion of SmartWatch capabilities with InfraRed light sources equipped with wavelengths of 970 nm and 1450 nm. Evaluation of the accuracy and characteristics of PPG sensors has been performed with biomedical optics-based simulation framework using Monte Carlo simulations. We performed rigorous validation of the developed technology using experimental and clinical studies. The developed pipeline serves as a tool in the ongoing studies of the next generation of optical sensing technology.
Strengthening the mechanical characteristics and cathodic delamination resistance of fiber-reinforced polymer through chemical surface modification of glass fibers
Authors: Shariatmadar M. , Feizollahi S. , Gholamhosseini P. , Abdorrezaee Z. , Ghorbanzadeh S. , Hosseini F. S. , Shahraki F. Azad , Mahdavian M.
Published: August 2023

This work aims to scrutinize the effect of the silanization of glass fibers (GF) on the mechanical properties and cathodic disbonding resistance of an epoxy composite coating. Successful silanization was approved based on different characterization techniques, including Fourier transform infrared spectra, field emission-scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy, and thermogravimetric analysis. Tensile strength measurement exhibited a significant effect of silanization on the mechanical performance of the fiber-reinforced polymer (FRP). FE-SEM cross-sectional images illustrated improved interfacial bonding between the epoxy matrix and GF upon silanization. Pull-off measurements revealed improved wet adhesion strength of the FRP to the mild steel surface after exposure to the salt spray chamber when the GF were silanized. In addition, silanization revealed enhanced resistance to cathodic delamination (CD). Electrochemical impedance spectroscopy and electrochemical noise assessments proved silanization's significant influence on the FRP's CD resistance.