bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxic microenvironment-induced exosomes confer temozolomide resistance in glioma through transfer of pyruvate kinase M2
Authors: Li Guofu , Xiong Ziyu , Li Ying , Yan Cong , Cheng Yingying , Wang Yuwen , Li Jingwei , Dai Zifeng , Zhang Dongdong , Du Wenzhong , Men Chunyang , Shi Changbin
Published: April 2024

Objective

Glioma, a malignant primary brain tumor, is notorious for its high incidence rate. However, the clinical application of temozolomide (TMZ) as a treatment option for glioma is often limited due to resistance, which has been linked to hypoxic glioma cell-released exosomes. In light of this, the present study aimed to investigate the role of exosomal pyruvate kinase M2 (PKM2) in glioma cells that exhibit resistance to TMZ.

Methods

Sensitive and TMZ-resistant glioma cells were subjected to either a normoxic or hypoxic environment, and the growth patterns and enzymatic activity of glycolysis enzymes were subsequently measured. From these cells, exosomal PKM2 was isolated and the subsequent effect on TMZ resistance was examined and characterized, with a particular focus on understanding the relevant mechanisms. Furthermore, the intercellular communication between hypoxic resistant cells and tumor-associated macrophages (TAMs) via exosomal PKM2 was also assessed.

Results

The adverse impact of hypoxic microenvironments on TMZ resistance in glioma cells was identified and characterized. Among the three glycolysis enzymes that were examined, PKM2 was found to be a critical mediator in hypoxia-triggered TMZ resistance. Upregulation of PKM2 was found to exacerbate the hypoxia-mediated TMZ resistance. Exosomal PKM2 were identified and isolated from hypoxic TMZ-resistant glioma cells, and were found to be responsible for transmitting TMZ resistance to sensitive glioma cells. The exosomal PKM2 also contributed towards mitigating TMZ-induced apoptosis in sensitive glioma cells, while also causing intracellular ROS accumulation. Additionally, hypoxic resistant cells also released exosomal PKM2, which facilitated TMZ resistance in tumor-associated macrophages.

Conclusion

In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma.
A new approach to calculate CO2 displacement recovery considering near miscibility in tight oil reservoirs
Authors: Yang Song , Tian Xiaofeng
Published: April 2024

Near miscibility widely exists in carbon dioxide (CO2) injection development projects. However, there is no existing approach to quantify the effect of near miscibility on oil recovery. In this paper, slim tube experiments were conducted to study near miscible region. The oil displacement efficiency curve is divided into immiscibility, near miscibility and miscibility. And three linear function is obtained, respectively. Then, the space between production well and CO2 injection well is discrete to characterize the effect of near miscibility on oil recovery. Then, a new approach is proposed to calculate oil recovery of CO2 displacement in tight oil reservoirs. This approach can calculate oil recovery considering near miscibility. It is found that minimum miscibility pressure (MMP) without considering near miscibility is 4 MPa lower than considering near miscibility. The near miscible pressure range is from 0.77 times to 1 time MMP considering near miscibility. Oil displacement efficiency difference reaches to be the maximum when the pressure is the minimum miscibility pressure without considering near miscibility. The maximum of the oil displacement efficiency difference is 3.4%. The optimal formation pressure considering near miscibility is 5 MPa larger than that without considering near miscibility. The oil recovery considering near miscibility is from 0.9 to 1.3% lower than that not considering near miscibility. It reaches to be the maximum when the pressure is the optimal formation pressure level without considering near miscibility. The maximum of the oil recovery difference is 1.3%.
Spanish GDP short-term point and density forecasting using a mixed-frequency dynamic factor model
Authors: Fresoli Diego
Published: April 2024

We have assessed the effect of data releases when constructing short-term point and density forecasts of the Spanish gross domestic product growth. For this purpose, we considered a real-forecasting exercise in which we defined several pseudo-data vintages that had a mixture of monthly and quarterly frequencies and were unbalanced towards the end of the sample. We implemented a mixed-frequency dynamic factor model to deal with data features and to produce gross domestic product forecasts. We evaluated the predictive content of data releases from point and density forecast perspectives, the latter aspect of the analysis being previously unexplored in the literature producing Spanish gross domestic product short-term forecasts. We observed significant improvements in point forecasts as information is released throughout the quarter, confirming existing results. Additionally, our findings indicated substantial enhancements in the accuracy of density forecasts as new data releases materialized.
‘I want to scream it from the rooftops now […] there are other pathways’: What young people learned from a co-designed post-secondary transition programme
Authors: Ryan Juliana , Luguetti Carla , Eckersley Bill , Howard Amy , Hansen Chloe , Ford Chloe , Craig Sarah , Brown Claire
Published: April 2024

This paper uses the framework of transition as becoming to explore what young people learned from participating in a post-secondary transition program that was co-designed by young people. The 9-week youth participatory action research (YPAR) involved six staff collaborators (SCs) and seven youth collaborators (YCs). Data comprised recordings of weekly group meetings, group interviews, reflections and artefacts such as planning documents, graphic organisers and writing. We discuss the findings using two themes that we identified together as a team of YCs and SCs. The first represents how YCs became aware of and vocalised understandings of life after secondary school as a diverse and fluid process. The second describes and interrogates how YCs became more confident and empowered, showing the importance of critical consciousness, reflection and action in seeking transformation. We conclude that conceptualising transition as becoming enables us to collectively make sense of the diverse ways we co-construct life experiences and directions.
Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson’s Disease Model by Modulating Hippo Signaling
Authors: Choi Junwon , Park Sun Wha , Lee Hyunji , Kim Do Hyun , Kim Sung Won
Published: April 2024

Background:

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, following Alzheimer’s disease. The onset of PD is characterized by the loss of dopaminergic neurons in the substantia nigra. Stem cell therapy has great potential for the treatment of neurodegenerative diseases, and human nasal turbinate-derived stem cells (hNTSCs) have been found to share some characteristics with mesenchymal stem cells. Although the Hippo signaling pathway was originally thought to regulate cell size in organs, recent studies have shown that it can also control inflammation in neural cells.

Methods:

Dopaminergic neuron-like cells were differentiated from SH-SY5Y cells (DA-Like cells) and treated with 1-Methyl-4-phenylpyridinium iodide to stimulate Reactive oxidative species (ROS) production. A transwell assay was conducted to validate the effect of hNTSCs on the Hippo pathway. We generated an MPTP-induced PD mouse model and transplanted hNTSCs into the substantia nigra of PD mice via stereotaxic surgery. After five weeks of behavioral testing, the brain samples were validated by immunoblotting and immunostaining to confirm the niche control of hNTSCs.

Results:

In-vitro experiments showed that hNTSCs significantly increased cell survival and exerted anti-inflammatory effects by controlling ROS-mediated ER stress and hippocampal signaling pathway factors. Similarly, the in-vivo experiments demonstrated an increase in anti-inflammatory effects and cell survival rate. After transplantation of hNTSCs, the PD mouse model showed improved mobility and relief from PD symptoms.

Conclusion:

hNTSCs improved the survival rate of dopaminergic neurons by manipulating the hippocampal pathway through Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) by reducing inflammatory cytokines. In this study, we found that controlling the niche of hNTSCs had a therapeutic effect on PD lesions.
Prospective evaluation of a novel device for ultrasound-guided percutaneous treatment of carpal tunnel and trigger finger disease. Efficacy and safety of sono-instruments®
Authors: Moungondo Fabian , Van Rompaey Hannah , Moussa Mohamad K. , Schuind Frédéric
Published: April 2024

Purpose

To evaluate the safety and effectiveness of percutaneous release procedures under sonography using Sono-Instruments® in the treatment of carpal tunnel syndrome (CTS) and trigger finger (TF).

Methods

Prospective study involving 30 patients, divided into two groups (15 CTS, and 15 TF). The primary outcomes were surgical performance-related outcomes (visibility, ease of use, satisfaction, duration) using Sono-Instruments® and patient-related outcomes (pain, activity limitations, time to return to work, functional scores). Secondary outcomes included complications. Patients were followed for two months post-operatively.

Results

In the CTS group, the average age of the patients was 58.7 years. The percutaneous release of the transverse carpal ligament was effectively completed in all cases, with excellent device performance and no adverse events. At one week, all patients could wash their hands, 80% could perform activities of daily living, and 80% of those working had returned to their activities. At two months, all patients had resumed all activities. Pillar pain was still present in 53.3%. In the TF group, the patients had an average age of 57.9 years. The percutaneous release of the A1 annular pulley was successful in all cases, with excellent device performance and no adverse events. At one week, all patients could wash their hands, 93.3% could do all activities of daily living, and 75% of those working were back to their professional activities. At two months, all patients were back to all activities of daily living and work. The DASH score was significantly improved at two months, compared to preoperative, for both groups (p < 0.001).

Conclusion

Percutaneous sono-guided release using Sono-Instruments® is safe and efficient, and associated with quick functional recovery.

Level of evidence

II.
Unpacking Neighborhood Socioeconomic Status in Children’s Health Research from an Environmental Justice Perspective: A Scoping Review
Authors: Bhaktaram Ananya , Kress Amii M. , Li Zone , Knapp Emily A.
Published: April 2024

Purpose of Review

Clearly defining and measuring neighborhood socioeconomic status (nSES) is a key first step in achieving environmental justice, as the disproportionate distribution of environmental hazards and access to resources is heavily influenced by socioeconomic factors. This scoping review explores the definition of neighborhoods, measurement of neighborhood socioeconomic status (nSES), and studies that evaluated the association between nSES and child health in accordance with PRISMA guidelines.

Recent Findings

We identified 4112 articles published on US pediatric populations between 2013 and 2022. We identified 170 distinct indicators across seven broad domains of nSES used to create 121 different measures of nSES across the 206 publications included in this review. While there is considerable interest in nSES and children’s health, there is also substantial variation in the measurement of neighborhood as a geographic unit and nSES as a construct.

We observed methodological challenges related to the identification of neighborhood boundaries, indicator selection, and nSES measure definition(s). We discuss common pitfalls in neighborhood research that can complicate identifying, targeting, and resolving environmental injustices. Lastly, we put forward a series of recommendations to reduce measurement error and improve inference, in addition to reporting recommendations for neighborhoods and health research that can aid in improving our understanding of pathways between neighborhood context and child health, inform policy development, and allocate resources to achieve environmental justice.
Die Diabetesinzidenz bei Kindern und Jugendlichen in Österreich steigt weiter!
Authors: Nagl Katrin
Published: April 2024

Seit 1989 verfügt Österreich über ein Diabetes-Inzidenz-Register für Kinder unter 15 Jahren. Eine aktuelle Auswertung zeigte, dass die Inzidenz von Typ-1-Diabetes (T1D) wieder steigt und im Jahr 2021 einen Höchststand erreichte. Diese Zusammenfassung gibt einen Überblick über die Entwicklung von Diabetesinzidenzen bei Kindern in Österreich mit besonderem Fokus auf T1D und Typ-2-Diabetes (T2D) sowie deren potenziellen Zusammenhang mit der COVID-19-Pandemie und anderen Einflussfaktoren. Da in den letzten Jahren ein eklatanter Anstieg an diabetischer Ketoazidose bei Diagnosestellung zu verzeichnen war, wird die Bedeutung von Screening, Prävention und Früherkennung im Zusammenhang mit T1D bei Kindern betont.
Wie man jemanden „bloß als Mittel“ gebraucht
Authors: Kleingeld Pauline
Published: April 2024

Das Verbot, andere „bloß als Mittel“ zu gebrauchen, ist eines der bekanntesten und einflussreichsten Elemente der Moralphilosophie von Immanuel Kant. Es wird jedoch weithin als unmöglich angesehen, die Bedingungen, unter denen dieses Verbot verletzt wird, genau zu bestimmen. Auf der Grundlage einer erneuten Prüfung der kantischen Texte entwickelt dieser Aufsatz eine neue Interpretation der Bedingungen, unter denen jemand „bloß als Mittel“ gebraucht wird. Es wird argumentiert, dass diese Interpretation nicht nur durch die Texte verlässlich gestützt wird, sondern auch erhebliche philosophische Vorteile gegenüber alternativen Lesarten aufweist.
Multi-Trait Body Shape Phenotypes and Breast Cancer Risk in Postmenopausal Women: A Causal Mediation Analysis in the UK Biobank Cohort
Authors: Amadou Amina , Freisling Heinz , Sedlmeier Anja M. , Bohmann Patricia , Fontvieille Emma , Weber Andrea , Konzok Julian , Stein Michael J. , Peruchet-Noray Laia , Jansana Anna , Noh Hwayoung , His Mathilde , Gan Quan , Baurecht Hansjörg , Fervers Béatrice
Published: April 2024

Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.
Assessing the water quality dynamics in the coastal waters of Kollam (Kerala, India) using Sentinel images
Authors: Prasad Anagha , Prasad P. Rama Chandra , Rao N. Srinivasa
Published: April 2024

Coastal waters are complex, dynamic, and sensitive, and any change in the system impacts the marine environment and life. Coastal water quality has been decreasing due to the incursion of anthropogenic derived waste and toxins into the ocean. This study investigates water quality along the Kollam coast of Kerala State, India, using Sentinel-2 Multispectral Imager (MSI) data for the period of 2019–2022. Four key water quality parameters, chlorophyll (Chl-a), total suspended matter (TSM), turbidity, and coloured dissolved organic matter (CDOM), were analysed for seasonal variations and driving factors. The study highlights the potential of web-based platforms like Google Earth Engine for facilitating large-scale water quality assessments. The results reveal a distinct seasonal pattern in all parameters, primarily influenced by monsoonal riverine discharge and anthropogenic activities as contributing factors to water quality degradation. Overall, the study emphasises the need for comprehensive monitoring and management strategies to ensure the long-term sustainability of the coastal ecosystem.
Aus der Geschichte der Föderation deutscher Psychologenvereinigungen (BDP und DGPs)
Authors: Dutke Stephan , Schönpflug Wolfgang
Published: April 2024

Zusammenfassung: Der Berufsverband Deutscher Psychologinnen und Psychologen (BDP) und die Deutsche Gesellschaft für Psychologie (DGPs) bilden seit 1964 eine Föderation. Als Föderation haben die beiden Vereinigungen die deutsche Psychologie in internationalen Verbänden vertreten und die Reform des Psychologiestudiums sowie die Professionalisierung des Psychologieberufs in Deutschland mitgestaltet. Dabei sind BDP und DGPs selbständige Vereinigungen geblieben, welche auch voneinander abweichende fachpolitische Positionen einnehmen konnten.
Suicide-Related Media Reporting With a Focus on Sexual and Gender Minority Identities
Authors: Kirchner Stefanie , Till Benedikt , Laido Zrinka , Niederkrotenthaler Thomas
Published: April 2024

Abstract: Background: Little is known about the quality of media reports on suicide and prevention targeting persons with sexual or gender minority identities (LGBTQ+). Aims: To assess the quality of suicide-related media reporting of LGBTQ+ people and its consistency with media guidelines. Method: We conducted a content analysis of 5,652 media items in two US states (Washington and Oregon) published within 1 year. Results: There were only few differences in the reporting about suicide in LGBTQ+ as compared to non-LGBTQ+ reports. LGBTQ+ media items more often portrayed suicide as monocausal [Oregon: OR = 1.75, 95% CI (1.03–2.98), p = .038; Washington: OR = 3.00, 95% CI (1.81–4.97), p < .001] and linked them to adverse life experiences [ OR = 2.16, 95% CI (1.38–3.38), p < .001; OR = 2.09, 95% CI (1.30–3.38), p = .002] than non-LGBTQ+ items. They also more often featured mental health experts [ OR = 1.79, 95% CI (1.04–3.10), p = .034; OR = 2.12, 95% CI (1.23–3.67), p = .006] and contacts to support services [ OR = 2.22, 95% CI (1.41–3.48), p < .001; OR = 2.70, 95% CI (1.64–4.45), p < .001]. Limitations: Aspects possibly influencing the portrayal of LGBTQ+ suicide and prevention beyond the characteristics listed were not investigated. Conclusion: Suicide-related media reporting related to LGBTQ+ issues features potentially beneficial aspects but tends to overlook multifactorial causes of suicide. Diverse factors contributing to LGBTQ+ suicide and prevention warrant greater attention.
Longitudinal Variations of Mars Thermosphere CO2, Ar, N2, and O Densities From MAVEN: Dependencies on Species Mass, Solar Flux, and Local Time
Authors: Forbes Jeffrey M. , Fang Xiaohua , Zhang Xiaoli , Benna Mehdi , González‐Galindo Francisco
Published: April 2024

Measurements of CO2, Ar, N2, and O densities between 150 and 200 km from the Mars Atmosphere and Volatile Evolution Neutral Gas and Ion Mass Spectrometer during February 2015 to February 2022 are analyzed to provide a comprehensive analysis of their longitudinal wavenumber k = 1, 2, and 3 components. Variations in density amplitudes (Ak) with solar flux are marginally detectable during this period. The Ak binned and averaged in latitude, local solar time and Ls are referenced to diurnal‐ and zonal‐mean backgrounds in accord with how tides and stationary planetary waves (SPWs) are defined in theory and modeling. The resulting global Ak distributions are the interference patterns formed by superposition of diurnal tides, SPWs and/or semidiurnal tides; consequently, a simple dependence on species mass consistent with thermal expansion (diffusive equilibrium) that might exist for some individual wave components is obscured. Additionally, vertical winds likely contribute to deviations from diffusive equilibrium. Complementary analyses of the Mars Climate Database indicate that the major contributors to the Ak are DE2, SE1, DE1, and SPW1, 2, 3; support the absence of significant variability due to solar flux; and indicate a more well‐defined sensitivity to species mass. The Ak and their phases (longitudes of maxima) for the whole data set are available as part of Supporting Information S1.
An Ensemble Learning Model Reveals Accelerated Reductions in Snow Depth Over Arctic Sea Ice Under High‐Emission Scenarios
Authors: Li H. L. , Ke C. Q. , Shen X. Y. , Zhu Q. H. , Cai Y.
Published: April 2024

There are significant differences in snow depth predictions among different earth system models, and many models underestimate snow depth, restricting their application. Here, major factors influencing snow depth changes in the Coupled Model Intercomparison Project Phase 6 (CMIP6) were identified and evaluated. Based on satellite‐derived snow depth and CMIP6 data, an ensemble learning model based on multiple deep learning methods (hereafter referred to as the Multi‐DL model) was developed to predict future snow depth. According to satellite observations and two Operation IceBridge products, the Multi‐DL model yielded root mean square errors of 7.48, 6.20, and 6.17 cm. A continuous decrease in snow depth was observed from 2002 to 2100, and the rate of decrease accelerated with increasing emissions. Under the highest emission scenario, the first snow‐free year occurred in 2047, within the same decade as the first ice‐free year (2056). The predicted warm season snow depth was sensitive to sea ice velocity, sea ice concentration (siconc), precipitation, sea surface temperature (tos) and albedo, while the predicted cold season snow depth was sensitive to tos, air temperature, and siconc. The above parameters introduce some snow depth uncertainty. This method provides new ideas for predicting snow depth, and the generated snow depth records can provide data support for formulating Arctic‐related policies.
First Observation of Electron Rolling‐Pin Distribution in Jupiter's Magnetosphere
Authors: Wang C. Q. , Fu H. S. , Cao J. B. , Wang Z. , Guo Z. Z. , Fu W. D. , Yao Z. H. , Wei Y. , Zhang B. Z.
Published: April 2024

The electron rolling‐pin distribution, showing electron pitch angles primarily at 0°, 90°, and 180°, has been widely studied in the Earth's magnetosphere, but has never been reported in other planetary environments. Here, by utilizing the Jupiter Near‐polar Orbiter (Juno) measurements, we report for the first time the electron rolling‐pin distribution in Jupiter's magnetosphere. We reveal the energy range of such distribution and find it appears only above 19.5 keV, falling well into the suprathermal energy range. Moreover, we quantitively reproduce the formation processes of such distribution by using an analytical model. Gratifyingly, the distribution derived from the analytical model agrees well with the Juno observations, indicating such distribution is formed by the combination of global‐scale Fermi acceleration and local‐scale betatron acceleration. These results, demonstrating that the electron rolling‐pin distribution exists beyond the Earth, can improve our knowledge of electron dynamics in planetary magnetosphere.
Role of dietary interventions on microvascular health in South-Asian Surinamese people with type 2 diabetes in the Netherlands: A randomized controlled trial
Authors: van der Velden Anouk I. M. , IJpelaar Daphne H. T. , Chandie Shaw Prataap K. , Pijl Hanno , Vink Hans , van der Vlag Johan , Rabelink Ton J. , van den Berg Bernard M.
Published: April 2024

Background/objectives

We investigated whether dietary interventions, i.e. a fasting mimicking diet (FMD, Prolon®) or glycocalyx mimetic supplementation (EndocalyxTM) could stabilize microvascular function in Surinamese South-Asian patients with type 2 diabetes (SA-T2DM) in the Netherlands, a patient population more prone to develop vascular complications.

Subjects/methods

A randomized, placebo controlled, 3-arm intervention study was conducted in 56 SA-T2DM patients between 18 and 75 years old, for 3 consecutive months, with one additional follow up measurement 3 months after the last intervention. Sublingual microcirculation was assessed with SDF-imaging coupled to the GlycoCheckTM software, detecting red blood cell velocity, capillary density, static and dynamic perfused boundary region (PBR), and the overall microvascular health score (MVHS). Linear mixed models and interaction analysis were used to investigate the effects the interventions had on microvascular function.

Results

Despite a temporal improvement in BMI and HbA1c after FMD the major treatment effect on microvascular health was worsening for RBC-velocity independent PBRdynamic, especially at follow-up. Glycocalyx supplementation, however, reduced urinary MCP-1 presence and improved both PBRdynamic and MVHSdynamic, which persisted at follow-up.

Conclusions

We showed that despite temporal beneficial changes in BMI and HbA1c after FMD, this intervention is not able to preserve microvascular endothelial health in Dutch South-Asian patients with T2DM. In contrast, glycocalyx mimetics preserves the microvascular endothelial health and reduces the inflammatory cytokine MCP-1.

Clinical study registration

NCT03889236.
Propensity score-matched evaluation of palliative transurethral resection and holmium laser enucleation of the prostate for bladder outlet obstruction in patients with prostate cancer
Authors: Tamalunas Alexander , Keller Patrick , Schott Melanie , Stadelmeier Leo Federico , Kidess Marc , Atzler Michael , Ebner Benedikt , Hennenberg Martin , Stief Christian G. , Magistro Giuseppe
Published: April 2024

Background

While transurethral resection of the prostate (TURP) is the standard-of-care, Holmium laser enucleation of the prostate (HoLEP) is widely accepted as a size-independent method for surgical treatment of patients with lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction (BOO). However, in an ageing society an increasing number of patients presents with BOO due to locally advanced prostate cancer. There is currently no guidelines recommendation as to the enucleation or resection technique. Therefore, we compared intraoperative performance, postoperative outcomes, and safety for palliative (p)TURP and (p)HoLEP.

Methods

We conducted a retrospective, propensity score-matched analysis of 1373 and 2705 men who underwent TURP or HoLEP for LUTS/BOO between 2014 and 2021, respectively. Patients were matched for age, prostate size and preoperative international prostate symptom score (IPSS). Patients were stratified by technique and groups were compared for perioperative parameters, safety, and functional outcomes.

Results

While postoperative symptoms and urodynamic parameters improved irrespective of technique, we report significantly increased resection and enucleation times for palliative indication. For corresponding efficiency parameters, we observed a two-fold higher surgical performance (g/min) for both techniques in patients without prostate cancer. While adverse events were comparable between groups, we found a two-fold higher hemoglobin drop in palliative patients.

Conclusions

Currently, there is no standard-of-care for patients with BOO and locally advanced prostate cancer. Our data show that both TURP and HoLEP offer adequate symptom improvement and comparable safety profiles. While HoLEP is feasible even in larger prostates, both procedures become more difficult in patients with prostate cancer. Taken together, this study covers an important gap in current literature, helping urological surgeons to make evidence-based decisions for the benefit of their patients.
Comparison of incident hypertension between SGLT2 inhibitors vs. DPP4 inhibitors
Authors: Suzuki Yuta , Kaneko Hidehiro , Okada Akira , Komuro Jin , Fujiu Katsuhito , Takeda Norifumi , Morita Hiroyuki , Ako Junya , Nishiyama Akira , Yano Yuichiro , Ieda Masaki , Node Koichi , Yasunaga Hideo , Komuro Issei
Published: April 2024

Although several randomized clinical trials have reported the potential benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in reducing blood pressure (BP), whether SGLT2i can reduce incident hypertension is unknown. We analyzed individuals with diabetes who were newly prescribed SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) in a large-scale epidemiological database. The primary outcome was the incidence of hypertension. A propensity score matching algorithm was employed to compare the subsequent development of hypertension between the SGLT2i and DPP4i groups. After propensity score matching, 5708 well-balanced pairs of SGLT2i and DPP4i users were identified. SGLT2i administration was associated with a reduced risk of hypertension (HR 0.91, 95% CI: 0.84–0.97). The advantage of SGLT2i use over DPP4i use for incident hypertension was generally consistent in several sensitivity analyses, and subgroup analyses showed that SGLT2i use was significantly associated with a lower risk of hypertension in men, patients with baseline HbA1c of <7.5%, and baseline systolic blood pressure ≥127 mmHg. Our investigation using nationwide real-world data demonstrated the potential advantage of SGLT2i over DPP4i in reducing the development of hypertension in individuals with diabetes.
The effect of hypertension on cerebrovascular carbon dioxide reactivity in atrial fibrillation patients
Authors: Walsh Harvey J. , Junejo Rehan T. , Lip Gregory Y. H. , Fisher James P.
Published: April 2024

Atrial fibrillation (AF) and hypertension (HTN) are both associated with impaired cerebrovascular carbon dioxide reactivity (CVRCO2), an indicator of cerebral vasodilatory reserve. We hypothesised that CVRCO2 would be lower in patients with both AF and HTN (AF + HTN) compared to normotensive AF patients, due to an additive effect of AF and HTN on CVRCO2. Forty AF (68 ± 9 years) and fifty-seven AF + HTN (68 ± 8 years) patients underwent transcranial Doppler ultrasound measurement of middle cerebral artery blood velocity (MCA Vm) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). A cerebrovascular conductance index (CVCi) was calculated as the ratio of MCA Vm and mean arterial pressure (MAP). CVRCO2 was determined from the linear slope for MCA Vm and MCA CVCi vs PETCO2. Baseline MAP was higher in AF + HTN than AF (107 ± 9 vs. 98 ± 9 mmHg, respectively; p < 0.001), while MCA Vm was not different (AF + HTN:49.6 [44.1–69.0]; AF:51.7 [45.2–63.3] cm.s−1; p = 0.075), and CVCi was lower in AF + HTN (0.46 [0.42–0.57] vs. 0.54 [0.44–0.63] cm.s−1.mmHg−1; p < 0.001). MCA Vm CVRCO2 was not different (AF + HTN: 1.70 [1.47–2.19]; AF 1.74 [1.54–2.52] cm/s/mmHg−2; p = 0.221), while CVCi CVRCO2 was 13% lower in AF + HTN (0.013 ± 0.004 vs 0.015 ± 0.005 cm.s−1.mmHg−1; p = 0.047). Our results demonstrate blunted cerebral vasodilatory reserve (determined as MCA CVCi CVRCO2) in AF + HTN compared to AF alone. This may implicate HTN as a driver of further cerebrovascular dysfunction in AF that may be important for the development of AF-related cerebrovascular events and downstream cognitive decline.
The nature of non-phononic excitations in disordered systems
Authors: Schirmacher Walter , Paoluzzi Matteo , Mocanu Felix Cosmin , Khomenko Dmytro , Szamel Grzegorz , Zamponi Francesco , Ruocco Giancarlo
Published: April 2024

The frequency scaling exponent of low-frequency excitations in microscopically small glasses, which do not allow for the existence of waves (phonons), has been in the focus of the recent literature. The density of states g(ω) of these modes obeys an ωs scaling, where the exponent s, ranging between 2 and 5, depends on the quenching protocol. The orgin of these findings remains controversal. Here we show, using heterogeneous-elasticity theory, that in a marginally-stable glass sample g(ω) follows a Debye-like scaling (s = 2), and the associated excitations (type-I) are of random-matrix type. Further, using a generalisation of the theory, we demonstrate that in more stable samples, other, (type-II) excitations prevail, which are non-irrotational oscillations, associated with local frozen-in stresses. The corresponding frequency scaling exponent s is governed by the statistics of small values of the stresses and, therefore, depends on the details of the interaction potential.
Zero modes activation to reconcile floppiness, rigidity, and multistability into an all-in-one class of reprogrammable metamaterials
Authors: Wu Lei , Pasini Damiano
Published: April 2024

Existing mechanical metamaterials are typically designed to either withstand loads as a stiff structure, shape morph as a floppy mechanism, or trap energy as a multistable matter, distinct behaviours that correspond to three primary classes of macroscopic solids. Their stiffness and stability are sealed permanently into their architecture, mostly remaining immutable post-fabrication due to the invariance of zero modes. Here, we introduce an all-in-one reprogrammable class of Kagome metamaterials that enable the in-situ reprogramming of zero modes to access the apparently conflicting properties of all classes. Through the selective activation of metahinges via self-contact, their architecture can be switched to acquire on-demand rigidity, floppiness, or global multistability, bridging the seemingly uncrossable gap between structures, mechanisms, and multistable matters. We showcase the versatile generalizations of the metahinge and remarkable reprogrammability of zero modes for a range of properties including stiffness, mechanical signal guiding, buckling modes, phonon spectra, and auxeticity, opening a plethora of opportunities for all-in-one materials and devices.
Salmonella exploits membrane reservoirs for invasion of host cells
Authors: Zhu Hongxian , Sydor Andrew M. , Boddy Kirsten C. , Coyaud Etienne , Laurent Estelle M. N. , Au Aaron , Tan Joel M. J. , Yan Bing-Ru , Moffat Jason , Muise Aleixo M. , Yip Christopher M. , Grinstein Sergio , Raught Brian , Brumell John H.
Published: April 2024

Salmonella utilizes a type 3 secretion system to translocate virulence proteins (effectors) into host cells during infection1. The effectors modulate host cell machinery to drive uptake of the bacteria into vacuoles, where they can establish an intracellular replicative niche. A remarkable feature of Salmonella invasion is the formation of actin-rich protuberances (ruffles) on the host cell surface that contribute to bacterial uptake. However, the membrane source for ruffle formation and how these bacteria regulate membrane mobilization within host cells remains unclear. Here, we show that Salmonella exploits membrane reservoirs for the generation of invasion ruffles. The reservoirs are pre-existing tubular compartments associated with the plasma membrane (PM) and are formed through the activity of RAB10 GTPase. Under normal growth conditions, membrane reservoirs contribute to PM homeostasis and are preloaded with the exocyst subunit EXOC2. During Salmonella invasion, the bacterial effectors SipC, SopE2, and SopB recruit exocyst subunits from membrane reservoirs and other cellular compartments, thereby allowing exocyst complex assembly and membrane delivery required for bacterial uptake. Our findings reveal an important role for RAB10 in the establishment of membrane reservoirs and the mechanisms by which Salmonella can exploit these compartments during host cell invasion.
Radionuclide tracing based in situ corrosion and mass transport monitoring of 316L stainless steel in a molten salt closed loop
Authors: Wang Yafei , Olson Aeli P. , Falconer Cody , Kelleher Brian , Mitchell Ivan , Zhang Hongliang , Sridharan Kumar , Engle Jonathan W. , Couet Adrien
Published: April 2024

In the study, we report an in situ corrosion and mass transport monitoring method developed using a radionuclide tracing technique for the corrosion study of 316L stainless steel (316L SS) in a NaCl–MgCl2 eutectic molten salt natural circulation loop. This method involves cyclotron irradiation of a small tube section with 16 MeV protons, later welds at the hot leg of the molten salt flow loop, generating radionuclides 51Cr, 52Mn, and 56Co at the salt–alloy interface. By measuring the activity variations of these radionuclides at different sections along the loop, both the in situ monitoring of the corrosion attack depth of 316L SS and corrosion product transport and its precipitation in flowing NaCl–MgCl2 molten salt are achieved. While 316L SS is the focus of this study, the technique reported herein can be extended to other structural materials being used in a wide range of industrial applications.
Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations
Authors: Lu Jiuwei , Guo Yiran , Yin Jiekai , Chen Jianbin , Wang Yinsheng , Wang Gang Greg , Song Jikui
Published: April 2024

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis
Authors: Bei Cheng , Zhu Junhao , Culviner Peter H. , Gan Mingyu , Rubin Eric J. , Fortune Sarah M. , Gao Qian , Liu Qingyun
Published: April 2024

Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) – the variability of gene expression in response to environmental changes – remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also find that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.
Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin
Authors: Pušnik Jernej , Zorn Jasmin , Monzon-Posadas Werner O. , Peters Kathrin , Osypchuk Emmanuil , Blaschke Sabine , Streeck Hendrik
Published: April 2024

Several studies have suggested the imprinting of SARS-CoV-2 immunity by original immune challenge without addressing the formation of the de novo response to successive antigen exposures. As this is crucial for the development of the original antigenic sin, we assessed the immune response against the mutated epitopes of omicron SARS-CoV-2 after vaccine breakthrough. Our data demonstrate a robust humoral response in thrice-vaccinated individuals following omicron breakthrough which is a recall of vaccine-induced memory. The humoral and memory B cell responses against the altered regions of the omicron surface proteins are impaired. The T cell responses to mutated epitopes of the omicron spike protein are present due to the high cross-reactivity of vaccine-induced T cells rather than the formation of a de novo response. Our findings, therefore, underpin the speculation that the imprinting of SARS-CoV-2 immunity by vaccination may lead to the development of original antigenic sin if future variants overcome the vaccine-induced immunity.
Fast pseudorandom quantum state generators via inflationary quantum gates
Authors: Chamon Claudio , Mucciolo Eduardo R. , Ruckenstein Andrei E. , Yang Zhi-Cheng
Published: April 2024

We propose a mechanism for reaching pseudorandom quantum states, computationally indistinguishable from Haar random, with shallow log-ndepth quantum circuits, wherenis the number of qudits. We argue that$$\log n$$logndepth 2-qubit-gate-based generic random quantum circuits that are claimed to provide a lower bound on the speed of information scrambling, cannot produce computationally pseudorandom quantum states. This conclusion is connected with the presence of polynomial (inn) tails in the stay probability of short Pauli strings that survive evolution through such shallow circuits. We show, however, that stay-probability-tails can be eliminated and pseudorandom quantum states can be accomplished with shallow$$\log n$$logndepth circuits built from a special universal family of “inflationary” quantum (IQ) gates. We prove that IQ-gates cannot be implemented with 2-qubit gates, but can be realized either as a subset of 2-qudit-gates inU(d2) withd ≥ 3 anddprime, or as special 3-qubit gates.
Investigating lexical categorization in reading based on joint diagnostic and training approaches for language learners
Authors: Gagl Benjamin , Gregorová Klara
Published: April 2024

Efficient reading is essential for societal participation, so reading proficiency is a central educational goal. Here, we use an individualized diagnostics and training framework to investigate processes in visual word recognition and evaluate its usefulness for detecting training responders. We (i) motivated a training procedure based on the Lexical Categorization Model (LCM) to introduce the framework. The LCM describes pre-lexical orthographic processing implemented in the left-ventral occipital cortex and is vital to reading. German language learners trained their lexical categorization abilities while we monitored reading speed change. In three studies, most language learners increased their reading skills. Next, we (ii) estimated, for each word, the LCM-based features and assessed each reader’s lexical categorization capabilities. Finally, we (iii) explored machine learning procedures to find the optimal feature selection and regression model to predict the benefit of the lexical categorization training for each individual. The best-performing pipeline increased reading speed from 23% in the unselected group to 43% in the machine-selected group. This selection process strongly depended on parameters associated with the LCM. Thus, training in lexical categorization can increase reading skills, and accurate computational descriptions of brain functions that allow the motivation of a training procedure combined with machine learning can be powerful for individualized reading training procedures.
FOXO1 is a master regulator of memory programming in CAR T cells
Authors: Doan Alexander E. , Mueller Katherine P. , Chen Andy Y. , Rouin Geoffrey T. , Chen Yingshi , Daniel Bence , Lattin John , Markovska Martina , Mozarsky Brett , Arias-Umana Jose , Hapke Robert , Jung In-Young , Wang Alice , Xu Peng , Klysz Dorota , Zuern Gabrielle , Bashti Malek , Quinn Patrick J. , Miao Zhuang , Sandor Katalin , Zhang Wenxi , Chen Gregory M. , Ryu Faith , Logun Meghan , Hall Junior , Tan Kai , Grupp Stephan A. , McClory Susan E. , Lareau Caleb A. , Fraietta Joseph A. , Sotillo Elena , Satpathy Ansuman T. , Mackall Crystal L. , Weber Evan W.
Published: April 2024

A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2–6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.