bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular and metabolic comorbidities in patients with thyroid nodules: the impact of incidental diagnosis
Authors: Croce L. , Ruggeri R. M. , Cappelli C. , Virili C. , Coperchini F. , Laganà M. , Costa P. , Dal Molin M. , Chytiris S. , Magri F. , Chiovato L. , Centanni M. , Cannavò S. , Rotondi M.
Published: September 2023

Purpose

The prevalence of thyroid nodules (TN) in the general population has increased as screening procedures are implemented and an association with metabolic and cardiovascular disorders has been reported. The aim of this study was to investigate the reason leading to the diagnosis of TN and to compare the clinical characteristics of patients diagnosed incidentally with those of patients diagnosed for thyroid-related reasons.

Methods

We designed a retrospective cross-sectional study including consecutive patients with TN from two high-volume hospital-based centers for thyroid diseases (Pavia and Messina) in Italy. Data regarding reason leading to TN diagnosis, age, sex, BMI, presence of cardio-metabolic comorbidities were collected.

Results

Among the 623 enrolled subjects, the US diagnosis of TN was prompted by thyroid-related reasons in 421 (67.6%, TD group) and incidental in 202 (32.4%, ID group) with a similar distribution in the two centers (p = 0.960). The ID group patients were more frequently males (38.6% vs 22.1%, p < 0.001) and significantly older (58.9 ± 13.7 vs 50.6 ± 15.5 years, p < 0.001) than the TD group ones, and had a higher rate of cardiovascular comorbidities (73.8% vs 47.5%, p < 0.001), despite having a similar BMI (27.9 ± 5.2 vs 27.8 ± 13.5, p = 0.893).

Conclusions

Stratification of patients with TN according to the diagnostic procedure leading to diagnosis allows a better epidemiological characterization of this inhomogeneous and large population.
Management of type 2 diabetes in the new era
Authors: Liakos Aris , Karagiannis Thomas , Avgerinos Ioannis , Malandris Konstantinos , Tsapas Apostolos , Bekiari Eleni
Published: September 2023

Purpose

Management of type 2 diabetes is advancing beyond glycemic control and is increasingly based on cardiovascular risk stratification. This review summarizes recent advances in the field and identifies existing knowledge gaps and areas of ongoing research.

Methods

A bibliographic search was carried out in PubMed for recently published cardiorenal outcome trials, relevant guidelines, and studies on antidiabetic agents in the pipeline.

Results

Findings from cardiovascular outcome trials support the use of glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with established cardiovascular disease or multiple risk factors, although it as yet remains uncertain whether the benefits are transferable to patients at lower absolute cardiovascular risk. Additionally, robust evidence suggests that SGLT-2 inhibitors improve clinical outcomes for people with concomitant heart failure or chronic kidney disease. Gut hormone multiagonists will likely represent another major addition to the therapeutic armamentarium for morbidly obese individuals with diabetes. Moreover, nonalcoholic fatty liver disease is a common comorbidity and several liver outcome trials are awaited with great interest. Use of insulin as first-line injectable therapy has been displaced by GLP-1 receptor agonists. Once-weekly formulations of basal insulins along with combinations with GLP-1 receptor agonists are also under development and could increase patient convenience. Technologies of glucose sensors are rapidly evolving and have the potential to reduce the burden of frequent blood glucose measurements, mainly for patients treated with intensified insulin regimens.

Conclusion

Management of type 2 diabetes requires a holistic approach and recent breakthroughs are expected to improve the quality of care.
The effect of selected aminoglycoside antibiotics on human serum albumin antioxidant activity: a spectroscopic and calorimetric comparative study
Authors: Rogóż Wojciech , Mac Kinga , Owczarzy Aleksandra , Kulig Karolina , Pożycka Jadwiga , Maciążek-Jurczyk Małgorzata
Published: September 2023

Background

Human serum albumin (HSA) is a valuable component of non-enzymatic and endogenous antioxidant mechanisms. The antioxidant activity of HSA can be modulated by ligands, including drugs. Although this is a central topic in the field of oxidation, there is still a lack of information about the protection against the effects of elevated free radical levels.

Methods

The aim of this study was to investigate the antioxidant activity of kanamycin (KAN) and neomycin (NEO) and their effect on the antioxidant potential of HSA using spectroscopic and microcalorimetric techniques.

Results

Despite the fact that kanamycin and neomycin interact with HSA, no changes in the secondary structure of the protein have been observed. The analysis of the aminoglycoside antibiotics showed their low antioxidant activity and a synergistic effect of the interaction, probably due to the influence of ligands (KAN, NEO) on the availability of HSA amino acid residues functional groups, such as the free thiol group (Cys-34).

Conclusions

Based on the spectroscopic and microcalorimetric data, both KAN and NEO can be considered modulators of the HSA antioxidant activity.
Numerical and thermal analysis of a caloric refrigeration device operating near room temperature
Authors: Kehileche Brahim , Chiba Younes , Tlemçani Abdelhalim , Henini Noureddine
Published: September 2023

The application of external stimuli such as the magnetic and electric field in magnetocaloric and electrocaloric materials, and stress and pressure in elastocaloric and barocaloric materials give rise to a new generation of a refrigeration technology based on caloric materials which are considered an emerging alternative to classical refrigeration. Active caloric regenerator (ACR) made in parallel plates is studied under a large number of materials with Comsol multiphysics for a 2D numerical model. In this work, we compare various types of caloric materials, in terms of their thermodynamic properties, working mechanisms, and potential applications as solid refrigerant on caloric refrigeration devices. For this purpose, the energy equation, Navier-Stocks equation, and continuity equation are considered to study the heat transfer phenomena in refrigerator. The water was used as a carrier fluid to transport the thermal energy from the solid refrigerants to heat exchanger. This study is performed at velocity 0.06 m/s and the frequency 2 Hz at room temperature. Among them, Gadolinium show the best results in term temperature span, coefficient of performance, and the cooling power, higher than every other caloric materials, conferring to magnetocaloric cooling globally the most promising system. Our analysis provides insights into the selection and optimization of caloric materials for caloric refrigeration, which can contribute to the development of sustainable energy systems.
Impact of measurement and feedback on chlorhexidine gluconate bathing among intensive care unit patients: A multicenter study
Authors: Rhee Yoona , Hayden Mary K. , Schoeny Michael , Baker Arthur W. , Baker Meghan A. , Gohil Shruti , Rhee Chanu , Talati Naasha J. , Warren David K. , Welbel Sharon , Lolans Karen , Bahadori Bardia , Bell Pamela B. , Bravo Heilen , Dangana Thelma , Fukuda Christine , Habrock Bach Tracey , Nelson Alicia , Simms Andrew T. , Tolomeo Pam , Wolf Robert , Yelin Rachel , Lin Michael Y. ,   for the CDC Prevention Epicenters Program
Published: September 2023

Objective:

To assess whether measurement and feedback of chlorhexidine gluconate (CHG) skin concentrations can improve CHG bathing practice across multiple intensive care units (ICUs).

Design:

A before-and-after quality improvement study measuring patient CHG skin concentrations during 6 point-prevalence surveys (3 surveys each during baseline and intervention periods).

Setting:

The study was conducted across 7 geographically diverse ICUs with routine CHG bathing.

Participants:

Adult patients in the medical ICU.

Methods:

CHG skin concentrations were measured at the neck, axilla, and inguinal region using a semiquantitative colorimetric assay. Aggregate unit-level CHG skin concentration measurements from the baseline period and each intervention period survey were reported back to ICU leadership, which then used routine education and quality improvement activities to improve CHG bathing practice. We used multilevel linear models to assess the impact of intervention on CHG skin concentrations.

Results:

We enrolled 681 (93%) of 736 eligible patients; 92% received a CHG bath prior to survey. At baseline, CHG skin concentrations were lowest on the neck, compared to axillary or inguinal regions (P < .001). CHG was not detected on 33% of necks, 19% of axillae, and 18% of inguinal regions (P < .001 for differences in body sites). During the intervention period, ICUs that used CHG-impregnated cloths had a 3-fold increase in patient CHG skin concentrations as compared to baseline (P < .001).

Conclusions:

Routine CHG bathing performance in the ICU varied across multiple hospitals. Measurement and feedback of CHG skin concentrations can be an important tool to improve CHG bathing practice.
Monitoring health disparities in healthcare-associated infection surveillance: A Society for Healthcare Epidemiology of America (SHEA) Research Network (SRN) Survey
Authors: McGrath Caitlin L. , Logan Latania K. , Deloney Valerie M. , Rubin Lorry G. , Ravin Karen A. , Muller Martha , Bartlett Allison H. , de St. Maurice Annabelle , Linam W. Matthew , Caughell Carolyn , Ramirez-Avila Lynn
Published: September 2023

We investigated whether and how infection prevention programs monitor for health disparities as part of healthcare-associated infection (HAI) surveillance through a survey of healthcare epidemiology leaders. Most facilities are not assessing for disparities in HAI rates. Professional society and national guidance should focus on addressing this gap.
Impact of the sequential implementation of a pharmacy-driven methicillin-resistant Staphylococcus aureus (MRSA) nasal-swab ordering policy and vancomycin 72-hour restriction protocol on standardized antibiotic administration ratio (SAAR) data for antibiotics used for resistant gram-positive infections
Authors: Pettit Natasha N. , Nguyen Cynthia T. , Lew Alison K. , Pisano Jennifer
Published: September 2023

Objective:

Vancomycin is often initiated in hospitalized patients; however, it may be unnecessary or continued for longer durations than needed. Oversight of all vancomycin orders may not be feasible with widespread prescribing and strategies to enlist other clinicians to serve as stewards of vancomycin use are needed. We implemented 2 sequential interventions: a protocol in which the pharmacist orders MRSA nasal swab followed by a protocol requiring approval from pharmacists to continue vancomycin for >72 hours.

Methods:

In this single-center, retrospective, quasi-experimental study, we evaluated vancomycin use after implementation of a pharmacy-driven MRSA nasal-swab ordering protocol and a vancomycin 72-hour restriction protocol. The primary outcome was the change in the standardized antibiotic administration ratio (SAAR) for antibacterial agents for resistant gram-positive infections. We also evaluated the impact on antibiotic utilization.

Results:

Following the MRSA swab protocol, the SAAR decreased from 1.26 to 1.13 (P < .001; 95% confidence interval [CI], 1.16–1.25). After the 72-hour approval process, the SAAR was 0.96 (P < .001; 95% CI, 1.0–1.12). Vancomycin utilization decreased from 138.9 to 125.3 days of therapy per 1,000 patient days following the MRSA swab protocol (P < .001) and to 112.7 (P < .001) following the 72-hour approval protocol. Interrupted time-series analysis identified a similar rate of decline in utilization following the 2 interventions (−0.3 and −0.5; P = .16). Both interventions combined resulted in a significant reduction (−1.5; P < .001).

Conclusion:

Implementation of a pharmacist-driven MRSA nasal-swab ordering protocol, followed by a 72-hour approval protocol, was associated with a significant reduction in the SAAR for antibiotics used in the treatment of resistant gram-positive infections and a reduction in vancomycin utilization. Leveraging the oversight of primary service clinical pharmacists through these protocols proved to be an effective strategy.
On the flow past ellipses in a Hele-Shaw cell
Authors: Klettner C.A. , Dang T.D. , Smith F.T.
Published: September 2023

In this work we investigate the effect of vertical confinement and inertia on the flow past thin ellipses in a Hele-Shaw cell (with centre line velocity

$U_c$

and height 2

$h$

) with different aspect ratios for symmetrical flows and at an angle of attack, using asymptotic methods and numerical simulations. A Stokes region is identified at the ellipse vertices which results in flow different to flow past bluff bodies. Comparison with asymptotic analysis indicates close agreement over the ‘flat’ portion of the ellipse, for

$\delta =(b/a)=0.05$

, where

$a$

and

$b$

are the semi-major and -minor ellipse axes, respectively. Two flow conditions are investigated for ellipses at an angle of attack of 10

$^\circ$

for a fixed

$\delta =0.05$

. Firstly, for

$\varLambda =(U_ca/\nu )(h/a)^2 \ll 1$

, the effect of increasing the vertical confinement of the Hele-Shaw cell results in the rear stagnation point (RSP) moving from close to the potential-flow prediction when

$\epsilon =h/a$

is very small to the two-dimensional Stokes-flow prediction when

$\epsilon$

is large. Secondly, for a fixed

$\epsilon \ll 1$

, when inertia is increased past

$\varLambda ={O}(\epsilon )$

the RSP moves towards the trailing edge and is located there for

$\varLambda ={O}(1)$

. Under these conditions an attached exponentially decaying shear layer or ‘viscous tail’ is formed. A modified Bernoulli equation of the depth-averaged flow, together with the Kutta–Joukowski theorem is used to predict the drag and lift coefficients on the ellipse, which include a linear and a nonlinear contribution, corresponding to a Hele-Shaw and circulation component, respectively. Close agreement is found up to

$\varLambda ={O}(1)$

.
MONETARY POLICY: PRICES VERSUS QUANTITIES
Authors: Broadbent Ben
Published: September 2023

Should the transmission of monetary policy be understood in terms of its impacts on interest rates and bond yields, or monetary aggregates? This article considers the relationship between those aggregates and inflation, both over the past and more recently. And explains how the MPC takes account of “QT” in its forecasts.
Farmers’ heterogeneous preferences for traits of improved varieties: Informing demand-oriented crop breeding in Tanzania
Authors: Regassa Mekdim D. , Miriti Philip K. , Melesse Mequanint B.
Published: September 2023

Understanding farmers’ preferences and willingness to pay for different traits is critical for demand-driven varietal development and designing targeted strategies that stimulate adoption of varieties by farmers. This study uses choice experiment data from a random sample of 1299 Tanzanian farmers to analyze their preferences for traits of groundnut varieties, investigate trade-offs involved in valuation of attributes, and explore heterogeneity in preferences. Results reveal that farmers have strong preferences for groundnut varieties that are high yielding, tolerant to environmental stresses, early-maturing, red-colored, and fetching high sale prices in grain markets. Farmers are willing to pay the highest premium for high-yielding attributes, closely followed by the tolerance trait. Further, a latent class analysis identifies four distinct classes of farmers, confirming considerable heterogeneity in farmers’ preferences for various groundnut traits. A specific distinction is notable between preferences of consumption-oriented and market-oriented farmer classes. Our results have important implications for demand-driven variety development and targeted dissemination of improved varieties.
Validating the biosocial model of borderline personality disorder: Findings from a longitudinal study
Authors: Lee Stephanie S. M. , Keng Shian-Ling , Hong Ryan Y.
Published: September 2023

This longitudinal study aimed to validate the biosocial theory of borderline personality disorder (BPD) by examining the transactional relationship between individual vulnerabilities and parental invalidation, and their links to BPD symptoms. We recruited a sample of 332 adolescents (mean age = 14.18 years; 58.3% female) residing in Singapore and administered self-report measures across three time-points (six months apart). Results from our path analytic model indicated that parental invalidation, impulsivity, and emotional vulnerability exhibited unique predictive associations with emotion dysregulation six months later. There was also a reciprocal prospective relationship between emotion regulation difficulties and BPD symptoms. Using random-intercepts cross-lagged panel models, we found partial evidence for a within-individual reciprocal relationship between parental invalidation and emotional vulnerability, and a unidirectional relationship of within-individual changes in impulsivity positively predicting changes in parental invalidation six months later. Overall, the study provided partial empirical support for the biosocial model in a Singaporean context.
Individual life insurance during epidemics
Authors: Francis Laura , Steffensen Mogens
Published: September 2023

The coronavirus pandemic has created a new awareness of epidemics, and insurance companies have been reminded to consider the risk related to infectious diseases. This paper extends the traditional multi-state models to include epidemic effects. The main idea is to specify the transition intensities in a Markov model such that the impact of contagion is explicitly present in the same way as in epidemiological models. Since we can study the Markov model with contagious effects at an individual level, we consider individual risk and reserves relating to insurance products, conforming with the standard multi-state approach in life insurance mathematics. We compare our notions with other but related notions in the literature and perform numerical illustrations.
The Nausicaa experience: Teaching Ancient Greek in French preschools and primary schools
Authors: Duchemin Laurence , Durand Adrienne , Franceschetti Brigitte
Published: September 2023

In the Marseille region in France, ancient Greek has been taught in pre-school and primary school for more than 20 years. The ‘Nausicaa’ Association was created in 1996 with an express purpose in mind. As Nausicaa was Odysseus' guide and helped him regain his dignity as a man and a king, so our association supports children in becoming more complete and richer humans, or so we hope. Nausicaa has grown enormously in the past 20 years, and currently operates in various schools in the South of France, in particular in Marseille and Aix-en-Provence. Around ten volunteers (teachers working in middle school, high school or retired) teach ancient Greek to pupils from pre-school to the end of primary school. All activities are done at school during class teaching time and in the school setting. This paper presents an outline of the activities of the Nausicaa Association and how it benefits pupils of all abilities in learning about the ancient Greeks and their language.
Sixty Years Later
Authors: Fransen Marieke L. , Mollen Saar , Rains Stephan A. , Das Enny , Vermeulen Ivar
Published: September 2023

Abstract: Inoculation theory was introduced 60 years ago, after McGuire and Papageorgis (1961) published their first study on how resistance to persuasion can be induced. They demonstrated that people who are pre-exposed to weakened arguments against an attitude or position they currently hold (i.e., inoculated) are less affected by a subsequent strong counter-attitudinal message than people who are pre-exposed to arguments consistent with their attitude (i.e., supportive defense treatment) or to no arguments. Although these results significantly impacted both science and practice on a general level, rigid tests of the key theoretical propositions are lacking. We conducted a highly powered replication study ( N = 679) and found that an inoculation treatment is more effective in increasing resistance toward persuasion compared to a supportive defense treatment and a no-treatment control condition. Our results were mostly consistent with McGuire and Papageorgis’s original work.
Prolongation of Compound Dry–Hot Seasons Over Europe Under Climate Change Scenarios
Authors: Lhotka Ondřej , Bešťáková Zuzana , Kyselý Jan
Published: September 2023

Compound effects of drought and heat are regarded as one of the greatest hazards in relation to climate change. We study characteristics of dry–hot seasons in Europe in an ensemble of CORDEX regional climate models (RCMs). Evaluation against the E‐OBS gridded data set for 1976–2005 showed that the RCMs were able to reproduce the spatial pattern of the dry–hot season length but the simulated seasons tended to start later and interannual variability of their length was underestimated. Bias was larger (smaller) in the case of maximum (minimum) length over the 30‐year period compared to the median length. Changes in the dry–hot seasons were then analyzed for three time slices (2006–2035, 2036–2065, and 2066–2095) and low and high greenhouse gas concentration pathways. Distinct prolongation (compared to the 1976–2005 simulated climate) was projected for 2036–2065 in the Mediterranean and Western Europe (10–30 days), regardless of the concentration pathway. The dry–hot seasons length was similar in the 2036–2065 and 2066–2095 time slices under the low concentration pathway but major extensions were found under the high concentration scenario over large parts of Europe (20–50 days). The projected spatial patterns of changes in the dry–hot seasons length depend primarily on the driving global climate model. Although the extensions are predominantly driven by increasing temperature, simulated precipitation changes modulate the resulting pattern by amplifying (reducing) the dry–hot seasons length in Southern (Northern) Europe.
Identifying the Impacts of Sea Ice Variability on the Climate and Surface Mass Balance of West Antarctica
Authors: Kromer Jessica D. , Trusel Luke D.
Published: September 2023

The Antarctic ice sheet (AIS) is the largest freshwater body on Earth and a major component of the sea level budget. Over the satellite era, the AIS has experienced ∼130 Gt/year of mass loss. Net losses are partially mitigated by snow accumulation that varies ∼100–130 Gt/yr, underscoring a need to understand the drivers of snowfall variability. Here, we evaluate impacts of decreased sea ice in the Amundsen Sea region of West Antarctica on the overlying atmosphere and surface mass balance of the adjacent AIS using composites, spatial correlations, and a causal effect network method. Importantly, our findings show sea ice declines in the Amundsen Sea lead to enhanced integrated water vapor that is subsequently transported to the AIS resulting in positive anomalies in West Antarctic ice sheet snowfall. Our results suggest future decreases in sea ice may likely enhance ice sheet snowfall, thus partially offsetting Antarctic sea level contributions.
Period‐ and Pressure‐Dependent Hydraulic Properties of a Fractured Granite Inferred From Periodic Pumping Tests
Authors: Barbosa Nicolás D. , Jiménez Martínez Victoria A. , Gholizadeh Doonechaly Nima , Müller Tobias M. , Holliger Klaus
Published: September 2023

Fractures can greatly impact fluid flow and pore pressure distribution in the upper crust. By conducting borehole hydraulic experiments, we can determine the ability of fractures to transport fluids and affect pressure diffusion under in situ conditions. We performed a series of periodic hydraulic tests in a borehole at the Bedretto Underground Laboratory for Geosciences and Geoenergies (Switzerland). We investigated the period‐ and pressure‐dependent response of a fractured granite by controlling the flow rate of harmonic and non‐harmonic oscillations, covering a wide range of periods as well as mean‐ and amplitude‐pressure values. By analyzing the phase and amplitude relation between the flow rate and fluid pressure in the injection interval, we found that the intersected fracture zone exhibits a period‐dependent hydraulic response close to radial flow perturbed by fracture‐related hydromechanical coupling effects. The main features of the interval's hydraulic response were reproduced by an uncoupled diffusion solution for radial flow, which was used to derive apparent hydraulic properties. The largest deviations from this model occur for the phase shifts and correlate with the pressure amplitude. This non‐linear expression of hydromechanical coupling associated with deformable fractures was interpreted in terms of a pressure‐dependent effective compliance of the fractures that affects their effective storativity. The period dependence is likely related to the spatial heterogeneity expected in fractured rocks and the varying sensitivity of the hydraulic response for different periods. Accounting for these effects is necessary for a correct hydraulic characterization in fractured environments and is valuable for inferring fracture mechanical behavior.
Lactobacillus-derived extracellular vesicles counteract Aβ42-induced abnormal transcriptional changes through the upregulation of MeCP2 and Sirt1 and improve Aβ pathology in Tg-APP/PS1 mice
Authors: Kwon Hyejin , Lee Eun-Hwa , Park So-Young , Park Jin-Young , Hong Jin-Hwan , Kim Eun-Kyung , Shin Tae-Seop , Kim Yoon-Keun , Han Pyung-Lim
Published: September 2023

Mounting evidence suggests that probiotics are beneficial for treating Alzheimer’s disease (AD). However, the mechanisms by which specific probiotics modify AD pathophysiology are not clearly understood. In this study, we investigated whether Lactobacillus paracasei-derived extracellular vesicles (Lpc-EV) can directly act on neuronal cells to modify amyloid-beta (Aβ)-induced transcriptional changes and Aβ pathology in the brains of Tg-APP/PS1 mice. Lpc-EV treatment in HT22 neuronal cells counteracts Aβ-induced downregulation of Brain-derived neurotrophic factor (Bdnf), Neurotrophin 3 (Nt3), Nt4/5, and TrkB receptor, and reverses Aβ-induced altered expression of diverse nuclear factors, including the downregulation of Methyl-CpG binding protein 2 (Mecp2) and Sirtuin 1 (Sirt1). Systematic siRNA-mediated knockdown experiments indicate that the upregulation of Bdnf, Nt3, Nt4/5, and TrkB by Lpc-EV is mediated via multiple epigenetic factors whose activation converges on Mecp2 and Sirt1. In addition, Lpc-EV reverses Aβ-induced downregulation of the Aβ-degrading proteases Matrix metalloproteinase 2 (Mmp-2), Mmp-9, and Neprilysin (Nep), whose upregulation is also controlled by MeCP2 and Sirt1. Lpc-EV treatment restores the downregulated expression of Bdnf, Nt4/5, TrkB, Mmp-2, Mmp-9, and Nep; induces the upregulation of MeCP2 and Sirt1 in the hippocampus; alleviates Aβ accumulation and neuroinflammatory responses in the brain; and mitigates cognitive decline in Tg-APP/PS1 mice. These results suggest that Lpc-EV cargo contains a neuroactive component that upregulates the expression of neurotrophic factors and Aβ-degrading proteases (Mmp-2, Mmp-9, and Nep) through the upregulation of MeCP2 and Sirt1, and ameliorates Aβ pathology and cognitive deficits in Tg-APP/PS1 mice.
Major vault protein (MVP) suppresses aging- and estrogen deficiency-related bone loss through Fas-mediated apoptosis in osteoclasts
Authors: Wang Ruobing , Yang Yan , Zhang Zhongyin , Zhao Na , Wiemer Erik A. C. , Ben Jingjing , Ma Junqing , Yuan Lichan
Published: September 2023

Osteoclasts (OCs), derived from monocyte/macrophage lineage, are key orchestrators in bone remodeling. Targeting osteoclast apoptosis is a promising approach to cut down excessive osteoclast numbers, and thus slow down the rate of bone mass loss that inevitably occurs during aging. However, the therapeutic target of apoptosis in osteoclasts has not been fully studied. Our previous work generated Mvpf/fLyz2-Cre mice, conditionally depleting major vault protein (MVP) in monocyte lineage, and identified MVP as a bone protector for its negative role in osteoclastogenesis in vivo and in vitro. Here, we observed a notable decline of MVP in osteoclasts with aging in mice, encouraging us to further investigate the regulatory role of osteoclast MVP. Then, Mvpf/fLyz2-Cre mice were exploited in two osteoporosis contexts, aging and abrupt loss of estrogen, and we revealed that conditional knockout of MVP inhibited osteoclast apoptosis in vivo and in vitro. Moreover, we reported the interaction between MVP and death receptor Fas, and MVP-Fas signaling cascade was identified to positively regulate the apoptosis of osteoclasts, thus preventing osteoporosis. Collectively, our comprehensive discovery of MVP’s regulatory role in osteoclasts provides new insight into osteoclast biology and therapeutic targets for osteoporosis.
miR-92a-3p regulates cisplatin-induced cancer cell death
Authors: Larrue Romain , Fellah Sandy , Boukrout Nihad , De Sousa Corentin , Lemaire Julie , Leboeuf Carolane , Goujon Marine , Perrais Michael , Mari Bernard , Cauffiez Christelle , Pottier Nicolas , Van der Hauwaert Cynthia
Published: September 2023

Non-small cell lung cancer is characterized by a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Therefore, the identification of new molecular determinants underlying sensitivity of cancer cells to existing therapy is of particular importance to develop new effective combinatorial treatment strategy. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been established as master regulators of a variety of cellular processes that play a key role in tumor initiation, progression and metastasis. This, along with their widespread deregulation in many distinct cancers, has triggered enthusiasm for miRNAs as novel therapeutic targets for cancer management, in particular in patients with refractory cancers such as those harboring KRAS mutations. In this study, we performed a loss-of-function screening approach to identify miRNAs whose silencing promotes sensitivity of lung adenocarcinoma (LUAD) cells to cisplatin. Our results showed in particular that antisense oligonucleotides directed against miR-92a-3p, a member of the oncogenic miR-17 ~ 92 cluster, caused the greatest increase in the sensitivity of KRAS-mutated LUAD cells to cisplatin. In addition, we demonstrated that this miRNA finely regulates the apoptotic threshold and the proliferative capacity of various tumor cell lines with distinct genetic alterations. Collectively, these data suggest that targeting miR-92a-3p may serve as an effective strategy to overcome treatment resistance of solid tumors.
A single-cell atlas of West African lungfish respiratory system reveals evolutionary adaptations to terrestrialization
Authors: Zhang Ruihua , Liu Qun , Pan Shanshan , Zhang Yingying , Qin Yating , Du Xiao , Yuan Zengbao , Lu Yongrui , Song Yue , Zhang Mengqi , Zhang Nannan , Ma Jie , Zhang Zhe , Jia Xiaodong , Wang Kun , He Shunping , Liu Shanshan , Ni Ming , Liu Xin , Xu Xun , Yang Huanming , Wang Jian , Seim Inge , Fan Guangyi
Published: September 2023

The six species of lungfish possess both lungs and gills and are the closest extant relatives of tetrapods. Here, we report a single-cell transcriptome atlas of the West African lungfish (Protopterus annectens). This species manifests the most extreme form of terrestrialization, a life history strategy to survive dry periods that can last for years, characterized by dormancy and reversible adaptive changes of the gills and lungs. Our atlas highlights the cell type diversity of the West African lungfish, including gene expression consistent with phenotype changes of terrestrialization. Comparison with terrestrial tetrapods and ray-finned fishes reveals broad homology between the swim bladder and lung cell types as well as shared and idiosyncratic changes of the external gills of the West African lungfish and the internal gills of Atlantic salmon. The single-cell atlas presented here provides a valuable resource for further exploration of the respiratory system evolution in vertebrates and the diversity of lungfish terrestrialization.
Global impact of somatic structural variation on the cancer proteome
Authors: Chen Fengju , Zhang Yiqun , Chandrashekar Darshan S. , Varambally Sooryanarayana , Creighton Chad J.
Published: September 2023

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels considerably extend the numbers of patients with tumors somatically altered for critical pathways. We catalog both SV breakpoint patterns involving patient survival and genes with nearby SV breakpoints associated with increased cell dependency in cancer cell lines. Pan-cancer proteogenomics identifies targetable non-coding alterations, by virtue of the associated deregulated genes.
Human OPRM1 and murine Oprm1 promoter driven viral constructs for genetic access to μ-opioidergic cell types
Authors: Salimando Gregory J. , Tremblay Sébastien , Kimmey Blake A. , Li Jia , Rogers Sophie A. , Wojick Jessica A. , McCall Nora M. , Wooldridge Lisa M. , Rodrigues Amrith , Borner Tito , Gardiner Kristin L. , Jayakar Selwyn S. , Singeç Ilyas , Woolf Clifford J. , Hayes Matthew R. , De Jonghe Bart C. , Bennett F. Christian , Bennett Mariko L. , Blendy Julie A. , Platt Michael L. , Creasy Kate Townsend , Renthal William R. , Ramakrishnan Charu , Deisseroth Karl , Corder Gregory
Published: September 2023

With concurrent global epidemics of chronic pain and opioid use disorders, there is a critical need to identify, target and manipulate specific cell populations expressing the mu-opioid receptor (MOR). However, available tools and transgenic models for gaining long-term genetic access to MOR+ neural cell types and circuits involved in modulating pain, analgesia and addiction across species are limited. To address this, we developed a catalog of MOR promoter (MORp) based constructs packaged into adeno-associated viral vectors that drive transgene expression in MOR+ cells. MORp constructs designed from promoter regions upstream of the mouse Oprm1 gene (mMORp) were validated for transduction efficiency and selectivity in endogenous MOR+ neurons in the brain, spinal cord, and periphery of mice, with additional studies revealing robust expression in rats, shrews, and human induced pluripotent stem cell (iPSC)-derived nociceptors. The use of mMORp for in vivo fiber photometry, behavioral chemogenetics, and intersectional genetic strategies is also demonstrated. Lastly, a human designed MORp (hMORp) efficiently transduced macaque cortical OPRM1+ cells. Together, our MORp toolkit provides researchers cell type specific genetic access to target and functionally manipulate mu-opioidergic neurons across a range of vertebrate species and translational models for pain, addiction, and neuropsychiatric disorders.
Learning heterogeneous reaction kinetics from X-ray videos pixel by pixel
Authors: Zhao Hongbo , Deng Haitao Dean , Cohen Alexander E. , Lim Jongwoo , Li Yiyang , Fraggedakis Dimitrios , Jiang Benben , Storey Brian D. , Chueh William C. , Braatz Richard D. , Bazant Martin Z.
Published: September 2023

Reaction rates at spatially heterogeneous, unstable interfaces are notoriously difficult to quantify, yet are essential in engineering many chemical systems, such as batteries1 and electrocatalysts2. Experimental characterizations of such materials by operando microscopy produce rich image datasets3–6, but data-driven methods to learn physics from these images are still lacking because of the complex coupling of reaction kinetics, surface chemistry and phase separation7. Here we show that heterogeneous reaction kinetics can be learned from in situ scanning transmission X-ray microscopy (STXM) images of carbon-coated lithium iron phosphate (LFP) nanoparticles. Combining a large dataset of STXM images with a thermodynamically consistent electrochemical phase-field model, partial differential equation (PDE)-constrained optimization and uncertainty quantification, we extract the free-energy landscape and reaction kinetics and verify their consistency with theoretical models. We also simultaneously learn the spatial heterogeneity of the reaction rate, which closely matches the carbon-coating thickness profiles obtained through Auger electron microscopy (AEM). Across 180,000 image pixels, the mean discrepancy with the learned model is remarkably small (<7%) and comparable with experimental noise. Our results open the possibility of learning nonequilibrium material properties beyond the reach of traditional experimental methods and offer a new non-destructive technique for characterizing and optimizing heterogeneous reactive surfaces.
Single-cell brain organoid screening identifies developmental defects in autism
Authors: Li Chong , Fleck Jonas Simon , Martins-Costa Catarina , Burkard Thomas R. , Themann Jan , Stuempflen Marlene , Peer Angela Maria , Vertesy Ábel , Littleboy Jamie B. , Esk Christopher , Elling Ulrich , Kasprian Gregor , Corsini Nina S. , Treutlein Barbara , Knoblich Juergen A.
Published: September 2023

The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders1–4. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.
Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor
Authors: Zhang Danyang , Ivica Josip , Krieger James M. , Ho Hinze , Yamashita Keitaro , Stockwell Imogen , Baradaran Rozbeh , Cais Ondrej , Greger Ingo H.
Published: September 2023

AMPA glutamate receptors (AMPARs), the primary mediators of excitatory neurotransmission in the brain, are either GluA2 subunit-containing and thus Ca2+-impermeable, or GluA2-lacking and Ca2+-permeable1. Despite their prominent expression throughout interneurons and glia, their role in long-term potentiation and their involvement in a range of neuropathologies2, structural information for GluA2-lacking receptors is currently absent. Here we determine and characterize cryo-electron microscopy structures of the GluA1 homotetramer, fully occupied with TARPγ3 auxiliary subunits (GluA1/γ3). The gating core of both resting and open-state GluA1/γ3 closely resembles GluA2-containing receptors. However, the sequence-diverse N-terminal domains (NTDs) give rise to a highly mobile assembly, enabling domain swapping and subunit re-alignments in the ligand-binding domain tier that are pronounced in desensitized states. These transitions underlie the unique kinetic properties of GluA1. A GluA2 mutant (F231A) increasing NTD dynamics phenocopies this behaviour, and exhibits reduced synaptic responses, reflecting the anchoring function of the AMPAR NTD at the synapse. Together, this work underscores how the subunit-diverse NTDs determine subunit arrangement, gating properties and ultimately synaptic signalling efficiency among AMPAR subtypes.
An intensive longitudinal dataset of in-game player behaviour and well-being in PowerWash Simulator
Authors: Vuorre Matti , Magnusson Kristoffer , Johannes Niklas , Butlin James , Przybylski Andrew K.
Published: September 2023

The potential impacts that video games might have on players’ well-being are under increased scrutiny but poorly understood empirically. Although extensively studied, a level of understanding required to address concerns and advise policy is lacking, at least partly because much of this science has relied on artificial settings and limited self-report data. We describe a large and detailed dataset that addresses these issues by pairing video game play behaviors and events with in-game well-being and motivation reports. 11,080 players (from 39 countries) of the first person PC game PowerWash Simulator volunteered for a research version of the game that logged their play across 10 in-game behaviors and events (e.g. task completion) and 21 variables (e.g. current position), and responses to 6 psychological survey instruments via in-game pop-ups. The data consists of 15,772,514 gameplay events, 726,316 survey item responses, and 21,202,667 additional gameplay status records, and spans 222 days. The data and codebook are publicly available with a permissive CC0 license.
A simple approach for image-based modelling of the heart that enables robust simulation of highly heterogeneous electrical excitation
Authors: Colman Michael A. , Benson Alan P.
Published: September 2023

Remodelling of cardiac tissue structure, including intercellular electrical coupling, is a major determinant of the complex and heterogeneous excitation patterns associated with cardiac arrhythmias. Evaluation of the precise mechanisms by which local tissue structure determines global arrhythmic excitation patterns is a major challenge that may be critically important for the development of effective treatment strategies. Computational modelling is a key tool in the study of cardiac arrhythmias, yet the established approaches for organ-scale modelling are unsuitable to capture the impact of local conduction heterogeneities; a novel approach is required to provide this multi-scale mechanistic insight. We present a fundamentally simple yet powerful approach to simulate electrical excitation in highly heterogeneous whole-heart models that exploits the underlying discreteness of the myocardium. Preliminary simulations demonstrate that this approach can capture lower conduction velocities and reproduce wave breakdown and the development of re-entry in a range of conditions.
Facile preparation of silver based radiosensitizers via biomineralization method for enhanced in vivo breast cancer radiotherapy
Authors: Ghaffarlou Mohammadreza , Mohammadi Ali , Mousazadeh Navid , Salehiabar Marziyeh , Kalantari Yahya , Charmi Jalil , Barsbay Murat , Ertas Yavuz Nuri , Danafar Hossein , Rezaeejam Hamed , Nosrati Hamed , Javani Siamak
Published: September 2023

To solve the traditional radiotherapy obstacles, and also to enhance the radiation therapy efficacy various radiosensitizers have been developed. Radiosensitizers are promising agents that under X-ray irradiation enhance injury to tumor tissue by accelerating DNA damage. In this report, silver-silver sulfide nanoparticles (Ag-Ag2S NPs) were synthesized via a facile, one-pot and environmentally friendly biomineralization method. Ag-Ag2S was coated with bovine serum albumin (BSA) in situ and applied as an X-ray sensitizer to enhance the efficiency of radiotherapy. Also, folic acid (FA) was conjugated to Ag-Ag2S@BSA to impart active targeting capability to the final formulation (Ag-Ag2S@BSA-FA). Prepared NPs were characterized by transmission electron microscopes (TEM), scanning electron microscope (SEM), dynamic light scattering (DLS), ultraviolet–visible spectroscopy (UV–Vis), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS) techniques. Results show that most of the NPs have well-defined uniform Janus structures. The biocompatibility of the NPs was then evaluated both in vitro and in vivo. A series of in vitro assays were performed on 4T1 cancer cells to evaluate the therapeutic efficacy of the designed NPs. In addition, the radio-enhancing ability of the NPs was tested on the 4T1 breast cancer murine model. MTT, live and dead cell staining, apoptosis, ROS generation, and clonogenic in vitro assays demonstrated the efficacy of NPs as radiosensitizers in radiotherapy. In vivo results as well as H&E staining tumor tissues confirmed tumor destruction in the group that received Ag-Ag2S@BSA-FA NPs and exposed to X-ray. The results showed that prepared tumor-targeted Ag-Ag2S@BSA-FA NPs could be potential candidates as radiosensitizers for enhanced radiotherapy.
Comprehensive analyses of the occurrence of a fungicide resistance marker and the genetic structure in Erysiphe necator populations
Authors: Pintye Alexandra , Németh Márk Z. , Molnár Orsolya , Horváth Áron N. , Matolcsi Fruzsina , Bókony Veronika , Spitzmüller Zsolt , Pálfi Xénia , Váczy Kálmán Z. , Kovács Gábor M.
Published: September 2023

Genetically distinct groups of Erysiphe necator, the fungus causing grapevine powdery mildew infect grapevine in Europe, yet the processes sustaining stable genetic differences between those groups are less understood. Genotyping of over 2000 field samples from six wine regions in Hungary collected between 2017 and 2019 was conducted to reveal E. necator genotypes and their possible differentiation. The demethylase inhibitor (DMI) fungicide resistance marker A495T was detected in all wine regions, in 16% of the samples. Its occurrence differed significantly among wine regions and grape cultivars, and sampling years, but it did not differ between DMI-treated and untreated fields. Multilocus sequence analyses of field samples and 59 in vitro maintained isolates revealed significant genetic differences among populations from distinct wine regions. We identified 14 E. necator genotypes, of which eight were previously unknown. In contrast to the previous concept of A and B groups, European E. necator populations should be considered genetically more complex. Isolation by geographic distance, growing season, and host variety influence the genetic structuring of E. necator, which should be considered both during diagnoses and when effective treatments are planned.