bluuebunny/crossref_metadata_2025 huggingface dataset:
Modern ocean island basalt–like 182W signature in Paleoarchean mafic rocks: Implications for the generation, preservation, and destruction of early mantle heterogeneities
Authors: Mei Qing-Feng , Yang Jin-Hui , Li Chao-Feng , Wang Xuan-Ce , Konnunaho Jukka , Wu Ya-Dong , Zhong Hong , Xu Yi-Gang , Wang Hao
Published: July 2023

Komatiites and picrites generated by high degrees of mantle partial melting serve as potential probes of Earth’s deep mantle. Tungsten (W) isotopes in these rocks offer a rare chance to better understand early differentiation, late accretion, core-mantle interaction, and subsequent evolution of Earth’s mantle. We present new W isotope data for Archean komatiites and basalts from the Barberton (South Africa) and Suomussalmi (Finland) Greenstone Belts and Permian picrites from the Emeishan large igneous province (China). The Paleoarchean samples from the Barberton Greenstone Belt have modern ocean island basalt (OIB)–like μ182W values ranging from –20.4 to +5.6, whereas the Mesoarchean komatiites from the Suomussalmi Greenstone Belt show μ182W values of –2.2 to +11.3. The Permian Emeishan picrites give μ182W values of –7.1 to +3.1. Our data, combined with the published global data set, show that W isotope heterogeneity in the mantle has existed throughout Earth’s history, with positive μ182W values transitioning to near-zero in the upper mantle by the end of the Archean. The negative μ182W values of Paleoarchean samples in the Barberton Greenstone Belt and modern OIBs likely result from either early differentiation or core-mantle interaction. The incorporation of a plume-delivered negative μ182W component and enhanced mantle mixing is a viable mechanism to explain the transition of μ182W values in the upper mantle from positive to near-zero, while recycling of crustal materials into the mantle would result in a shift of negative μ182W values of the lower mantle closer to zero since the onset of plate tectonics. The latter process could possibly explain the slightly negative to near-zero μ182W values of the Emeishan picrites and some kimberlites. The well-resolved negative μ182W anomalies observed in this study provide important insights into the generation, preservation, and obliteration of W isotope heterogeneities in the lower mantle.
Decompositions in Semirings
Authors: Batueva Ts. Ch.-D. , Schwidefsky M. V.
Published: July 2023

We prove that each element of a complete atomic $ l $-semiring has a canonical decomposition.
We also find some sufficient conditions for the decomposition to be unique
that are expressed by first-order sentences.
As a corollary, we obtain a theorem of Avgustinovich–Frid which claims that
each factorial language has the unique canonical decomposition.
Epidural pain management in advanced gastric cancer with inoperable malignant bowel obstruction
Authors: Bohan Riley , Budweg Jeffery , Vose Stephen , Sorin Mircea
Published: July 2023

Presented is a case of a man in his 20s with gastric cancer with metastasis to a perineal nodule and the splenic flexure (previously resected due to acute bowel obstruction) who presented with prolonged, intermittent, inoperable bowel obstruction likely due to adhesions, exacerbated by functional ileus due to substantial opioid requirement. In an episode of obstruction during the described admission, the patient remained obstructed after more than 10 days of medical management. The patient suffered from intense abdominal distention and pain, necessitating hundreds of oral morphine equivalents daily. A ropivacaine thoracic epidural infusion was initiated, allowing decreased opioid use and relief of opioid-induced ileus contributing to his bowel obstruction. He subsequently had multiple formed bowel movements, which quickly decreased the patient’s abdominal distention and immediate risk of perforation. This case explores epidurals as an underutilised approach to pain management in metastatic gastric malignancy and inoperable malignant bowel obstructions.
It takes quality improvement to cross the chasm
Authors: Pirritano Matthew , Miller Parrish Katrina , Kim Yonsu , Solomon Henock , Keene Jordan
Published: July 2023

Healthcare organisations in the USA rank significantly lower in quality of care compared with other developed nations. Research shows US performance emphasises expensive treatment over effective prevention programmes. This study demonstrates how a comprehensive quality improvement programme can improve health outcomes in a large county-based Medicaid health plan. The health plan serves a diverse community of members spanning racial and ethnic groups with varying levels of clinical risk and social determinants of health burdens. We used a regression discontinuity design to evaluate the impact of a comprehensive quality improvement programme vs using mainly pay-for-performance on Healthcare Effectiveness Data and Information Set (HEDIS) metrics over the course of 10 years. We found significant improvements in several HEDIS metrics that occurred after the quality improvement programme was implemented. These results demonstrate the importance of using a comprehensive quality improvement strategy along with pay-for-performance to improve health outcomes. It was determined that this research was exempt from institutional review board approval, as it used administrative healthcare data, and did not involve direct interventions with human subjects.
Abstracts from international emergency medicine journals
Authors: Production EMJ
Published: July 2023

Editor’s note: EMJ has partnered with the journals of multiple international emergency medicine societies to share from each a highlighted research study, as selected by their editors. This edition will feature an abstract from each publication.
Review of the National Institute for Health and Care Excellence guidelines on the management of atrial and ventricular arrhythmias
Authors: Lambiase Pier D , Maclean Edd
Published: July 2023

The National Institute for Health and Care Excellence (NICE) guidelines present a synopsis of extensive internal evidence and technology reviews, with a particular focus on clinical efficacy and cost-effectiveness within the NHS in England. This approach has delivered a novel perspective on arrhythmia management, with important distinctions from other policymakers’ recommendations. For example, when compared with the European Society of Cardiology (ESC) and the American Heart Association (AHA)/Heart Rhythm Society (HRS)/American College of Cardiology (ACC) guidelines on atrial fibrillation (AF), NICE advocates unique strategies regarding arrhythmia detection, stroke and bleeding risk stratification, and rhythm control (NICE CG 196). Likewise, for patients at risk of sudden cardiac death, NICE TA314 not only recommends device therapy based on New York Heart Association class and ECG findings, but also incorporates quality-adjusted life year data from analysis of key randomised controlled trials.

This review examines the NICE guidelines, together with those from the AHA/HRS/ACC and ESC, on the management of AF and ventricular arrhythmias and highlights the key common features and discrepancies between these important documents.
Pattern recognition receptor agonists in pathogen vaccines mediate antitumor T-cell cross-priming
Authors: Aleynick Mark , Svensson-Arvelund Judit , Pantsulaia Gvantsa , Kim Kristy , Rose Samuel A , Upadhyay Ranjan , Yellin Michael , Marsh Henry , Oreper Daniel , Jhunjhunwala Suchit , Moussion Christine Carine , Merad Miriam , Brown Brian D , Brody Joshua D
Published: July 2023

Background

Cancer immunotherapies are generally effective in patients whose tumors contain a priori primed T-cells reactive to tumor antigens (TA). One approach to prime TA-reactive T-cells is to administer immunostimulatory molecules, cells, or pathogens directly to the tumor site, that is, in situ vaccination (ISV). We recently described an ISV using Flt3L to expand and recruit dendritic cells (DC), radiotherapy to load DC with TA, and pattern recognition receptor agonists (PRRa) to activate TA-loaded DC. While ISV trials usingsyntheticPRRa have yielded systemic tumor regressions, the optimal method to activate DCs is unknown.

Methods

To discover optimal DC activators and increase access to clinical grade reagents, we assessed whether viral or bacterial components found in common pathogen vaccines are an effective source ofnatural PRRa(naPRRa). Using deep profiling (155-metric) of naPRRa immunomodulatory effects and gene editing of specific PRR, we defined specific signatures and molecular mechanisms by which naPRRa potentiate T-cell priming.

Results

We observed that vaccine naPRRa can be even more potent in activating Flt3L-expanded murine and human DCs than synthetic PRRa, promoting cross-priming of TA-reactive T-cells. We developed a mechanistically diverse naPRRa combination (BCG, PedvaxHIB, Rabies) and noted more potent T-cell cross-priming than with any single naPRRa. The naPRRa triplet—as part of Flt3L-primed ISV—induced greater intratumoral CD8 T-cell infiltration, T-cells reactive to a newly defined tumorous neoantigen, durable tumor regressions.

Conclusions

This work provides rationale for the translation of pathogen vaccines as FDA-approved clinical-grade DC activators which could be exploited as immune-stimulants for early phase trials.
An Overview of Speech Enhancement Based on Deep Learning Techniques
Authors: Jannu Chaitanya , Vanambathina Sunny Dayal
Published: July 2023

Recent years have seen a significant amount of studies in the area of speech enhancement. This review looks at several speech improvement methods as well as Deep Neural Network (DNN) functions in speech enhancement. Speech transmissions are frequently distorted by ambient noise, background noise, and reverberations. There are processing methods, such as Short-time Fourier Transform, Short-time Autocorrelation, and Short-time Energy (STE), that can be used to enhance speech. To reduce speech noise, features such as the Mel-Frequency Cepstral Coefficients (MFCCs), Logarithmic Power Spectrum (LPS), and Gammatone Frequency Cepstral Coefficients (GFCCs) can be retrieved and input to a DNN. DNN is essential to speech improvement since it builds models using a lot of training data and evaluates the efficacy of the enhanced speech using certain performance metrics. Since the beginning of deep learning publications in 1993, a variety of speech enhancement methods have been examined in this study. This review provides a thorough examination of the several neural network topologies, training algorithms, activation functions, training targets, acoustic features, and databases that were employed for the job of speech enhancement and were gathered from various articles published between 1993 and 2022.
Image Processing-Based Method of Evaluation of Stress from Grain Structures of Through Silicon Via (TSV)
Authors: Sharma Manvinder , Saripalli Sudhakara Reddy , Gupta Anuj Kumar , Palta Pankaj , Pandey Digvijay
Published: July 2023

Visualization of material composition across numerous grains and complicated networks of grain boundaries using image processing techniques can reveal fresh insights into the material’s structural evolution and upcoming functional capabilities for a variety of applications. Three-dimensional integrated circuits (3D IC) are the most practical technology for increasing transistor density in future semiconductor applications. One of the key benefits of 3D IC is heterogeneous integration, which results in shorter interconnections due to vertical stacking. However, one of the most significant challenges in building higher-density microelectronics devices is the stress generated by material mismatches in the coefficient of thermal expansion (CTE). The purpose of this study is to analyze grain boundary migration caused by variations in strain energy density using image processing methods for 3D grain continuum modeling. Temperature changes in polycrystalline structures generate stresses and strain energy densities, which may be calculated using FEM software. Single crystal Cu’s anisotropic elastic properties are twisted to suit grain orientation in space and each grain is treated as a single crystal. Grain boundary speeds are calculated using a simple model that relates grain boundary mobility to variations in strain energy density on both sides of grain boundaries. Using the grain continuum model, researchers will be able to investigate the effect of thermally generated stresses on grain boundary motion caused by atomic flux driven by strain energy. Using finite-element modeling of the grain structure in a Through Silicon Via, the stress effect on grain boundaries caused by grain rotation due to CTE mismatch was investigated (TSV). The structure must be modeled using a scanning electron microscopes Electron Backscatter Diffraction (EBSD) image (SEM). Grain growth and subsequent grain boundary rotation can be performed using the appropriate extrapolation method to measure their influence on stress and, as a result, the TSV’s overall reliability.
THE ROLE OF ETHICAL ORGANISATIONAL CLIMATE IN ENHANCING INTERNATIONAL EXECUTIVES’ INDIVIDUAL AND TEAM CREATIVITY
Authors: SWALHI ABDELAZIZ , MNISRI KAMEL , AMARI AMINA , HOFAIDHLLAOUI MAHRANE
Published: July 2023

This research aims to investigate how creativity at individual and team levels relates to ethical organisational climate (EOC). A mediated and moderated model is proposed to explain the role of EOC in enhancing individual and team creativity of international business executives. Applying moderating-mediating model design, based on feedback from 302 employees, our research reveals and confirms that creativity and ethics can co-exist. A positive relationship is found between EOC and individual creativity, while EOC is linked to team creativity through individual creativity. Further, we found that business size moderates the relationship between EOC and creativity at individual and team levels. This study contributes to the literature by offering empirical evidence on how EOC can be a catalyst to creativity. Managerial and theoretical implications of our findings are also discussed.
New insights on the upper Silurian Fegaguira Formation shale-oil play in the Chotts Basin (southern Tunisia)
Authors: Belhaj Mohamed Anis , Soussi Mohamed , Saidi Moncef , Jarvie D.M.
Published: July 2023

In Tunisia Chotts Basin, the upper Silurian (Ludfordian) Fegaguira Formation comprises organic-rich black mudstones deposited during a major anoxic event. It is a prolific source rock, having yielded a large volume of oil and gas from conventional reservoirs that reached about 69 MMboe, with around 45 MMboe as recoverable reserves still to be produced. Based on various investigations, the stratigraphy of the Fegaguira Formation is updated and its unconventional play potential is assessed.

It is divided, in the present work, into three units (HSII.1, HSII.2 and HSII.3) characterized by gamma-ray values of up to 400° API, organic matter content (up to 17 wt% total organic carbon) and petroleum potential (up to 60 mgHC g
−1
rock) with mature Type II marine kerogen. The first and the second units, which are dominantly organic-rich mudstones, can be compared to the Mississippian Barnett, Miocene Antelope and Cretaceous Tuscaloosa shales of the USA.

Evaluation of the brittleness index shows that the HSII.1 and HSII.2 units are mostly ductile and comparable to tight oil and gas reservoirs, while the third HSII.3 unit, where organic-rich facies are juxtaposed to organic-lean limestone beds with natural fractures (porosity between 3 and 7%), may be compared to the Niobrara B Formation.

Within the shale-oil fairway of the Chotts Basin, the estimated recoverable oil is around 1.3 Bbbl. It is comparable to the recoverable oil estimated volume for the Middle Member of the Bakken in the USA. This study demonstrates that the Fegaguira Formation source rock should be considered as an additional unconventional oil-shale target for Tunisia.
ArchRepair
: Block-Level Architecture-Oriented Repairing for Deep Neural Networks
Authors: Qi Hua , Wang Zhijie , Guo Qing , Chen Jianlang , Juefei-Xu Felix , Zhang Fuyuan , Ma Lei , Zhao Jianjun
Published: July 2023

Over the past few years, deep neural networks (DNNs) have achieved tremendous success and have been continuously applied in many application domains. However, during the practical deployment in industrial tasks, DNNs are found to be erroneous-prone due to various reasons such as overfitting and lacking of robustness to real-world corruptions during practical usage. To address these challenges, many recent attempts have been made to repair DNNs for version updates under practical operational contexts by updating weights (i.e., network parameters) through retraining, fine-tuning, or direct weight fixing at a neural level. Nevertheless, existing solutions often neglect the effects of neural network architecture and weight relationships across neurons and layers. In this work, as the first attempt, we initiate to repair DNNs by jointly optimizing the architecture and weights at a higher (i.e., block level).

We first perform empirical studies to investigate the limitation of whole network-level and layer-level repairing, which motivates us to explore a novel repairing direction for DNN repair at the block level. To this end, we need to further consider techniques to address two key technical challenges, i.e.,
block localization
, where we should localize the targeted block that we need to fix; and how to perform
joint architecture and weight repairing
. Specifically, we first propose
adversarial-aware spectrum analysis for vulnerable block localization
that considers the neurons’ status and weights’ gradients in blocks during the forward and backward processes, which enables more accurate candidate block localization for repairing even under a few examples. Then, we further propose the
architecture-oriented search-based repairing
that relaxes the targeted block to a continuous repairing search space at higher deep feature levels. By jointly optimizing the architecture and weights in that space, we can identify a much better block architecture. We implement our proposed repairing techniques as a tool, named
ArchRepair
, and conduct extensive experiments to validate the proposed method. The results show that our method can not only repair but also enhance accuracy and robustness, outperforming the state-of-the-art DNN repair techniques.
Static and Streaming Data Structures for Fréchet Distance Queries
Authors: Filtser Arnold , Filtser Omrit
Published: July 2023

Given a curve
P
with points in ℝ

d

in a streaming fashion, and parameters ɛ > 0 and
k
, we construct a distance oracle that uses

\(O(\frac{1}{\varepsilon })^{kd}\log \varepsilon ^{-1}\)

space, and given a query curve
Q
with
k
points in ℝ

d

returns in

\(\tilde{O}(kd)\)

time a 1+ɛ approximation of the discrete Fréchet distance between
Q
and
P
.

In addition, we construct simplifications in the streaming model, oracle for distance queries to a sub-curve (in the static setting), and introduce the zoom-in problem. Our algorithms work in any dimension
d
, and therefore we generalize some useful tools and algorithms for curves under the discrete Fréchet distance to work efficiently in high dimensions.
MicroRNA-140 is not involved in sepsis-induced muscle atrophy
Authors: Shin Jaehoon , Miyaki Shigeru , Asahara Hiroshi , Akimoto Takayuki
Published: July 2023

We used miR-140−/− mice to determine the function of miR-140 in LPS-induced skeletal muscle atrophy. To our knowledge, this study is the first to examine slow-twitch muscles in LPS-induced muscle wasting after miR-140 manipulation.
Advancing our understanding of bioreactors for industrial-sized cell culture: health care and cellular agriculture implications
Authors: Ge Chang , Selvaganapathy P. Ravi , Geng Fei
Published: July 2023

Bioreactors are advanced biomanufacturing tools that have been widely used to develop various applications in the fields of health care and cellular agriculture. In recent years, there has been a growing interest in the use of bioreactors to enhance the efficiency and scalability of these technologies. In cell therapy, bioreactors have been used to expand and differentiate cells into specialized cell types that can be used for transplantation or tissue regeneration. In cultured meat production, bioreactors offer a controlled and efficient means of producing meat without the need for animal farming. Bioreactors can support the growth of muscle cells by providing the necessary conditions for cell proliferation, differentiation, and maturation, including the provision of oxygen and nutrients. This review article aims to provide an overview of the current state of bioreactor technology in both cell therapy and cultured meat production. It will examine the various bioreactor types and their applications in these fields, highlighting their advantages and limitations. In addition, it will explore the future prospects and challenges of bioreactor technology in these emerging fields. Overall, this review will provide valuable insights for researchers and practitioners interested in using bioreactor technology to develop innovative solutions in the biomanufacturing of therapeutic cells and cultured meat.
Heat Transfer and Performance Enhancement of Porous Split Elliptical Fins
Authors: Ranjan Alok , Das Ranjan , Barik Debabrata , Pal Sagnik , Majumder Arindam , Deb Madhujit , Dennison Milon Selvam
Published: July 2023

To augment the heat transfer phenomenon, the infusion of various fin geometry over the heated plate is being investigated by various researchers. Solid fins of the porous medium can enhance the convective heat transfer, providing a higher surface area-to-volume ratio for heat transfer. In this work, the fluid flow pattern and thermodynamic analysis of porous-based split elliptical fins mounted staggered over a heated base plate is numerically studied with the Reynolds numbers in the range of 783 to 1839, which is dependent on the fin dimension. The variable parameters were dimensionless transverse offset (

TO

∗

=
transverse
 
offset
/
diameter

), which varied from 0 to 0.5; dimensionless longitudinal offset (

L

O

∗

=
longitudinal
 
offset
/
diameter

), which varied from 0 to 0.25; porosity (ɸ), which varies from 0.8 to 0.92; pores per inch (PPI), which was 10; permeability (

P

n

); and inertial parameter (

F

). To count the viscous and inertial effect inside the porous zone, the Forchheimer–Brinkman extended Darcy model was adopted. The associated parameters, the Nusselt number (Nu), frictional coefficient (

C

f

), and performance evaluation criteria (PEC), are thoroughly analyzed over the TO

∗

and LO

∗

combination. The results of the investigation revealed that the highest value of Nu and PEC was obtained by

TO

∗

=
0.5

and

L

O

∗

=
0

at

ɸ
=
0.92

, which were approximately 54% and 79% higher than the solid circular fin at

Re
=
1839

. Additionally, a response function based on Nu was obtained using the response surface method, and cuckoo optimization was assessed to identify the optimal Nu. The optimal Nu is established at

TO

∗

=
0.4141

and

L

O

∗

=
0

(

ɸ
=
0.92

and

Re
=
1839

) and was validated with the present investigation with an accuracy of 1.20%.
First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma
Authors: Hamilton Erika P. , Wang Judy S. , Oza Amit M. , Patel Manish R. , Ulahannan Susanna V. , Bauer Todd , Karlix Janet L. , Zeron-Medina Jorge , Fabbri Giulia , Marco-Casanova Paola , Moorthy Ganesh , Hattersley Maureen M. , Littlewood Gillian M. , Mitchell Patrick , Saeh Jamal , Pouliot Gayle P. , Moore Kathleen N.
Published: July 2023

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.
FIGURE 5 from Clinically Defined Mutations in MEN1 Alter Its Tumor-suppressive Function Through Increased Menin Turnover
Authors: Duan Suzann , Sheriff Sulaiman , Elvis-Offiah Uloma B. , Witten Brandon L. , Sawyer Travis W. , Sundaresan Sinju , Cierpicki Tomasz , Grembecka Jolanta , Merchant Juanita L.
Published: July 2023

Clinical MEN1 mutations and variants exhibit loss of growth-suppressive function in a cell-dependent manner. A, Representative bright-field images of crystal violet-stained AGS, MKN-45G, and GLUTag following 72 hours transfection with empty vector (pcDNA), wild-type (WT) menin, and the three mutated menin proteins. Images taken at 100X magnification. BrdU incorporation was assayed 1, 2, and 5 days posttransfection in MEF (B), MEFΔMen1 (C), AGS (D), MKN-45G (E), BON-1 (F), and GLUTag (G) cell lines. n = 3–5 experimental replicates. Asterisks represent comparisons between each timepoint. *, P < 0.05; **, P < 0.01; ****, P < 0.0001 by two-way ANOVA with Tukey post hoc test; mean ± SEM.
Data from Clinically Defined Mutations in MEN1 Alter Its Tumor-suppressive Function Through Increased Menin Turnover
Authors: Duan Suzann , Sheriff Sulaiman , Elvis-Offiah Uloma B. , Witten Brandon L. , Sawyer Travis W. , Sundaresan Sinju , Cierpicki Tomasz , Grembecka Jolanta , Merchant Juanita L.
Published: July 2023

Loss of the tumor suppressor protein menin is a critical event underlying the formation of neuroendocrine tumors (NET) in hormone-expressing tissues including gastrinomas. While aberrant expression of menin impairs its tumor suppression, few studies explore the structure–function relationship of clinical multiple endocrine neoplasia, type 1 (MEN1) mutations in the absence of a complete LOH at both loci. Here, we determined whether clinical MEN1 mutations render nuclear menin unstable and lead to its functional inactivation. We studied the structural and functional implications of two clinical MEN1 mutations (R516fs, E235K) and a third variant (A541T) recently identified in 10 patients with gastroenteropancreatic (GEP)-NETs. We evaluated the subcellular localization and half-lives of the mutants and variant in Men1-null mouse embryo fibroblast cells and in hormone-expressing human gastric adenocarcinoma and NET cell lines. Loss of menin function was assessed by cell proliferation and gastrin gene expression assays. Finally, we evaluated the effect of the small-molecule compound MI-503 on stabilizing nuclear menin expression and function in vitro and in a previously reported mouse model of gastric NET development. Both the R516fs and E235K mutants exhibited severe defects in total and subcellular expression of menin, and this was consistent with reduced half-lives of these mutants. Mutated menin proteins exhibited loss of function in suppressing tumor cell proliferation and gastrin expression. Treatment with MI-503 rescued nuclear menin expression and attenuated hypergastrinemia and gastric hyperplasia in NET-bearing mice. Clinically defined MEN1 mutations and a germline variant confer pathogenicity by destabilizing nuclear menin expression.
Significance:
We examined the function of somatic and germline mutations and a variant of MEN1 sequenced from gastroenteropancreatic NETs. We report that these mutations and variant promote tumor cell growth and gastrin expression by rendering menin protein unstable and prone to increased degradation. We demonstrate that the menin-MLL (mixed lineage leukemia) inhibitor MI-503 restores menin protein expression and function in vitro and in vivo, suggesting a potential novel therapeutic approach to target MEN1 GEP-NETs.
Phenotypic Characterization of Acoustically Enriched Extracellular Vesicles from Pathogen-Activated Platelets
Authors: Palm Frida , Broman Axel , Marcoux Genevieve , Semple John W. , Laurell Thomas L. , Malmström Johan , Shannon Oonagh
Published: July 2023

Extracellular vesicles (EVs) are derived from the membrane of platelets and released into the circulation upon activation or injury. Analogous to the parent cell, platelet-derived EVs play an important role in hemostasis and immune responses by transfer of bioactive cargo from the parent cells. Platelet activation and release of EVs increase in several pathological inflammatory diseases, such as sepsis. We have previously reported that the M1 protein released from the bacterial pathogen Streptococcus pyogenes directly mediates platelet activation. In this study, EVs were isolated from these pathogen-activated platelets using acoustic trapping, and their inflammation phenotype was characterized using quantitative mass spectrometry-based proteomics and cell-based models of inflammation. We determined that M1 protein mediated release of platelet-derived EVs that contained the M1 protein. The isolated EVs derived from pathogen-activated platelets contained a similar protein cargo to those from physiologically activated platelets (thrombin) and included platelet membrane proteins, granule proteins, cytoskeletal proteins, coagulation factors, and immune mediators. Immunomodulatory cargo, complement proteins, and IgG3 were significantly enriched in EVs isolated from M1 protein-stimulated platelets. Acoustically enriched EVs were functionally intact and exhibited pro-inflammatory effects on addition to blood, including platelet-neutrophil complex formation, neutrophil activation, and cytokine release. Collectively, our findings reveal novel aspects of pathogen-mediated platelet activation during invasive streptococcal infection.
Impact of Coronary Artery Calcium Score Screening on Cardiovascular Risk Stratification of Patients with Atrial Fibrillation Undergoing Ablation
Authors: Fernandes Sara , Cruz Inês , Faria Rita , Almeida João , Fonseca Paulo , Ferreira Nuno , Primo João José , Fontes-Carvalho Ricardo , Ladeiras-Lopes Ricardo
Published: July 2023

Introduction: There is a well-established association between atrial fibrillation (AF) and coronary artery disease. Coronary artery calcium score (CACS) is a helpful tool to refine cardiovascular (CV) risk stratification and inform on the best strategies for primary CV prevention. This study aims to evaluate the impact of opportunistic screening with CACS on risk stratification and decision of preventive therapies, in patients with AF. Methods: Cross-sectional study including patients with AF or atrial flutter undergoing cardiac computed tomography for ablation procedure planning, from 2017 to 2019. Baseline clinical and demographical data were collected. CACS was assessed in patients without coronary artery disease using the Agatston method. Results: A total of 474 patients were included (93% with AF, mean age of 58 ± 10 years, 62% male). CACS >0 was present in 254 (54%) patients. According to CACS and the Society of Cardiovascular Computed Tomography recommendations, 25% of the patients would be candidates for statin therapy and 17% would be candidates for changes in the current statin intensity; in 11 patients (8%), acetylsalicylic acid would be recommended. Conclusion: In our study, more than half of the patients undergoing cardiac computed tomography before AF catheter ablation had CACS above zero. Our findings suggest that an opportunistic evaluation of CACS at the time of ablation can be an important tool to improve CV risk stratification, with important clinical and therapeutic implications.
Ventricular Electrograms Duration Map to Detect Ventricular Arrhythmia Substrate: the VEDUM Project Study
Authors: Rossi Pietro , Cauti Filippo Maria , Niscola Marta , Magnocavallo Michele , Polselli Marco , Capone Silvia , Della Rocca Domenico Giovanni , Rodriguez-Garrido Jorge , Piccirillo Gianfranco , Anguera Ignasi , Dallaglio Paolo , Bianchi Stefano
Published: July 2023

BACKGROUND:

The analysis of the wave-front activation patterns is crucial for the comprehension and treatment of ventricular tachycardia (VT). The ventricular electrograms duration map (VEDUM) is a potential method to identify areas (VEDUM area) with slow and inhomogeneous activation. There is no available data on the characteristics and the arrhythmogenic role of VEDUM areas identified during sinus/paced rhythm.

METHODS:

Patients referred for VT ablation were enrolled at 3 different centers. VEDUM maps during sinus/paced rhythm as well as substrate and functional maps were created; activation mapping was performed for all hemodynamically tolerated VT.

RESULTS:

Thirty-two patients (mean age:70.1±9.4 years; males 93.8%) were enrolled. The VEDUM approach was achieved in all patients and the mean size of the VEDUM area was 12.1±6.9 cm
2
(interquartile range, 7.8–14.9 cm
2
). A significative difference was observed between the electrogram duration in the VEDUM area and the normal tissue (163.7 ms [interquartile range, 142.3–199.2 ms]; versus 65.5 ms [interquartile range, 59.5–76.2 ms];
P
<0.001). The VEDUM area was visualized in a dense scar (<0.5 mV) in 19 (59.4%) patients. A deceleration zone and late potentials were recorded inside the VEDUM area in 56.3% and 81.3%, respectively. When a complete VT activation mapping was available, the isthmus projected in the VEDUM area in 93.5% of patients; 8 of them had multiple VTs mapped and in the 87.5% all VT isthmuses were included in the VEDUM area.

CONCLUSIONS:

VEDUM maps allow the identification of discrete areas of inhomogeneous and slow conduction. They represent a potential target for VT ablation, including patients with multiple morphologies.
Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency Inhibits Pathological Cardiac Hypertrophy
Authors: Wang Yinhui , Song Jia , Yu Kun , Nie Daan , Zhao Chengcheng , Jiao Liping , Wang Ziyi , Zhou Ling , Wang Feng , Yu Qilin , Zhang Shu , Wen Zheng , Wu Junfang , Wang Cong-Yi , Wang Dao Wen , Cheng Jia , Zhao Chunxia
Published: July 2023

BACKGROUND:

Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy.

METHODS:

Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography–mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA.

RESULTS:

IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice’s hearts using liquid chromatography–mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis.

CONCLUSIONS:

This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.
Sex-Specific Effects of Blood Pressure Lowering Pharmacotherapy for the Prevention of Cardiovascular Disease: An Individual Participant-Level Data Meta-Analysis
Authors: Bidel Zeinab , Nazarzadeh Milad , Canoy Dexter , Copland Emma , Gerdts Eva , Woodward Mark , Gupta Ajay K. , Reid Christopher M. , Cushman William C. , Wachtell Kristian , Teo Koon , Davis Barry R. , Chalmers John , Pepine Carl J. , Rahimi Kazem ,   on behalf of the Blood Pressure Lowering Treatment Trialists’ Collaboration
Published: July 2023

BACKGROUND:

Whether the relative effects of blood pressure (BP)–lowering treatment on cardiovascular outcomes differ by sex, particularly when BP is not substantially elevated, has been uncertain.

METHODS:

We conducted an individual participant-level data meta-analysis of randomized controlled trials of pharmacological BP lowering. We pooled the data and categorized participants by sex, systolic BP categories in 10-mm Hg increments from <120 to ≥170 mm Hg, and age categories spanning from <55 to ≥85 years. We used fixed-effect one-stage individual participant-level data meta-analyses and applied Cox proportional hazard models, stratified by trial, to analyze the data.

RESULTS:

We included data from 51 randomized controlled trials involving 358 636 (42% women) participants. Over 4.2 years of median follow-up, a 5-mm Hg reduction in systolic BP decreased the risk of major cardiovascular events both in women and men (hazard ratio [95% CI], 0.92 [0.89–0.95] for women and 0.90 [0.88–0.93] for men;
P
for interaction, 1). There was no evidence for heterogeneity of relative treatment effects by sex for the major cardiovascular disease, its components, or across the different baseline BP categories (all
P
for interaction, ≥0.57). The effects in women and men were consistent across age categories and the types of antihypertensive medications (all
P
for interaction, ≥0.14).

CONCLUSIONS:

The effects of BP reduction were similar in women and men across all BP and age categories at randomization and with no evidence to suggest that drug classes had differing effects by sex. This study does not substantiate sex-based differences in BP-lowering treatment.
Clinical Penetrance of the Transthyretin V122I Variant in Older Black Patients With Heart Failure: The SCAN‐MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) Study
Authors: Madhani Avni , Sabogal Natalia , Massillon Daniel , Paul Ludwine D. , Rodriguez Carlos , Fine Denise , Helmke Stephen , Winburn Morgan , Kurian Damian , Raiszadeh Farbod , Teruya Sergio , Cohn Elizabeth , Einstein Andrew J. , Miller Edward J. , Connors Lawreen H. , Maurer Mathew S. , Ruberg Frederick L.
Published: July 2023

Background

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is an underdiagnosed cause of heart failure (HF) among patients ≥60 years of age. Although the V122I (valine to isoleucine substitution at position 122 of the transthyretin protein) variant associated with hereditary ATTR‐CM is present in 3.4% of self‐identified Black individuals in the United States (or 1.5 million people), the phenotypic penetrance is not known.

Methods and Results

The SCAN‐MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study is a currently accruing prospective multisite study designed to determine the prevalence of ATTR‐CM using technetium‐99m‐pyrophosphate imaging in older (≥60 years of age) self‐identified Black and Hispanic individuals with HF. Calculations of the penetrance and prevalence of the V122I allele, along with analyses of functional, biochemical, and echocardiographic parameters, were performed for the first 278 Black participants in SCAN‐MP. The prevalence of ATTR‐CM was 6.8% (95% CI, 4.2–10.5; n=19 cases), of whom 63% were ATTR wild‐type. The prevalence of V122I was 6.5% (n=18 carriers), of whom 7 had ATTR‐CM, yielding a phenotypic penetrance of 39% (95% CI, 17–64). V122I carriers with ATTR‐CM evidenced more advanced HF than carriers without ATTR‐CM. Prealbumin concentration was lowest among V122I carriers with ATTR‐CM (12.9 mg/dL) versus carriers without ATTR‐CM (21.0 mg/dL) and HF controls (25.0 mg/dL,
P
<0.0001).

Conclusions

Among older Black individuals with HF and increased left ventricular wall thickness, of those with ATTR‐CM, 63% had wild‐type, and of those with V122I, the phenotypic penetrance of ATTR‐CM was 39% (95% CI, 17–64), suggesting that genotype alone is insufficient for diagnosis. Prealbumin concentration may be useful to identify V122I carriers with ATTR‐CM.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03812172.
Longitudinal Assessment of Sleep Apnea in the Year After Stroke in a Population-Based Study
Authors: Lisabeth Lynda D. , Zhang Guanghao , Chervin Ronald D. , Shi Xu , Morgenstern Lewis B. , Campbell Morgan , Tower Susan , Brown Devin L.
Published: July 2023

BACKGROUND:

The aim of this study was to characterize change in sleep-disordered breathing severity in the year following stroke, overall, and by ethnicity, within the population-based Brain Attack Surveillance in Corpus Christi Project.

METHODS:

First-ever ischemic strokes (n=414) were ascertained by active and passive surveillance and validated by stroke-trained physicians. Patients with stroke were invited to participate in portable sleep apnea testing (ApneaLink Plus) at baseline and 3, 6, and 12 months poststroke. Sleep-disordered breathing severity was assessed by the respiratory event index (apneas and hypopneas/hour of recording). The component obstructive apnea index and central apnea index were also assessed. Time and ethnicity effects on outcomes, as well as ethnic differences in time effects, were analyzed using generalized estimating equations with multivariable adjustment for confounding factors.

RESULTS:

Mean age (n=414) was 63.9 years (SD=10.9); 68.4% were Mexican American. Baseline mean respiratory event index, obstructive apnea index, and central apnea index were 21.3 (SD=16.6), 8.6 (SD=11.5), and 1.5 (SD=3.2), respectively. There was no time effect on respiratory event index (
P
=0.35) but obstructive apnea index increased over time (
P
<0.01). Averaged over follow-up, respiratory event index and obstructive apnea index were significantly higher in Mexican American than non-Hispanic White persons. No ethnic difference in the time effect was found for either outcome. For central apnea index, there was an ethnicity-time interaction (
P
=0.01) such that central apnea index increased in non-Hispanic White but did not change in Mexican American persons.

CONCLUSIONS:

Sleep-disordered breathing severity was significant and stable for most individuals in the year after stroke. These results do not confirm previous reports of diminishing sleep-disordered breathing severity over time after stroke and would support early assessment and treatment where indicated.
IOHexperimenter: Benchmarking Platform for Iterative Optimization Heuristics
Authors: de Nobel Jacob , Ye Furong , Vermetten Diederick , Wang Hao , Doerr Carola , Bäck Thomas
Published: July 2023

We present IOHexperimenter, the experimentation module of the IOHprofiler project. IOHexperimenter aims at providing an easy-to-use and customizable toolbox for benchmarking iterative optimization heuristics such as local search, evolutionary and genetic algorithms, and Bayesian optimization techniques. IOHexperimenter can be used as a stand-alone tool or as part of a benchmarking pipeline that uses other modules of the IOHprofiler environment.

IOHexperimenter provides an efficient interface between optimization problems and their solvers while allowing for granular logging of the optimization process. Its logs are fully compatible with existing tools for interactive data analysis, which significantly speeds up the deployment of a benchmarking pipeline. The main components of IOHexperimenter are the environment to build customized problem suites and the various logging options that allow users to steer the granularity of the data records.
Noun Sequence Statistics Affect Serial Recall and Order Recognition Memory
Authors: Schwering Steven C. , MacDonald Maryellen C.
Published: July 2023

Most theories of verbal working memory recognize that language comprehension and production processes play a role in word memory for familiar sequences, but not for novel lists of nouns. Some language emergent theories propose that language processes can support verbal working memory even for novel sequences. Through corpus analyses, we identify sequences of two nouns that resemble patterns in natural language, even though the sequences are novel. We present 2 experiments demonstrating better recall in college students for these novel sequences over the same words in reverse order. In a third experiment, we demonstrate better recognition of the order of these sequences over a longer time scale. These results suggest verbal working memory and recognition of order over a delay are influenced by language knowledge processes, even for novel memoranda that approximate noun lists typically employed in memory experiments.
Holoparasitic Orobanchaceae in Georgia (Caucasus): taxonomic revision, diversity, distribution, habitats and host range
Authors: PIWOWARCZYK RENATA , SÁNCHEZ PEDRAJA ÓSCAR , KHUTSISHVILI MANANA , KHARAZISHVILI DAVIT
Published: July 2023

This study represents the first comprehensive monograph of the tribe Orobancheae (Orobanchaceae) in the four holoparasitic genera, Cistanche, Phelypaea, Phelipanche, and Orobanche, in Georgia. This country, as a part of the Caucasus, is one of the most important biodiversity centres in the world and includes poorly understood holoparasitic plants. Species delimitations are re-evaluated on the basis of critical observations on seven years of field work and examination of ca. 1000 herbarium sheets from 50 herbaria. Our work has resulted in the recognition of 33 species, among which 13 are endemic to the Caucasus. We present information on their distribution, localities, habitat, phenology, host range, images from the field, nomenclatural acts (taxonomic clarifications, proposals for new synonymisations, new combinations, lectotypifications), as well as a key for identification and preliminary geospatial conservation assessments for all species based on IUCN criteria. Lectotypes are designated for Cistanche fissa, C. sintenisii, Orobanche salsa var. ambigua f. fissa, O. salsa var. ambigua f. longiloba, O. coelestis f. confinis, O. ramosa var. penicillata, O. coerulescens, O. buhsei, O. glabrata, O. minor, O. libanotidis, O. flava; neotype for O. owerinii; nomenclatural novelties, new combinations and/or a name at new rank: O. doriae, Orobanche subg. Gamosepalae, Orobanche sect. Arcuatae.