bluuebunny/crossref_metadata_2025 huggingface dataset:
Species-selective nanoreactor molecular dynamics simulations based on linear-scaling tight-binding quantum chemical calculations
Authors: Nishimura Yoshifumi , Nakai Hiromi
Published: January 2023

Here, extensions to quantum chemical nanoreactor molecular dynamics simulations for discovering complex reactive events are presented. The species-selective algorithm, where the nanoreactor effectively works for the selected desired reactants, was introduced to the original scheme. Moreover, for efficient simulations of large model systems with the modified approach, the divide-and-conquer linear-scaling density functional tight-binding method was exploited. Two illustrative applications of the polymerization of propylene and cyclopropane mixtures and the aggregation of sodium chloride from aqueous solutions indicate that species-selective quantum chemical nanoreactor molecular dynamics is a promising method to accelerate the sampling of multicomponent chemical processes proceeding under relatively mild conditions.
Toward an efficient f-in-core/f-in-valence switchable description for DFTB calculations of Ce 4f states in ceria
Authors: Kocmaruk Bojana , Ammothum Kandy Akshay Krishna , Hermansson Kersti , Kullgren Jolla , Broqvist Peter
Published: January 2023

A computational protocol is developed for efficient studies of partially reduced redox-active oxides using the self-consistent charge density functional tight-binding method. The protocol is demonstrated for ceria, which is a prototypical reducible oxide material. The underlying idea is to achieve a consistent (and harmonized) set of Slater–Koster (SK) tables with connected repulsive potentials that enable switching on and off the in-valence description of the Ce 4f states without serious loss of accuracy in structure and energetics. The implicit treatment of the Ce 4f states, with the use of f-in-core SK-tables, is found to lead to a significant decrease in computational time. More importantly, it allows for explicit control of the oxidation states of individual Ce atoms. This makes it possible to “freeze” the electronic configuration, thereby allowing the exploration of the energetics for various meta-stable configurations. We anticipate that the outlined strategy can help to shed light on the interplay between the size, shape, and redox activity for nanoceria and other related materials.
Urokinase plasminogen activator surface receptor restricts HIV-1 replication by blocking virion release from the cell membrane
Authors: Pang Hailin , Ouyang Jiayue , Yang Zengwen , Shang Hong , Liang Guoxin
Published: January 2023

The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are predominantly expressed by blood cells, including neutrophils, monocytes, and macrophages, and play important roles in cell activation, adhesion, migration, and extravasation. Here, we report that PLAUR, which is highly expressed in macrophages and dendritic cells (DCs) but hardly expressed in CD4
+
T cells, inhibits the release of HIV-1 progeny virions from the cell membrane. Silencing
PLAUR
markedly enhanced the transmission of HIV-1 in macrophages and DCs. We further demonstrated that PLAUR is localized at the cell membrane to block the release of HIV-1 virions. Interestingly, we found that uPA compromises the PLAUR-mediated inhibition to slightly enhance HIV-1 production in primary macrophages and DCs. In the absence of PLAUR, this enhanced effect induced by uPA is abrogated. In conclusion, PLAUR is a new anti-HIV-1 protein produced in both macrophages and DCs where it inhibits HIV-1 transmission. This discovery may provide a novel therapeutic target for combating HIV.
Performance of the HYPERSCINT scintillation dosimetry research platform for the 1.5 T MR-linac
Authors: Uijtewaal Prescilla , Côté Benjamin , Foppen Thomas , de Vries Wilfred , Woodings Simon , Borman Pim , Lambert-Girard Simon , Therriault-Proulx François , Raaymakers Bas , Fast Martin
Published: January 2023

Objective. Adaptive radiotherapy techniques available on the MR-linac, such as daily plan adaptation, gating, and dynamic tracking, require versatile dosimetric detectors to validate end-to-end workflows. Plastic scintillator detectors (PSDs) offer great potential with features including: water equivalency, MRI-compatibility, and time-resolved dose measurements. Here, we characterize the performance of the HYPERSCINT RP-200 PSD (MedScint, Quebec, CA) in a 1.5 T MR-linac, and we demonstrate its suitability for dosimetry, including in a moving target. Approach. Standard techniques of detector testing were performed using a Beamscan water tank (PTW, Freiburg, DE) and compared to microDiamond (PTW, Freiburg, DE) readings. Orientation dependency was tested using the same phantom. An RW3 solid water phantom was used to evaluate detector consistency, dose linearity, and dose rate dependence. To determine the sensitivity to motion and to MRI scanning, the Quasar MRI4D phantom (Modus, London, ON) was used statically or with sinusoidal motion (A = 10 mm, T = 4 s) to compare PSD and Semiflex ionization chamber (PTW, Freiburg, DE) readings. Conformal beams from gantry 0° and 90° were used as well as a 15-beam 8 × 7.5 Gy lung IMRT plan. Main results. Measured profiles, PDD curves and field-size dependence were consistent with the microDiamond readings with differences well within our clinical tolerances. The angular dependence gave variations up to 0.8% when not irradiating directly from behind the scintillation point. Experiments revealed excellent detector consistency between repeated measurements (SD = 0.06%), near-perfect dose linearity (R
2 = 1) and a dose rate dependence <0.3%. Dosimetric effects of MRI scanning (≤0.3%) and motion (≤1.3%) were minimal. Measurements were consistent with the Semiflex (differences ≤1%), and with the treatment planning system with differences of 0.8% and 0.4%, with and without motion. Significance. This study demonstrates the suitability of the HYPERSCINT PSD for accurate time-resolved dosimetry measurements in the 1.5 T MR-linac, including during MR scanning and target motion.
Reply to ‘comments on comparison study of bound states for diatomic molecules using kratzer, morse, and modified morse potentials’
Authors: Sandouqa A S
Published: January 2023

In this reply, I presented clarification for the difference in calculating bound-state energy eigenvalues for HCl obtained using the modified morse potential between our results and the results of Samant et al [Al-Othman and Sandouqa 2022 Phys. Scr. 97 035401]. In their comments, Samant et al [Samant R, Lotliker, and Desai, Phys. Scr.] stated that the reason for this difference is the wrong expression of the parameter used in the modified morse potential. But we found that this difference is a result of using different values of α and β. While we use approximate values of α and β, Samant et al [2] used optimized values of these parameters. Therefore, the results of Samant et al [2] are more accurate.
Fiber-optic lead ion sensor based on MXene film integrated michelson interference structure
Authors: Xiong Guo Liang , Zhuang Jing Hao , Feng Wen Lin
Published: January 2023

Ti3C2Tx (MXene), a two-dimensional material prepared by solution etching, has abundant functional groups on its surface, which makes it have a great prospect in the field of biosensing environmental detection. In this work, a new optical fiber sensor integrated with MXene is proposed and fabricated. The sensor is constituted of a three-core fiber (TCF), a single-mode fiber (SMF), and a no-core fiber (NCF) to form a Michelson interference structure. The results indicate that MXene decorated fiber-optic sensor can detect trace lead ions (Pb2+) and has a good response to the Pb2+ solutions with the concentration of 0–100 μM. At 0.001 μM (i.e., 0.286 ppb) Pb2+, the response time is about 2 min. In addition, the fiber-optic sensor has excellent temperature, pH, and time stability. The present work provides a new idea for the detection of Pb2+ in heavy metal pollution fields.
Is there evidence for CIDER in the Universe?
Authors: Barros Bruno J. , Castelão Diogo , da Fonseca Vitor , Barreiro Tiago , Nunes Nelson J. , Tereno Ismael
Published: January 2023

In this work we analyze the full linear behaviour of the constrained interacting dark energy (CIDER) model, which is a conformally coupled quintessence model tailored to mimic a ΛCDM expansion. We compute the matter and temperature anisotropies power spectra and test the model against recent observational data. We shed light on some particular subtleties of the background behaviour that were not fully captured in previous works, and study the physics of the linear cosmological observables. One novelty found was that matter perturbations are enhanced at large scales when compared with the ones of the standard ΛCDM. The reason and impact of this trend on the cosmological observables and on the physics of the early Universe are considered. We find that the introduction of the coupling parameter alleviates the σ
8 tension between early and late time probes although Planck data favours the ΛCDM limit of the model.
Exotic states with

QQQ′¯Q′¯

configuration
Authors: Asadi Z , Boroun G R
Published: January 2023

In the framework of a non-relativistic quark model, we have calculated the masses of the

QQ

Q
′

¯

Q
′

¯

(Q = c, b, s and

Q

¯

′
=

c

¯

,

b

¯

,

s

¯

) tetraquark states. Using the linear and quadratic confinement potentials inside a Cornell-type potential along with all possible spin and color configurations, the Schrödinger equation masses of these tetraquark states have been calculated. Based on our numerical analysis, linear confinement and quadratic confinement produce acceptable results. Models that use linear confinement estimate charmonium-like tetraquark mass close to experimental data, as well as bottomonium-like tetraquark mass below the threshold of their meson–meson channels.
Continuous modulation of charge-spin conversion by electric field in Pt/Co2FeSi/Pb(Mg1/3Nb2/3)O3-Pb0.7Ti0.3O3 heterostructures
Authors: Zhao Yibing , Fang Xiaoxiao , Wang Zhirui , Cheng Miao , Tan Yongjia , Wei Dongxiong , Jiang Changjun , Yao Jinli
Published: January 2023

The half-metallic Heusler alloy Co2FeSi is an ideal material in spintronic devices due to its higher spin polarization, higher Curie temperature and lower damping parameters. In this work, the dynamic magnetism of Co2FeSi is modulated by electric field and it is demonstrated that the charge-spin conversion efficiency ξ is continuous and controllable by the electric field. We further find an extremely high ξ in ferromagnetic/ferroelectric (FM/FE) heterostructures, which could be ascribed to interfacial effect in FM/FE interface. Moreover, we investigate that the charge-spin conversion efficiency varies with the electric field in a butterfly-like behavior, which accords with the S–E curve of Pb(Mg1/3Nb2/3)O3-Pb0.7Ti0.3O3(PMN-PT) and could be attributed to strain effect. The modulation of charge-spin conversion efficiency in FM/FE heterostructures via electric field presents a profound potential for next-generation spintronic devices and applications of current-induced magnetization switching.
Effects of strain on the flat band in twisted bilayer graphene
Authors: Zhang 张 Zhen 镇 , Wen 文 Lu 露 , Qiao 乔 Youkai 友凯 , Li 李 Zhiqiang 志强
Published: January 2023

Based on the effective continuum model, we systematically study the electronic band structures and density of states of twisted bilayer graphene near the magic angle under the influence of different types of strain, including shear strain, volume-preserving strain and biaxial strain. We find that the flat bands behave very differently under various types of strain. Volume-preserving strain generically leads to broader van Hove singularities associated with the flat bands compared with those under shear strain, with dissimilar strain direction dependence. The band structures and density of states under shear and volume-preserving strains change with the strain direction, while those under biaxial strain are independent of the direction of strain. In particular, the effect of biaxial strain on twisted bilayer graphene is geometrically and electronically similar to the influence of the twisted angle. Our results reveal the characteristic structures in the band structures and density of states under various types of strain, which can serve as fingerprints for exploring the effects of strain on the novel physics of this system.
Test and characterisation of STS/MuCh-XYTER and integration with multiple detectors of CBM-MuCh detector systems
Authors: Saini J. , Ghosh C. , Dubey A.K. , Ahammed Z. , Mondal M. , Ganai R. , Sikder G. , Negi V. , Chattopadhyay S. , Chakrabarti A.
Published: January 2023

Compressed Baryonic Matter (CBM) is a fixed target experiment at the upcoming Facility for Anti-proton and Ion Research in Germany, having collision rates up to 10 MHz. Due to the proximity of the target and secondaries produced in absorbers, Muon Chambers (MuCh) of the CBM experiment will face a very high particle hit rate of up to 400 kHz/cm2 in its first two stations. To cope with these particle rates, a Gas Electron Multiplier (GEM) detector will be used for the first two stations while, due to relatively lower particle rates, the last two stations will use a low resistivity Bakelite Resistive Plate Chamber (RPC) detector. The electronics of these two MuCh detectors need different dynamic ranges.
A Silicon Tracking Station (STS) system made of 300 μm thick silicon micro-strip sensors will be installed upstream of the MuCh detector system. The sensors will be read out through multi-line micro-cables with fast electronics. The micro-strip sensors will be double-sided with a stereo angle of 7.5°, a strip width of 58 μm, and strip lengths between 20 and 120 mm requiring high-density readout.
To meet the high rate and high density requirements of MuCh and STS, respectively, a specialized 128-channel readout ASIC with a dual-gain feature is designed.
This is a highly configurable ASIC with about 30,000 configurable register bits which control various bias and threshold settings of the ASIC.
To integrate this ASIC with both the detector systems, detailed testing and characterization of the ASIC are required.
Due to the high number of configurable registers and several operating conditions, characterizing this ASIC is very challenging. This paper describes the optimization procedures of several configurable bias parameters in detail and also explains how this ASIC is integrated with both GEM and RPC detectors of the MuCh system.
Revealing how intra- and inter-annual variability of carbon uptake (GPP) affects wood cell biomass in an eastern white pine forest
Authors: Puchi Paulina F , Khomik Myroslava , Frigo Davide , Arain M Altaf , Fonti Patrick , Arx Georg von , Castagneri Daniele
Published: January 2023

Forests are major terrestrial carbon (C) sinks and play a crucial role in climate change mitigation. Despite extensive studies on forest C sequestration, the relationship between seasonal C uptake and its allocation to woody biomass is poorly understood. Here we used a novel dendro-anatomical approach to investigate the relationships between climate variability, C uptake, and woody biomass growth in an 80 year-old eastern white pine (Pinus strobus) plantation forest in Ontario, Canada. We used eddy covariance (EC) gross primary productivity (GPP) from 2003–2018 and woody biomass estimated from chronologies of cell wall area (CWA, a proxy for C storage in individual wood cells) and ring wall area (RWA) for earlywood (EW) and latewood (LW) from 1970–2018. Warm temperatures in early spring and high precipitation in mid-spring and summer positively and strongly affected GPP, while high temperature and high vapor pressure deficit in the summer had a negative effect. From 2003 to 2018, there was a steady increase in both GPP and woody cell biomass. Moreover, we found strong positive correlations between GPP and CWA both in EW (May—July GPP, r= 0.65) and LW (July—August GPP, r = 0.89). Strong positive correlations were also found between GPP and RWA both in EW and LW (April—September, r =⩾ 0.79). All these associations were stronger than the association between annual GPP and tree-ring width (r = 0.61) used in previous studies. By increasing the resolution of tree-ring analysis to xylem-cell level, we captured intra-annual variability in biomass accumulation. We demonstrated a strong control of seasonal C assimilation (source) over C accumulation in woody biomass at this site. Coupling high-resolution EC fluxes (GPP) and wood anatomical measurements can help to reduce existing uncertainties on C source-sink relationships, opening new perspectives in the study of the C cycle in forests.
“Mechanism”-a misused term?
Authors: Pederson Thoru
Published: January 2023

Many of us use the term “mechanism” when we shouldn’t. Here I offer some thoughts, especially as guidance for young scientists.
Relationship Between Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccines and Development of Breakthrough Infection in Solid Organ Transplant Recipients: The CONTRAST Cohort
Authors: Bonazzetti Cecilia , Tazza Beatrice , Gibertoni Dino , Pasquini Zeno , Caroccia Natascia , Fanì Francesca , Fornaro Giacomo , Pascale Renato , Rinaldi Matteo , Miani Beatrice , Gamberini Chiara , Morelli Maria Cristina , Tamé Mariarosa , Busutti Marco , Comai Giorgia , Potena Luciano , Borgese Laura , Salvaterra Elena , Lazzarotto Tiziana , Scudeller Luigia , Viale Pierluigi , Giannella Maddalena ,   the CONTRAST Study Group, Di Chiara Michela , Giacomini Maria Eugenia , Vatamanu Oana , Marconi Lorenzo , Horna Clara Solera , Campoli Caterina , Bartoletti Michele , Bussini Linda , Trapani Fabio , Attard Luciano , Gatti Milo , Gramegna Antonio , La Manna Gaetano , Grandinetti Valeria , Demetri Marcello , Barbuto Simona , Abenavoli Chiara , Vitale Giovanni , Turco Laura , Ravaioli Matteo , Cescon Matteo , Bertuzzo Valentina , Messina Paola , Trombi Alessandra , Masetti Marco , Prestinenzi Paola , Sabatino Mario , Giovannini Laura , Alessio Aloisio , Russo Antonio , Scuppa Maria Francesca , Dolci Giampiero , Paganelli Gianmaria , Gabrielli Liliana , Pavoni Matteo , Leone Marta , Lanna Federica
Published: January 2023

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in solid organ transplant (SOT) recipients is associated with poorer antibody response (AbR) compared with non-SOT recipients. However, its impact on the risk of breakthrough infection (BI) has yet to be assessed.

Methods

Single-center prospective longitudinal cohort study enrolling adult SOT recipients who received SARS-CoV-2 vaccination during a 1-year period (February 2021 – January 2022), end of follow-up April 2022. Patients were tested for AbR at multiple time points. The primary end-point was BI (laboratory-confirmed SARS-CoV-2 infection ≥14 days after the second dose). Immunization (positive AbR) was considered an intermediate state between vaccination and BI. Probabilities of being in vaccination, immunization, and BI states were obtained for each type of graft and vaccination sequence using multistate survival analysis. Then, multivariable logistic regression was performed to analyze the risk of BI related to AbR levels.

Results

614 SOT (275 kidney, 163 liver, 137 heart, 39 lung) recipients were included. Most patients (84.7%) received 3 vaccine doses. The first 2 consisted of BNT162b2 and mRNA-1273 in 73.5% and 26.5% of cases, respectively. For the third dose, mRNA-1273 was administered in 59.8% of patients. Overall, 75.4% of patients reached immunization and 18.4% developed BI. Heart transplant recipients showed the lowest probability of immunization (0.418) and the highest of BI (0.323); all mRNA-1273 vaccine sequences showed the highest probability of immunization (0.732) and the lowest of BI (0.098). Risk of BI was higher for non–high-level AbR, younger age, and shorter time from transplant.

Conclusions

SOT patients with non–high-level AbR and shorter time from transplantation and heart recipients are at highest risk of BI.
Maternal fasting glucose levels throughout the pregnancy and risk of adverse birth outcomes in newborns: a birth cohort study in Foshan city, Southern China
Authors: Yang Yin , Lin Qingmei , Ma Liming , Lai Zhihan , Xie Junxing , Zhang Zilong , Wu Xueli , Luo Weidong , Hu Pengzhen , Wang Xing , Guo Xiaoling , Lin Hualiang
Published: January 2023

Objective

We aimed to investigate the associations between maternal fasting plasma glucose (FPG) levels and glycemic fluctuations during different trimesters and adverse birth outcomes among newborns.

Methods

This cohort study used data from 63 213 pregnant women and their offspring in Foshan city from November 2015 to January 2019. Associations between maternal FPG and glycemic fluctuations during different trimesters and adverse birth outcomes [congenital heart defect (CHD), macrosomia, small/large for gestational age (SGA/LGA), and preterm birth (PTB)] in newborns were estimated using mixed-effects logistic regression models.

Results

A total of 45 516 participants accepted at least one FPG test throughout pregnancy, and 7852 of whom had glycemic trajectory data. In the adjusted model, higher maternal FPG throughout the pregnancy was associated with an increased risk of adverse birth outcomes (except for SGA). Each 1 mmol/L increase in maternal FPG during trimester 1 was associated with higher odds of CHD (OR = 1.14 (95% CI: 1.02, 1.26)). The same increase in maternal FPG during trimester 3 was associated with a higher risk of PTB (OR = 1.05 (95% CI: 1.01, 1.10)). Increment of maternal FPG during trimester 2 and trimester 3 was associated with a higher risk of macrosomia and LGA. Increase in FPG throughout the pregnancy was associated with slightly lower odds of SGA. Similar results were observed when analyzing the associations between glycemic fluctuations during different trimesters and adverse birth outcomes.

Conclusions

Our findings indicate higher maternal FPG levels during different trimesters were associated with different adverse birth outcomes, which suggests the importance of glycemic management throughout the pregnancy.
High frequency of heterozygous rare variants of the SLC34A1 and SLC9A3R1 genes in patients with atypical femur fracture
Authors: Marini Francesca , Giusti Francesca , Marasco Elena , Xumerle Luciano , Kwiatkowska Katarzyna Malgorzata , Garagnani Paolo , Biver Emmanuel , Ferrari Serge , Iolascon Giovanni , Iantomasi Teresa , Brandi Maria Luisa
Published: January 2023

Objective

Atypical femur fractures (AFFs) are rare fragility fractures originating at the lateral cortex of the femur, affecting the subtrochanteric or diaphyseal area of thebone with a transverse morphology. Occurrence of AFF is specifically associated with a small number of rare monogenic congenital metabolic bone disorders, such as hypophosphatasia, and with long-term treatment with antiresorptiondrugs. The exact pathogenesis of these fractures remains poorly understood and, except for cases of diagnosed HPP or other AFF-causing bone diseases, it is not possible to assess which patients are at higher riskof developing AFFs as a consequence of anti-resorption therapy.

Design

We genetically screened 25 unrelated patients who had developed at least one AFF.

Intervention

Genetic screening was performed through a nextgeneration sequencing analysis with a customized panel containing 76 human genes involved in the regulation of the mineralization processWe genetically screened 25 unrelated patients who had developed at least one AFF.

Results

We found a relatively high frequency (32.0%) of heterozygous rare variants inthe SLC34A1 and SLC9A3R1 genes, two genes whose heterozygous inactivating mutations have been respectively associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis types 1 and 2 (NPHLOP1and NPHLOP2). Other heterozygous rare variants were found in the BMPR1B, CYP27B1, FBN1, MEPE, PIGO, and PHOSPHO1 genes, each in a single AFF case (4.0%).

Conclusions and relevance

Our findings suggest that rarevariants of SLC34A1 and SLC9A3R1 could represent a possible genetic risk factor for the occurrence of AFFs. On the other hand, AFFs could represent an unsuspected clinical manifestation and/or an anti-resorption therapycorrelatedadverse event in patients with NPHLOP disorders.
State of African neurosurgical education: a protocol for an analysis of publicly available curricula
Authors: Ooi Setthasorn Zhi Yang , Dada Olaoluwa Ezekiel , Haizel-Cobbina Joseline , Bukenya George William , Mbangtang Celestin Bilong , Makambo Paix de Dieu Ngo , Djabo Adrien Tangmi , Kenfack Yves Jordan , Senyuy Wah Praise , Mbougo Olga Djoutsop , Abu-Bonsrah Nancy , Karekezi Claire , Mbaye Thioub , Konan Landry , Jokonya Luxwell , Alalade Andrew F , Kanmounye Ulrick Sidney
Published: January 2023

Background

Africa bears >15% of the global burden of neurosurgical disease. Yet to date, Africa still has the lowest neurosurgical workforce density globally, and efforts to fill this gap by 2030 need to be multiplied. Although the past decade has seen an increase in neurosurgery residency programs in the continent, it is unclear how these residency programs are similar or viable. This study aims to highlight the current status of neurosurgical training in Africa as well as the differences within departments, countries or African regions.

Methods

A literature search using keywords related to ‘neurosurgery’, ‘training’, and ‘Africa’ and relevant names of African countries will be performed on PubMed and Google Scholar. If unavailable online, the authors will contact local neurosurgeons at identified training programmes for their curricula. The residency curricula collected will be analysed against a standardized and validated medical education curriculum viability tool.

Results

The primary aim will be the description of African neurosurgical curricula. In addition, the authors will perform a comparative analysis of the identified African neurosurgical curricula using a standardized and validated medical education curriculum viability tool.

Discussion

This study will be the first to evaluate the current landscape of neurosurgery training in Africa and will highlight pertinent themes that may be used to guide further research. The findings will inform health system strengthening efforts by local training programme directors, governments, policymakers and stakeholders.
Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data
Authors: Kloner Robert A , Stanek Eric , Crowe Christopher L , Singhal Mukul , Pepe Rebecca S , Bradsher Julia , Rosen Raymond C
Published: January 2023

Background

Treatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED).

Aim

The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality.

Methods

A retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables.

Outcome

The primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling.

Results

Matched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor–exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P < .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P < .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P < .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022).

Clinical Implications

PDE-5is may have cardioprotective effects.

Strengths and Limitations

Strengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders.

Conclusions

In a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.
The N-terminal glycine of EHV-1 UL11 is essential for the localization of UL11 and EHV-1 replication in cultured cells
Authors: Fukushi Noriko , Badr Yassien , Fukushi Hideto
Published: January 2023

Equine herpesvirus type 1 (EHV-1) UL11 is a 74-amino-acid (aa) protein encoded by ORF51. UL11 is modified by acylation including myristoylation and palmitoylation. Myristoylation of EHV-1 UL11 is assumed to occur on the N-terminal glycine, while palmitoylation is assumed to occur on the seventh and ninth cysteines. ORF51, which encodes the first 24 aa, overlaps ORF50 encoding UL12. We previously demonstrated that UL11 was essential for EHV-1 replication in cultured cells and that UL11 was localized at the Golgi apparatus where herpesviruses obtain their final envelope. It is unclear whether the acylation is related to the localization of EHV-1 UL11 and viral replication. In this study, we investigated the role of UL11 acylation in the intracellular localization and viral growth and replication of EHV-1. We constructed seven UL11 acylation mutant plasmids and seven UL11 acylation mutant BAC DNAs; then, we analysed the localizations of the mutant UL11s and attempted virus rescue. We found that both the N-terminal glycine and the seventh or ninth cysteine, especially N-terminal glycine, were involved in the localization of UL11 and viral replication. Taken together, these results suggest that EHV-1 viral growth requires that UL11 is modified by myristoylation of an N-terminal glycine and by palmitoylation of at least one of the cysteines, and that UL11 is localized at the Golgi apparatus. This study shows that a single amino acid in EHV-1 can determine the fate of viral replication.
Genetic analysis of a large heterogeneous patient population with Familial Exudative Vitreoretinopathy
Authors: Drenser Kimberly A. , Capone Antonio , Trese Matthew
Published: January 2023

Purpose

The purpose of this study is to report the genetic findings of a large heterogeneous patient population (n=551) with the clinical diagnosis of Familial Exudative Vitreoretinopathy (FEVR).

Methods

Patients (n=486) were clinically diagnosed with FEVR by exam, birth history, family history, and wide-field fluorescein angiography (WFA). Patients were excluded if WFA was not performed to confirm a proper diagnosis. DNA samples were prospectively collected and analyzed for gene mutations associated with FEVR. The patients represent a heterogenous population: 40% Michigan residents; 48% U.S. residents (non-Michigan); 12% non-U.S. residents. Specifically, alterations in NDP, FZD4, LRP5, TSPAN12, ZNF408, CTNNB1, KIF11 were evaluated.

Results

The majority of FEVR patients (69%) had an identifiable gene mutation, with 55% of mutations affecting traditional Wnt-signaling genes: NDP 13%; FZD4 11%; LRP5 25%; TSPAN12 6%. Other affected genes represented 14% of mutations, with ZNF408 accounting for 9%.

Conclusions

FEVR remains a clinical diagnosis with WFA necessary for making the diagnosis of FEVR. This database demonstrated that, with proper diagnosis, the majority of patients have a definable genetic alteration.
The Impact of Homologous Recombination Deficiency on First-line Adjuvant Chemotherapy and First-line PARPi Maintenance Therapy in Chinese Patients with Epithelial Ovarian Cancer
Authors: Li Lei , Gu Yu , Zhang Mengpei , Shi Xiaohua , Li Zhe , Xu Xinyun , Sun Tianqi , Dong Yu , Xue Chao , Zhu Xiaoru , Lv Ran , Jiao Kai , Ji Xuwo , Liang Zhiyong , Jin Ying , Yin Rutie , Wu Ming , Liang Han
Published: January 2023

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526 to 0.899; P = 0.003) and OS (median, 89.5 months vs. 60.9 months; HR, 0.636; 95% CI, 0.423 to 0.955; P = 0.008). In the first-line PARPi maintenance therapy cohort (FPMT, N = 83), HRD status significantly improved PFS (median, NA vs 12 months; HR, 0.438; 95% CI, 0.201 to 0.957; P = 0.033) and OS (median, NA vs NA months; HR, 0.12; 95% CI, 0.029 to 0.505; P = 0.001). Our results demonstrate that HRD status is a significant predictor for PFS and OS in both first-line chemotherapy and first-line PARPi maintenance therapy, providing strong real-world evidence for conducting genetic testing and improving clinical recommendations for Chinese EOC patients.
STAT3 promotes a youthful epigenetic state in articular chondrocytes
Authors: Sarkar Arijita , Liu Nancy Q. , Magallanes Jenny , Tassey Jade , Lee Siyoung , Shkhyan Ruzanna , Lee Youngjoo , Lu Jinxiu , Ouyang Yuxin , Tang Hanhan , Bian Fangzhou , Tao Litao , Segil Neil , Ernst Jason , Lyons Karen , Horvath Steve , Evseenko Denis
Published: January 2023

Epigenetic mechanisms guiding articular cartilage regeneration and age‐related disease such as osteoarthritis (OA) are poorly understood. STAT3 is a critical age‐patterned transcription factor highly active in fetal and OA chondrocytes, but the context‐specific role of STAT3 in regulating the epigenome of cartilage cells remain elusive. In this study, DNA methylation profiling was performed across human chondrocyte ontogeny to build an epigenetic clock and establish an association between CpG methylation and human chondrocyte age. Exposure of adult chondrocytes to a small molecule STAT3 agonist decreased DNA methylation, while genetic ablation of STAT3 in fetal chondrocytes induced global hypermethylation. CUT&RUN assay and subsequent transcriptional validation revealed DNA methyltransferase 3 beta (DNMT3B) as one of the putative STAT3 targets in chondrocyte development and OA. Functional assessment of human OA chondrocytes showed the acquisition of progenitor‐like immature phenotype by a significant subset of cells. Finally, conditional deletion of Stat3 in cartilage cells increased DNMT3B expression in articular chondrocytes in the knee joint in vivo and resulted in a more prominent OA progression in a post‐traumatic OA (PTOA) mouse model induced by destabilization of the medial meniscus (DMM). Taken together these data reveal a novel role for STAT3 in regulating DNA methylation in cartilage development and disease. Our findings also suggest that elevated levels of active STAT3 in OA chondrocytes may indicate an intrinsic attempt of the tissue to regenerate by promoting a progenitor‐like phenotype. However, it is likely that chronic activation of this pathway, induced by IL‐6 cytokines, is detrimental and leads to tissue degeneration.
An ecological risk assessment for the impacts of offshore wind farms on birds in Australia
Authors: Reid Keith , Baker G. Barry , Woehler Eric J.
Published: January 2023

An ecological risk assessment, based on life‐history and behavioural attributes of 273 bird taxa, was used to identify which of those taxa are at high risk from negative interactions with offshore wind farms in Australia. The marine area of Australia was divided by state/territory boundaries perpendicular to the coast into eight regions, with Western Australia further divided into north and south, and a Bass Strait region bounded by the Victoria coast and the north coast of Tasmania. These regions were subdivided into coastal, inshore and offshore sub‐regions and a risk summary for all bird taxa occurring in each of these sub‐regions produced. In coastal and inshore sub‐regions of Bass Strait, South Australia and Tasmania, the species with the highest risk scores were Orange‐bellied Parrot Neophema chrysogaster, Furneaux White‐fronted Tern Sterna striata incerta, Swift Parrot Lathamus discolor, Shy Albatross Thalassarche cauta, Far Eastern Curlew Numenius madagascariensis and Anadyr Bar‐tailed Godwit Limosa lapponica anadyrensis. In offshore sub‐regions in southern Australia, the highest risk species were all albatrosses, comprising Northern Royal Diomedea sanfordi, Eastern Antipodean D. antipodensis antipodensis, Gibson's D. antipodensis gibsoni, Wandering D. exulans, Amsterdam D. amsterdamensis and Grey‐headed Albatross T. chrysostoma. Compared to onshore installations, there are logistical challenges to quantifying the potential and realized impacts of offshore wind farms that require different approaches to data collection and analyses. The extensive development of offshore wind farms in the Northern Hemisphere provides examples of best and emerging approaches to quantify and mitigate negative impacts of offshore wind farms that can be applied in an Australian context. Despite differences in the species involved, the same approaches to identifying high‐risk species and to the monitoring and mitigation of negative impacts should be applied in a coordinated, regional‐scale approach to the development of offshore wind farms in Australia.
Risk of colorectal advanced neoplasia in patients with acute diverticulitis with and without previous colonoscopy
Authors: Albshesh Ahmad , Ukashi Offir , Lahat Adi , Kopylov Uri , Horesh Nir , Pflantzer Barak , Laish Ido
Published: January 2023

Background and Aim

Guidelines recommend a colonoscopy after an episode of complicated diverticulitis and after a first episode of uncomplicated diverticulitis. The influence of a previous colonoscopy on postdiverticulitis colonoscopic findings has not been studied. The aim of this work was to examine the incidence of adenoma detection rate (ADR), advanced adenoma (AA) and colorectal cancer (CRC) in patients with diverticulitis with and without previous colonoscopy.

Method

This was a retrospective case–control study of subjects with acute diverticulitis. Subsequent and previous colonoscopies were abstracted for ADR, AA and CRC diagnoses. The incidence of neoplasia was compared between patients with and without previous colonoscopy and also with that of a screening population.

Results

Compared with a healthy control group (n = 975), diverticulitis patients without prior colonoscopy (n = 325) had a significantly higher ADR (26.8% vs. 20.5%, p = 0.019) and invasive CRC rate (0.9% vs. 0%, p = 0.016). Risk factors for advanced neoplasia included age ≥ 70 years and complicated diverticulitis. Among subjects with diverticulitis and previous colonoscopy (n = 124), only one patient developed AA and there were no cancer cases.

Conclusions

A previous normal colonoscopy within 5 years before diverticulitis probably overshadows other risk factors for findings of advanced neoplasia and should be considered in the decision to repeat a colonoscopy.
Response assessment of locally advanced rectal cancer after neoadjuvant chemoradiotherapy: Is apparent diffusion coefficient useful on 3 T magnetic resonance imaging?
Authors: Boraschi Piero , Cervelli Rosa , Donati Francescamaria , Landi Elena , Cacciato‐Insilla Andrea , Campani Daniela , Caramella Davide
Published: January 2023

Aim

To assess the diagnostic value of apparent diffusion coefficient (ADC) on 3 T device for the prediction of tumoral response to neoadjuvant chemoradiotherapy (nCRT) and for the response assessment after nCRT in patients with locally advanced rectal cancer (LARC), using pathology as a reference.

Methods

Forty‐one patients affected by LARC undergoing 3.0 T MRI before and after nCRT were retrospectively selected. After the conventional acquisition of high resolution T2‐weighted sequences, diffusion‐weighted MRI (DW‐MRI) was performed using a spin‐echo echo‐planar sequence with multiple b values (150, 500, 1000, 1500 s/mm2). Fitted ADC values were calculated for each rectal lesion before and after nCRT by drawing a hand‐made region of interest (ROI) around the tumour outline. All patients underwent surgery and pathological staging (classified according to tumour regression grading [TRG] and to tumour and node [TN]) represented the reference standard. Pretreatment ADC value (pre‐ADC), ADC value obtained after nCRT (post‐ADC) and the difference between post‐ADC and pre‐ADC (ΔADC) were correlated with both the TRG classes and the TN staging system in each patient.

Results

The ADC values obtained in the post nCRT examination and the ΔADC were statistically related both to TRG (p = 0.0004; p = 0.0126, respectively) and TN (p = 0.0484; p = 0.0673, respectively) stages at histopathology. On the contrary, the pre‐ADC was not related either to the TRG classes or to the lesion TN staging system (p > 0.05).

Conclusions

3 T DW‐MRI using ADC value can be useful to assess the efficacy of nCRT in LARC; in fact, post‐ADC and ΔADC values improve MR capability to evaluate tumour response.
Emergence of Covid‐19 as a Novel Concept Shifts Existing Semantic Spaces
Authors: Davis Charles P.
Published: January 2023

Conceptual knowledge is dynamic, fluid, and flexible, changing as a function of contextual factors at multiple scales. The Covid‐19 pandemic can be considered a large‐scale, global context that has fundamentally altered most people's experiences with the world. It has also introduced a new concept, COVID (or COVID‐19), into our collective knowledgebase. What are the implications of this introduction for how existing conceptual knowledge is structured? Our collective emotional and social experiences with the world have been profoundly impacted by the Covid‐19 pandemic, and experience‐based perspectives on concept representation suggest that emotional and social experiences are critical components of conceptual knowledge. Such changes in collective experience should, then, have downstream consequences on knowledge of emotion‐ and social‐related concepts. Using a naturally occurring dataset derived from the social media platform Twitter, we show that semantic spaces for concepts related to our emotional experiences with Covid‐19 (i.e., emotional concepts like FEAR)—but not for unrelated concepts (i.e., animals like CAT)—show quantifiable shifts as a function of the emergence of COVID‐19 as a concept and its associated emotional and social experiences, shifts which persist 6 months after the onset of the pandemic. The findings support a dynamic view of conceptual knowledge wherein shared experiences affect conceptual structure.
Testing habitat suitability for shellfish restoration with small‐scale pilot experiments
Authors: Benjamin Emilee D. , Handley Sean J. , Jeffs Andrew , Olsen Louis , Toone Trevyn A. , Hillman Jenny R.
Published: January 2023

The global loss in ecosystem engineers has initiated calls for restoration, which includes the UN declaration of 2021–2030 as the decade of ecosystem restoration. As researchers dive into this decade it is important to consider the current state of an ecosystem to ensure restoration success. Pilot‐scale restoration has been recommended by global guidelines and standards as an effective starting point for restoration to provide valuable initial information to increase efficiency and success of subsequent larger‐scale restoration. To test habitat suitability, 4 t of green‐lipped mussels were placed onto three 2.25 m2plots at five locations with differing benthic environments and assessed over 2 years. This study had a mean of 85% mussel survival at four of the five locations, while the restored shellfish in one location were completely extirpated, most likely by sea star predation. This pilot‐scale restoration revealed location‐specific differences that have implications for ensuring larger‐scale restoration success, including mussel survival, density, and health, and recommends a timeframe of at least 18 months to properly assess habitat suitability. Overall, the results validated the efficacy of using small‐scale pilot experiments to test habitat suitability and optimize location selection to maximize success and efficiency of larger‐scale restoration efforts.
ChAT::Cre transgenic rats show sex‐dependent altered fear behaviors, ultrasonic vocalizations and cholinergic marker expression
Authors: Tryon Sarah C. , Sakamoto Iris M. , Kaigler Kris F. , Gee Gabriella , Turner Jarrett , Bartley Katherine , Fadel Jim R. , Wilson Marlene A.
Published: January 2023

The cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre‐) littermates during fear learning, contextual and cue‐conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre‐ littermates, and displayed significant sex differences in contextual and cue‐conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre‐ rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses.