bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanoprodrugs encapsulated with mesoporous silica nanoparticles for combined with photothermal therapy for the treatment and care of gastric cancer
Authors: Jin Qiaoli , Pan Qin
Published: November 2022

In this study, mesoporous silica nanoparticles (MSNs) were surface-modified with polymer poly(HEMA-co-PEGMA via surface-initiated atom transfer radical polymerization and a multifunctional nanoplatform MSNP@poly(HEMA-co-PEGMA-g-doxorubicin (DOX)/Rhodamine 6 G (R6G) was developed to combine photothermal (PTT) and chemotherapy therapy effectively. PTT induced by near-infrared (NIR) radiations might further destroy gastric cancer cell lines while the small-dye molecule was co-loaded into the MSNP pores. A 65 % higher cumulative drug release over 50-h occurs when the cis-aconitic anhydride link breaks under low-pH stimulation (typical physiological environment). High temperatures accelerated reversible covalent bond breakage. The accumulative release of the drug increased by 24.3 %, illustrating that higher temperatures can decrease the time needed to complete blood drug concentrations by 24.3 %. More than 90% of gastric tumour cells were destroyed after 48 h following exposure to NIR light irradiation with the prodrug delivery system, compared to DOX alone in vitro cytotoxicity tests. Because of this, rapidly reversible chemical bond breaking and photothermal activity in MSNP@poly(HEMA-co-PEGMA-g-DOX/R6G) increased the synergic impact of the chemotherapy, which offers tremendous promise in combination with the treatment and care of gastric cancer therapy.
Modeling tungsten response under helium plasma irradiation: a review
Authors: YANG Zhangcan , FAN Junyi
Published: November 2022

Tungsten, a leading candidate for plasma-facing materials (PFM) in future fusion devices, will be exposed to high-flux low-energy helium plasma under the anticipated fusion operation conditions. In the past two decades, experiments have revealed that exposure to helium plasma strongly modifies the surface morphology and hence the sputtering, thermal and other properties of tungsten, posing a serious danger to the performance and lifetime of tungsten and the steady-state operation of plasma. In this article, we provide a review of modeling and simulation efforts on the long-term evolution of helium bubbles, surface morphology, and property changes of tungsten exposed to low-energy helium plasma. The current gap and outstanding challenges to establish a predictive modeling capability for dynamic evolution of PFM are discussed.
Assessment of recent global geopotential models based on the Auvergne test area data
Authors: Doğanalp Serkan
Published: November 2022

The gravitational field is important for many natural phenomena related to earth dynamics, especially mass transport. Its precise determination is essential for earth sciences such as geodesy, geophysics and oceanography. Determining the earth’s gravitational field is the same as determining the earth’s potential. Since this potential is a harmonic function outside the earth, spherical harmonic series are often used to represent the gravity field. Global Geopotential Models (GGMs) are sets of spherical harmonic coefficients representing the earth’s gravity field at different wavelengths. GGMs developed by scientists are published by the International Centre for Gravity Earth Models (ICGEM). When the structure of the GGMs is examined, it is seen that they consist of different degrees and various data groups. The accuracy and resolution provided by each GGM vary depending on the degree of the model and the data used for developing the GGM. Also, geodetic quantities such as potential, geoid undulation, deflection of the vertical components, gravity, and anomaly values can be derived from GGMs within the framework of mathematical principles. In this study, gravity, geoid heights, and free-air gravity anomaly values at test points using different GGMs produced in recent years have been investigated. The study area contains 98000 test points chosen from the Auvergne test area in France. Within the scope of the study, the geoid undulations, gravity values, and free-air gravity anomalies for all points derived from seven recent GGMs have been compared with ground-truth data and the statistical results have been obtained.
General Vapnik–Chervonenkis dimension bounds for quantum circuit learning
Authors: Chen Chih-Chieh , Sogabe Masaru , Shiba Kodai , Sakamoto Katsuyoshi , Sogabe Tomah
Published: November 2022

Quantifying the model complexity of quantum circuits provides a guide to avoid overfitting in quantum machine learning. Previously we established a Vapnik–Chervonenkis (VC) dimension upper bound for ‘encoding-first’ quantum circuits, where the input layer is the first layer of the circuit. In this work, we prove a general VC dimension upper bound for quantum circuit learning including ‘data re-uploading’ circuits, where the input gates can be single qubit rotations anywhere in the circuit. A linear lower bound is also constructed. The properties of the bounds and approximation-estimation trade-off considerations are discussed.
(Un)boundedness of directional maximal operators through a notion of “Perron capacity” and an application
Authors: D’Aniello Emma , Gauvan Anthony , Moonens Laurent
Published: November 2022

We introduce the notion of Perron capacity of a set of slopes

Ω
⊂

R

\Omega \subset \mathbb {R}

. Precisely, we prove that if the Perron capacity of

Ω
\Omega

is finite then the directional maximal operator associated

M
Ω

M_\Omega

is not bounded on

L
p

(

R

2

)

L^p(\mathbb {R}^2)

for any

1
>
p
>
∞

1 > p > \infty

. This allows us to prove that the set

Ω
c

=

{

cos
⁡
n

n

:
n
∈

N

∗

}

\begin{equation*} {\Omega _c} =\left \{ \frac {\cos n}{n}: n\in \mathbb {N}^* \right \} \end{equation*}

is not finitely lacunary which answers a question raised by A. Stokolos in private communications to the authors.
Improving Methods of Identifying Anaphylaxis for Medical Product Safety Surveillance Using Natural Language Processing and Machine Learning
Authors: Carrell David S , Gruber Susan , Floyd James S , Bann Maralyssa A , Cushing-Haugen Kara L , Johnson Ron L , Graham Vina , Cronkite David J , Hazlehurst Brian L , Felcher Andrew H , Bejan Cosmin A , Kennedy Adee , Shinde Mayura
U , Karami Sara , Ma Yong , Stojanovic Danijela , Zhao Yueqin , Ball Robert , Nelson Jennifer
C
Published: November 2022

We sought to determine whether machine learning and natural language processing (NLP) applied to electronic medical records could improve performance of automated health-care claims-based algorithms to identify anaphylaxis events using data on 516 patients with outpatient, emergency department, or inpatient anaphylaxis diagnosis codes during 2015–2019 in 2 integrated health-care institutions in the Northwest United States. We used one site’s manually reviewed gold-standard outcomes data for model development and the other’s for external validation based on cross-validated area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and sensitivity. In the development site 154 (64%) of 239 potential events met adjudication criteria for anaphylaxis compared with 180 (65%) of 277 in the validation site. Logistic regression models using only structured claims data achieved a cross-validated AUC of 0.58 (95% CI: 0.54, 0.63). Machine learning improved cross-validated AUC to 0.62 (0.58, 0.66); incorporating NLP-derived covariates further increased cross-validated AUCs to 0.70 (0.66, 0.75) in development and 0.67 (0.63, 0.71) in external validation data. A classification threshold with cross-validated PPV of 79% and cross-validated sensitivity of 66% in development data had cross-validated PPV of 78% and cross-validated sensitivity of 56% in external data. Machine learning and NLP-derived data improved identification of validated anaphylaxis events.
Interventions to reduce waste and improve billing compliance with medications in single-dose vials
Authors: Trovato Anthony , Tyler Linda S , Nickman Nancy A , Findlay Russell
Published: November 2022

Purpose

The purpose of this process improvement project was to implement features in the electronic health record to help reduce inappropriate drug waste and Medicare billing noncompliance for injectable drugs in single-dose vials in outpatient settings.

Methods

The pharmacy department mapped processes from order entry to dose administration and claims processing. They used the process map to identify gaps that could lead to inappropriate drug waste. The organization then chose 3 drugs they believed to be at high risk of excess waste and possible billing noncompliance after cross-referencing drug cost, volume of use, and previous Medicare audits in outpatient settings. They tested a grouper and dose rounding on these drugs and compared 3 months of claims before and after implementation to assess the impact on waste and billing compliance.

Results

This study evaluated 826 claims before implementation and 1,075 claims after implementation. A total of 455 of 826 (55.1%) preimplementation claims included drug waste compared to 224 of 1,075 (20.8%) postimplementation claims. Twenty-three claims before implementation included an amount of waste exceeding the smallest vial size, putting the institution at risk of billing noncompliance. No claims had excess waste in the postimplementation period. The approximate cost of total drug waste before implementation was $1,397,437, with approximately $23,730 from inappropriate carfilzomib claims. The approximate cost of waste after implementation was $569,041. This equated to a reduction in drug waste of approximately $828,396 for bevacizumab-bvzr, carfilzomib, and ipilimumab.

Conclusion

Using a grouper and implementing dose rounding, the institution reduced drug waste, saved money, and reduced the incidence of claims noncompliant with Medicare Part B billing requirements.
Gender Moderates the Association Between Cognitive Reappraisal and Alcohol-Related Problems Among Adolescents
Authors: Teeters Jenni B , Laves Eliza H , King Shelby A , Brausch Amy M
Published: November 2022

Background/Objective

Alcohol use typically begins in adolescence, and the risk of later alcohol use disorders increases with earlier age of onset. Emotion dysregulation in adolescence has been linked to alcohol use. The present study seeks to extend previous findings by examining whether gender moderates the association between emotion regulation strategies (suppression and cognitive reappraisal) and alcohol-related problems in a longitudinal sample of adolescents.

Method

Data were collected as part of an ongoing study of high school students from the south-central region of the USA. The sample included 693 adolescents who participated in a study on suicidal ideation and risk behaviors. The majority of participants were girls (54.8%), white (85%) and heterosexual (87.7%). Baseline (T1) and 6-month follow-up (T2) data were analyzed for the present study.

Results

Negative binomial moderation analyses revealed that gender moderated the association between cognitive reappraisal and alcohol-related problems, such that the association between reappraisal and alcohol-related problems was significantly stronger for boys than for girls. Gender did not moderate the association between suppression and alcohol-related problems.

Conclusions

The results suggest that emotion regulation strategies may be a particularly useful target for prevention and intervention efforts. Future research should consider tailoring adolescent alcohol prevention and intervention efforts focused on emotion regulation strategies by gender to bolster cognitive reappraisal skills and decrease suppression.
An in silico genome-wide screen for circadian clock strength in human samples
Authors: Wu Gang , Ruben Marc D , Francey Lauren J , Lee Yin Yeng , Anafi Ron C , Hogenesch John B
Published: November 2022

Motivation

Years of time-series gene expression studies have built a strong understanding of clock-controlled pathways across species. However, comparatively little is known about how ‘non-clock’ pathways influence clock function. We need a strong understanding of clock-coupled pathways in human tissues to better appreciate the links between disease and clock function.

Results

We developed a new computational approach to explore candidate pathways coupled to the clock in human tissues. This method, termed LTM, is an in silico screen to infer genetic influences on circadian clock function. LTM uses natural variation in gene expression in human data and directly links gene expression variation to clock strength independent of longitudinal data. We applied LTM to three human skin and one melanoma datasets and found that the cell cycle is the top candidate clock-coupled pathway in healthy skin. In addition, we applied LTM to thousands of tumor samples from 11 cancer types in the TCGA database and found that extracellular matrix organization-related pathways are tightly associated with the clock strength in humans. Further analysis shows that clock strength in tumor samples is correlated with the proportion of cancer-associated fibroblasts and endothelial cells. Therefore, we show both the power of LTM in predicting clock-coupled pathways and classify factors associated with clock strength in human tissues.

Availability and implementation

LTM is available on GitHub (https://github.com/gangwug/LTMR) and figshare (https://figshare.com/articles/software/LTMR/21217604) to facilitate its use.

Supplementary information

Supplementary data are available at Bioinformatics online.
Integrating transformer and imbalanced multi-label learning to identify antimicrobial peptides and their functional activities
Authors: Pang Yuxuan , Yao Lantian , Xu Jingyi , Wang Zhuo , Lee Tzong-Yi
Published: November 2022

Motivation

Antimicrobial peptides (AMPs) have the potential to inhibit multiple types of pathogens and to heal infections. Computational strategies can assist in characterizing novel AMPs from proteome or collections of synthetic sequences and discovering their functional abilities toward different microbial targets without intensive labor.

Results

Here, we present a deep learning-based method for computer-aided novel AMP discovery that utilizes the transformer neural network architecture with knowledge from natural language processing to extract peptide sequence information. We implemented the method for two AMP-related tasks: the first is to discriminate AMPs from other peptides, and the second task is identifying AMPs functional activities related to seven different targets (gram-negative bacteria, gram-positive bacteria, fungi, viruses, cancer cells, parasites and mammalian cell inhibition), which is a multi-label problem. In addition, asymmetric loss was adopted to resolve the intrinsic imbalance of dataset, particularly for the multi-label scenarios. The evaluation showed that our proposed scheme achieves the best performance for the first task (96.85% balanced accuracy) and has a more unbiased prediction for the second task (79.83% balanced accuracy averaged across all functional activities) when compared with that of strategies without imbalanced learning or deep learning.

Availability and implementation

The source code and data of this study are available at https://github.com/BiOmicsLab/TransImbAMP.

Supplementary information

Supplementary data are available at Bioinformatics online.
Role of progesterone on dexamethasone-induced alterations in placental vascularization and progesterone receptors in rats
Authors: Alawadhi Mariam , Kilarkaje Narayana , Mouihate Abdeslam , Al-Bader Maie D
Published: November 2022

Background

Intrauterine growth restriction (IUGR) is manifested by lower maternal progesterone levels, smaller placental size, and decreased placental vascularity indicated by lower expression of vascular endothelial growth factor (VEGF). Studies showed that progesterone increases angiogenesis and induces VEGF expression in different tissues. Therefore, the aim of the present study is to evaluate the effect of progesterone on placental vascular bed and VEGF expression and the modulation of nuclear and membranous progesterone receptors (PR) in dexamethasone-induced rat IUGR model.

Methods

Pregnant Sprague–Dawley rats were allocated into four groups and given intraperitoneal injections of either saline, dexamethasone, dexamethasone, and progesterone or progesterone. Injections started on gestation day (DG) 15 and lasted until the days of euthanization (19 and 21 DG). Enzyme-linked immunosorbent assay was used to evaluate plasma progesterone levels. Real-time PCR and western blotting were used to evaluate gene and protein expressions of VEGF, and PR in labyrinth and basal placental zones. Immunohistochemistry was used to locate VEGF and different PRs in placental cells. Immunofluorescence was used to monitor the expression of blood vessel marker (αSMA).

Results

Dexamethasone decreased the vascular bed fraction and the expression of VEGF in both placental zones. Progesterone co-treatment with dexamethasone prevented this reduction. Nuclear and membrane PRs showed tissue-specific expression in different placental zones and responded differently to both dexamethasone and progesterone.

Conclusions

Progesterone treatment improves the outcomes in IUGR pregnancy. Progesterone alleviated DEX-induced IUGR probably by promoting placental VEGF and angiogenesis.
Novel role for conceptus signals in mRNA expression regulation by DNA methylation in porcine endometrium during early pregnancy
Authors: Kaczynski Piotr , van der Weijden Vera , Goryszewska-Szczurek Ewelina , Baryla Monika , Ulbrich Susanne E , Waclawik Agnieszka
Published: November 2022

During early pregnancy, porcine conceptuses (the embryos with associated membranes) secrete estradiol-17β (E2)—their major signal for maternal recognition of pregnancy—and prostaglandin E2 (PGE2). Both hormones induce prominent changes of the endometrial transcriptome in vivo. Studies on endometrial pathologies have shown that E2 affects gene expression by epigenetic mechanisms related to DNA methylation. Herein, we determined the effects of E2 and PGE2 alone, and a combined E2 + PGE2 treatment administered into the uterine lumen in vivo on the expression and activity of DNA-methyltransferases (DNMTs) and on CpG methylation patterns of selected genes in porcine endometrium. To compare the effect of treatment with the physiological effect of pregnancy, endometria from day 12 pregnant/cyclic gilts were included. Both E2 and PGE2 significantly reduced the expression of DNMTs. Likewise, the expressions of DNMT1 and DNMT3A were decreased on day 12 of pregnancy compared to the estrous cycle. DNMT activity increased in endometrial samples following E2 treatment and in gilts on day 12 of pregnancy. Treatment with E2 alone and/or simultaneously with PGE2 altered endometrial DNA methylation of CpG sites of ADAMTS20, ADH1C, BGN, PSAT1, and WNT5A. Different CpG methylation patterns of ADAMTS20, BGN, DMBT1, RASSF1, and WNT5A were found in the endometrium on day 12 of pregnancy compared to day 12 of the estrous cycle. Significant correlations were detected between CpG methylation and gene expression for ADAMTS20, ADH1C, BGN, DMBT1, PSAT1, and WNT5A. Our results indicate that CpG methylation induced by embryonic signals may contribute to regulating endometrial gene expression during pregnancy establishment.
Beta-defensins as marker for male fertility: a comprehensive review
Authors: Solanki Subhash , Kumar Vijay , Kashyap Poonam , Kumar Rakesh , De Sachinandan , Datta Tirtha Kumar
Published: November 2022

Bovine male fertility in animals has a direct impact on the productivity of dairy herds. The epididymal sperm maturations involve extensive sperm surface modifications to gain the fertilizing ability, especially by absorptions of the plethora of biomolecules, including glycoprotein beta-defensins (BDs), enzymes, organic ions, protein, and phospholipids. Defensins are broad-range nonspecific antimicrobial peptides that exhibit strong relations with innate and adaptive immunity, but their roles in male fertility are relatively recently identified. In the course of evolution, BD genes give rise to different clusters with specific functions, especially reproductive functions, by undergoing duplications and nonsynonymous mutations. BD polymorphisms have been reported with milk compositions, disease resistance, and antimicrobial activities. However, in recent decades, the link of BD polymorphisms with fertility has emerged as an appealing improvement of reproductive performance such as sperm motility, membrane integrity, cervical mucus penetration, evading of uterus immunosurveillance, oviduct cell attachment, and egg recognition. The reproductive-specific glycosylated BD class-A BDs (CA-BDs) have shown age- and sex-specific expressions in male reproductive organs, signifying their physiological pleiotropism, especially in the sperm maturation and sperm transport in the female reproductive tract. By considering adult male reproductive organ-specific BD expressions, importance in sperm functionalities, and bioinformatic analysis, we have selected two bovine BBD126 and BBD129 genes as novel potential biomarkers of bovine male fertility. Despite the importance of BDs, however, genomic characterization of most BD genes across most livestock and nonmodel organisms remains predictive/incomplete. The current review discusses our understanding of BD pleiotropic functions, polymorphism, and genomic structural attributes concerning the fertilizability of the male gamete in dairy animals.
Hyperconnectivity and altered interactions of a nucleus accumbens network in post-stroke depression
Authors: Oestreich Lena K L , Wright Paul , O’Sullivan Michael J
Published: November 2022

Post-stroke depression is a common complication of stroke. To date, no consistent locus of injury is associated with this complication. Here, we probed network dynamics and structural alterations in post-stroke depression in four functional circuits linked to major depressive disorder and a visual network, which served as a control network. Forty-four participants with recent stroke (mean age = 69.03, standard deviation age = 8.59, age range = 51–86 and gender: female = 10) and 16 healthy volunteers (mean age = 71.53, standard deviation age = 10.62, age range = 51–84 and gender: female = 11) were imaged with 3-Tesla structural, diffusion and resting-state functional MRI. The Geriatric Depression Scale was administered to measure depression severity. Associations between depression severity and functional connectivity were investigated within networks seeded from nucleus accumbens, amygdala, dorsolateral prefrontal cortex and primary visual cortex. In addition, the default mode network was identified by connectivity with medial prefrontal cortex and posterior cingulate cortex. Circuits that exhibited altered activity associated with depression severity were further investigated by extracting within-network volumetric and microstructural measures from structural images. In the stroke group, functional connectivity within the nucleus accumbens-seeded network (left hemisphere: P = 0.001; and right hemisphere: P = 0.004) and default mode network (cluster one: P < 0.001; and cluster two: P < 0.001) correlated positively with depressive symptoms. Normal anticorrelations between these two networks were absent in patients with post-stroke depression. Grey matter volume of the right posterior cingulate cortex (Pearson correlation coefficient = −0.286, P = 0.03), as well as microstructural measures in the posterior cingulate cortex (right: Pearson correlation coefficient = 0.4, P = 0.024; and left: Pearson correlation coefficient = 0.3, P = 0.048), right medial prefrontal cortex (Pearson correlation coefficient = 0.312, P = 0.039) and the medial forebrain bundle (Pearson correlation coefficient = 0.450, P = 0.003), a major projection pathway interconnecting the nucleus accumbens-seeded network and linking to medial prefrontal cortex, were associated with depression severity. Depression after stroke is marked by reduced mutual inhibition between functional circuits involving nucleus accumbens and default mode network as well as volumetric and microstructural changes within these networks. Aberrant network dynamics present in patients with post-stroke depression are therefore likely to be influenced by secondary, pervasive alterations in grey and white matter, remote from the site of injury.
Use of omics analysis for low-dose radiotoxicology and health risk assessment: the case of uranium
Authors: Grison Stéphane , Souidi Maâmar
Published: November 2022

Exposure to environmental pollution and the increase in the incidence of multifactorial diseases in the population have become health problems for industrialized countries. In this context, the question of the health impact of exposure to these pollutants is not clearly identified in the low-dose range. This article looks at this problem using the example of preclinical studies of the effects of chronic low-dose exposure to uranium in rats. These studies demonstrate the value of molecular screening analyses (omics) and multimodal integrative approaches, of which the extreme sensitivity and breadth of observation spectrum make it possible to observe all the biological processes affected and the mechanisms of action triggered at the molecular level by exposure to low doses. They also show the value of these analytical approaches for finding diagnostic biomarkers or indicators of prognosis, which can be necessary to evaluate a risk. Finally, the results of these studies raise the question of the health risk caused by epigenomic deregulations occurring during critical developmental phases and their potential contribution to the development of chronic diseases that are metabolic in origin or to the development of certain cancer liable in the long term to affect the exposed adult and possibly its progeny.
Real-world perioperative outcomes of segmentectomy versus lobectomy for early-stage lung cancer: a propensity score-matched analysis
Authors: Ichinose Junji , Yamamoto Hiroyuki , Aokage Keiju , Kondo Haruhiko , Sato Yukio , Suzuki Kenji , Chida Masayuki
Published: November 2022

OBJECTIVES

This study aimed to compare the real-world outcomes of segmentectomy and lobectomy for lung cancer after adjusting for background factors and the extent of lymphadenectomy.

METHODS

This retrospective cohort study used a nationwide database in Japan. The data of patients with clinical stage 0/IA lung cancer who underwent segmentectomy or lobectomy between 2017 and 2019 were retrieved. Short-term postoperative outcomes were compared between the segmentectomy and lobectomy groups using propensity score-matched analysis.

RESULTS

In the total cohort of 59 663 patients, 11 975 and 47 688 patients were in the segmentectomy and lobectomy groups, respectively. After propensity score matching, 8426 matched patients from each group were retrieved. All confounders including age, sex, comorbidities, smoking history, respiratory function, tumour size, clinical stage, affected lobe and extent of lymphadenectomy were appropriately adjusted. The overall complication rate and the cardiopulmonary complication rate were lower in the segmentectomy group than in the lobectomy group (8.5% vs 11.2%, P < 0.001 and 7.5% vs 10.3%, P < 0.001, respectively). The incidence of prolonged air leak was also lower after segmentectomy than after lobectomy (3.6% vs 5.3%). Surgical mortality, operative time and blood loss volume were comparable between the 2 groups.

CONCLUSIONS

The postoperative complication rate was lower with segmentectomy than with lobectomy for early-stage lung cancer.
Security force assistance to Cameroon: how building enclave units deepens autocracy
Authors: Harkness Kristen A
Published: November 2022

Western countries have increasingly turned to security force assistance (SFA) to build partner capacity and counter terrorist threats in weakly governed states. This trend sits uncomfortably alongside widespread pessimism that coup-proofed and patronage ridden armies can be meaningfully reformed and made combat effective. Searching for new solutions, both scholars and practitioners have converged on the idea of creating ‘enclave units’—elite forces isolated from the broader military that can be proficiently trained and then deployed on counterterrorism missions. But can enclave units resolve the fundamental interest misalignments that have undermined SFA more broadly? This article leverages the case of the Bataillons d'Intervention Rapide in Cameroon to build theoretical insights into the promises and perils of enclave units. I find that achieving combat proficiency perversely deepens autocracy by strengthening the repressive capacity of dictators. When harshening policies and further marginalization then lead to uprisings, often among ethnic minority groups, embattled autocrats redeploy western trained enclave units against civilians. Extending these insights to the shadow cases of the Iraqi Golden Division and Somali Danab suggests that an indefinite western commitment to remain in-country and directly command enclave units may be necessary to prevent their political misuse.
Unravelling early sinus node dysfunction after pediatric cardiac surgery: a pre-existing arrhythmogenic substrate
Authors: Ramdat Misier Nawin L , Taverne Yannick J H J , van Schie Mathijs S , Kharbanda Rohit K , van Leeuwen Wouter J , Kammeraad Janneke A E , Bogers Ad J J C , de Groot Natasja M S
Published: November 2022

Early post-operative sinus node dysfunction (SND) is common in paediatric patients undergoing surgical correction of congenital heart defects (CHD). At present, the pathophysiology of these arrhythmias is incompletely understood. In this case series, we present three paediatric patients in whom we performed intraoperative epicardial mapping and who developed early post-operative SND. All patients had either an inferior or multiple sinoatrial node (SAN) exit sites, in addition to extensive conduction disorders at superior and inferior right atrium. Our findings contribute to the hypothesis that pre-existing alterations in SAN exit sites in combination with atrial conduction disorders may predispose paediatric patients with CHD for early post-operative SND. Such insights in the development of arrhythmias are crucial as it may be the first step in identifying high-risk patients.
Relative Stable Pairs and a Non-Calabi–Yau Wall Crossing
Authors: Pădurariu Tudor
Published: November 2022

Let $Y$ be a smooth projective threefold, and let $f:Y\to X$ be a birational map with $Rf_*\mathcal {O}_Y=\mathcal {O}_X$. When $Y$ is Calabi–Yau, Bryan–Steinberg (BS) defined enumerative invariants associated to such maps called $f$-relative stable (or BS) invariants. When $X$ has Gorenstein singularities and $f$ has relative dimension one, they compared these invariants to the Donaldson–Thomas, or equivalently Pandharipande–Thomas invariants (PT) of $Y$. We define BS invariants for maps $f$ as above without assuming that $Y$ is Calabi–Yau. For $X$ with Gorenstein and rational singularities, $f$ of relative dimension one, and for insertions from $X$ and arbitrary descendant levels, we conjecture a relation between the generating functions of BS and PT of $Y$. We check the conjecture for the contraction $f: Y\to X$ of a rational curve $C$ with normal bundle $N_{C/Y}\cong \mathcal {O}_C(-1)^{\oplus 2}$ using degeneration and localization techniques to reduce to a Calabi–Yau situation, which we then treat using Joyce’s motivic Hall algebra.
The Cheeger Constants of Random Belyi Surfaces
Authors: Shen Yang , Wu Yunhui
Published: November 2022

Brooks and Makover developed a combinatorial model of random hyperbolic surfaces by gluing certain hyperbolic ideal triangles. In this paper, we show that for any $\epsilon>0$, as the number of ideal triangles goes to infinity, a generic hyperbolic surface in Brooks–Makover’s model has Cheeger constant less than $\frac {3}{2\pi }+\epsilon $.
Multiomics characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates with heterogeneous intermediate resistance to vancomycin (hVISA) in Latin America
Authors: Castro Betsy E , Rios Rafael , Carvajal Lina P , Vargas Mónica L , Cala Mónica P , León Lizeth , Hanson Blake , Dinh An Q , Ortega-Recalde Oscar , Seas Carlos , Munita Jose M , Arias Cesar A , Rincon Sandra , Reyes Jinnethe , Diaz Lorena
Published: November 2022

Background

Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms.

Objective

To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches.

Methods

39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and hydrophilic interaction in six CC5-MRSA.

Results

Genomic relatedness of MRSA associated to hVISA phenotype was not detected. The change Try38 → His in Atl (autolysin) was identified in 92% of the hVISA. We identified SNPs and k-mers associated to hVISA in 11 coding regions with predicted functions in virulence, transport systems, carbohydrate metabolism and tRNA synthesis. Further, capABCDE, sdrD, esaA, esaD, essA and ssaA genes were overexpressed in hVISA, while lacABCDEFG genes were downregulated. Additionally, valine, threonine, leucine tyrosine, FAD and NADH were more abundant in VSSA, while arginine, glycine and betaine were more abundant in hVISA. Finally, we observed altered metabolic pathways in hVISA, including purine and pyrimidine pathway, CoA biosynthesis, amino acid metabolism and aminoacyl tRNA biosynthesis.

Conclusions

Our results show that the mechanism of hVISA involves major changes in regulatory systems, expression of virulence factors and reduction in glycolysis via TCA cycle. This work contributes to the understanding of the development of this complex resistance mechanism in regional strains.
Outcomes of modern antiretroviral therapy in obese individuals living with HIV
Authors: Zino L , Stalenhoef J , Colbers A , Burger D M
Published: November 2022

Obesity is a global epidemic and people living with HIV (PLWH) are showing similar obesity trends to those in the general population. Obesity is manifested by several physiological features that can alter volume of distribution, elimination and metabolism of various medications including ART. Some drugs are increasingly prone to pharmacokinetic alteration during obesity depending on their physicochemical properties and clearance mechanism. These considerations raise concerns of hampered efficacy, development of resistance or increased toxicity of ART in PLWH. Here, we summarize available literature on the exposure and antiviral outcomes of currently available antiretroviral drugs in the context of obesity and provide a panel of recommendations for the clinical management and follow-up in this growing patient population.
The antiviral efficacies of small-molecule inhibitors against respiratory syncytial virus based on the F protein
Authors: Dai Pei , Ruan Pinglang , Mao Yu , Tang Zhongxiang , Bajinka Ousman , Wu Guojun , Tan Yurong
Published: November 2022

Objectives

Respiratory syncytial virus (RSV) infection is one of the three most common causes of death in the infants, pre-schoolers, immunocompromised patients and elderly individuals due to many complications and lack of specific treatment. During RSV infection, the fusion protein (F protein) mediates the fusion of the virus envelope with the host cell membrane. Therefore, the F protein is an effective target for viral inhibition.

Methods

We identified potential small-molecule inhibitors against RSV-F protein for the treatment of RSV infection using virtual screening and molecular dynamics (MD) simulations. The CCK8 assay was used to determine the cytotoxicity and quantitative RT–PCR and indirect fluorescence assay (IFA) were used to determine the viral replication and RSV-induced inflammation in vitro. An RSV-infected mouse model was established, and viral replication was assayed using real-time quantitative PCR and IFA. Virus-induced complications were also examined using histopathological analysis, airway resistance and the levels of IL-1β, IL-6 and TNF-α.

Results

The top three potential inhibitors against the RSV-F protein were screened from the FDA-approved drug database. Z65, Z85 and Z74 significantly inhibited viral replication and RSV-induced inflammation. They also significantly alleviated RSV infection and RSV-induced complications in vivo. Z65 and Z85 had no cytotoxicity and better anti-RSV effects than Z74.

Conclusions

Z65 and Z85 may be suitable candidates for the treatment of RSV and serve as the basis for the development of new drugs.
Genomic analyses of gray fox lineages suggest ancient divergence and secondary contact in the southern Great Plains
Authors: Kierepka Elizabeth M , Preckler-Quisquater Sophie , Reding Dawn M , Piaggio Antoinette J , Riley Seth P D , Sacks Benjamin N
Published: November 2022

The gray fox (Urocyon cinereoargenteus) lineage diverged from all other extant canids at their most basal node and is restricted to the Americas. Previous mitochondrial analysis from coastal populations identified deeply divergent (up to 1 Mya) eastern and western lineages that predate most intraspecific splits in carnivores. We conducted genotyping by sequencing and mitochondrial analysis on gray foxes sampled across North America to determine geographic concordance between nuclear and mitochondrial contact zones and divergence times. We also estimated the admixture within the contact zone between eastern and western gray foxes based on nuclear DNA. Both datasets confirmed that eastern and western lineages met in the southern Great Plains (i.e. Texas and Oklahoma), where they maintained high differentiation. Admixture was generally low, with the majority of admixed individuals carrying <10% ancestry from the other lineage. Divergence times confirmed a mid-Pleistocene split, similar to the mitochondrial estimates. Taken together, findings suggest gray fox lineages represent an ancient divergence event, far older than most intraspecific divergences in North American carnivores. Low admixture may reflect a relatively recent time since secondary contact (e.g. post-Pleistocene) or, alternatively, ecological or reproductive barriers between lineages. Though further research is needed to disentangle these factors, our genomic investigation suggests species-level divergence exists between eastern and western gray fox lineages.
Frequencies of Anti-Troponin I vs Anti-Troponin T Autoantibodies and Degrees of Interference on Troponin Assays
Authors: Nakano Keiichi , Sugawa Satoshi , Seimiya Masanori , Murakami Satoshi , Yasuda Keiko , Watanabe Chiaki , Goto Hideki , Teshima Takanori
Published: November 2022

Objective

Presence of autoantibodies against troponin I (cTnI) or T (cTnT) has been reported to interfere with troponin assays. However, the extent of the interference with the measurement has not been explored sufficiently. The aims of this study were to examine the frequencies of autoantibodies against troponin I and troponin T and how much these antibodies would affect the measurement.

Methods

The study comprised 52 subjects who visited Hokkaido University Hospital with suspected ischemic heart diseases. To evaluate the presence of autoantibodies, we calculated the recoveries of cTnI or cTnT after immunoglobulin G depletion, and the distributions of peaks reactive with cTnI or cTnT by high-performance liquid chromatography were examined.

Results

Autoantibodies against cTnI and cTnT were identified in 8 subjects (15.4%) and 1 subject (1.9%), respectively. Although the greatest difference between cTnI and cTnT was 32-fold, the distributions of cTnI-to-cTnT ratios in groups with and without anti-cTnI were not statistically different.

Conclusion

Autoantibodies against cTnI were more frequent by several fold than those against cTnT. Their presence did not significantly expand the discrepancy between cTnI and cTnT assays.
Surgically targeted radiation therapy (STaRT) trials for brain neoplasms: A comprehensive review
Authors: Odia Yazmin , Gutierrez Alonso N , Kotecha Rupesh
Published: November 2022

The mainstays of radiation therapy include external beam radiation therapy (EBRT) and internally implanted radiation, or brachytherapy (BT), all with distinct benefits and risks in terms of local or distant tumor control and normal brain toxicities, respectively. GammaTile® Surgically Targeted Radiation Therapy (STaRT) attempts to limit the drawbacks of other BT paradigms via a permanently implanted, bioresorbable, conformable, collagen tile containing four uniform intensity radiation sources, thus preventing deleterious direct contact with the brain and optimizing interseed spacing to homogenous radiation exposure. The safety and feasibility of GammaTile® STaRT therapy was established by multiple clinical trials encompassing the spectrum of primary and secondary brain neoplasms, both recurrent and newly-diagnosed. Implantable GT tiles were FDA approved in 2018 for use in recurrent intracranial neoplasms, expanded to newly-diagnosed malignant intracranial neoplasms by 2020. The current spectrum of trials focuses on better defining the relative efficacy and safety of non-GT standard-of-care radiation strategies for intracranial brain neoplasm. We summarize the key design and eligibility criteria for open and future trials of GT therapy, including registries and randomized trials for newly-diagnosed and recurrent brain metastases as well as recurrent and newly-diagnosed glioblastoma in combination with approved therapies.
Turning on the light for brain tumor surgery: A 5-aminolevulinic acid story
Authors: McCracken David J , Schupper Alexander J , Lakomkin Nikita , Malcolm James , Painton Bray David , Hadjipanayis Constantinos G
Published: November 2022

To aid surgeons in more complete and safe resection of brain tumors, adjuvant technologies have been developed to improve visualization of target tissue. Fluorescence-guided surgery relies on the use of fluorophores and specific light wavelengths to better delineate tumor tissue, inflammation, and areas of blood–brain barrier breakdown. 5-aminolevulinic acid (5-ALA), the first fluorophore developed specifically for brain tumors, accumulates within tumor cells, improving visualization of tumors both at the core, and infiltrative margin. Here, we describe the background of how 5-ALA integrated into the modern neurosurgery practice, clinical evidence for the current use of 5-ALA, and future directions for its role in neurosurgical oncology.

Maximal safe resection remains the standard of care for most brain tumors. Gross total resection of high-grade gliomas (HGGs) is associated with greater overall survival and progression-free survival (PFS) in comparison to subtotal resection or adjuvant treatment therapies alone.1–3 A major challenge neurosurgeons encounter when resecting infiltrative gliomas is identification of the glioma tumor margin to perform a radical resection while avoiding and preserving eloquent regions of the brain. 5-aminolevulinic acid (5-ALA) remains the only optical-imaging agent approved by the FDA for use in glioma surgery and identification of tumor tissue.4 A multicenter randomized, controlled trial revealed that 5-ALA fluorescence-guided surgery (FGS) almost doubled the extent of tumor resection and also improved 6-month PFS.5 In this review, we will highlight the current evidence for use of 5-ALA FGS in brain tumor surgery, as well as discuss the future directions for its use.
Formation of the Nephrite Deposit With Five Mineral Assemblage Zones in the Central Western Kunlun Mountains, China
Authors: Zhang Xiaochong , Shi Guanghai , Zhang Xuemei , Gao Kong
Published: November 2022

The Saidikulam nephrite deposit, which is famous for its high-quality white nephrite no matter in history and nowadays, is located in the eastern part of the Western Kunlun Orogen, in the northwestern margin of the Tibetan Plateau, Yutian County, Xinjiang, China. Field investigations and petrographic observations revealed the presence of five mineral assemblage zones from granodiorite to dolomitic marble in the Saidikulam nephrite deposit: slightly epidote-altered granodiorite → epidote-altered diopsidite → nephrite → calcite tremolitite → calcite-bearing dolomitic marble. However, little is known about the relationships among these five zones or the formation age of the deposit. The slightly epidote-altered granodiorite consists of plagioclase, orthoclase, quartz, biotite, and epidote, with accessory apatite, zircon, and allanite. They exhibit slightly negative Eu anomalies (0.69–0.72), with declined light rare earth element (LREE) and flat heavy rare earth element (HREE) patterns. They are also strongly enriched in Rb, Zr, U, and Sm and depleted in Hf, Ti, P, and Nb. The epidote-altered diopsidite close to the granodiorite intrusions is a relatively high-temperature metasomatic rock composed of Fe-rich diopside and actinolite, while the calcite tremolitite adjacent to the dolomitic marble is a relatively low-temperature rock composed of prismatic tremolite and calcite. The main mineral component of the nephrite is tremolite, with minor epidote, chlorite, apatite, calcite, graphite, and allanite. The nephrites have low ∑REE contents (4.38–18.53 ppm), with declined LREE and flat HREE patterns. All of the analyzed nephrite exhibits pronounced negative Eu anomalies (δEu = 0.20–0.82), and they are strongly enriched in Rb, U, and Ti and relatively depleted in Ba and HFSEs. SHRIMP U–Pb dating of zircons from the granodiorite yielded a Concordia age of 453.8 ± 3.7 Ma, which is interpreted as the upper limit of the Saidikulam nephrite formation age. The zircons in the epidotized syenite in the deposit yielded a SHRIMP Concordia U–Pb age of 489.2 ± 4.2 Ma. These two ages indicate that the dolomitic marble experienced at least two thermal events. The approximate ages of the nephrite deposits along the giant Kunlun-Altyn Tagh belt indicate that the closure of the Proto-Tethys may have been the predominant driving force for the formation of the whole nephrite deposits. The multistage metasomatism and the Fe absorption of epidote-altered diopsidite had a positive impact on the formation of high-quality nephrite.
Epsilon-caprolactone-modified polyethylenimine as a genetic vehicle for stem cell-based bispecific antibody and exosome synergistic therapy
Authors: Tan Yan , Cai Jiali , Wang Zhiyong
Published: November 2022

Bispecific antibodies (BsAb) have gained significant momentum in clinical application. However, the rapid enzymolysis and metabolism of protein drugs usually induce short circulation in vivo, and developing an efficient protein delivery system still is a bottleneck. Mesenchymal stem cells (MSCs) have become an attractive therapeutic carrier for cancers. Genetic modification enables MSCs to express and secrete specific proteins, which is essential for therapeutic efficacy. However, efficient gene transfer into MSCs is still a challenge. In this study, we applied epsilon-caprolactone-modified polyethylenimine (PEI-CL) as an efficacy carrier for plasmid transfection into MSC that served as in situ ‘cell factory’ for anti-CD3/CD20 BsAb preparation. Herein, the PEI-CL encapsulates the minicircle plasmid and mediates cell transfection efficiently. Thus, the anti-CD3/CD20 BsAb is secreted from MSC and recruited T cell, resulting in highly sensitive cytotoxicity in the human B-cell lymphoma. Furthermore, these stem cells produce exosomes bearing MiR-15a/MiR-16, which could negatively regulate cancer’s oncogenes BCL-2 for adjuvant therapy. Meanwhile, high immunologic factors like tumor necrosis factor-α and interferon-γ are generated and enhance immunotherapy efficacy. The engineered MSCs are demonstrated as an efficient route for BsAb production, and these bioactive components contribute to synergistic therapy, which would be an innovative treatment.