bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishing the intracellular niche of obligate intracellular vacuolar pathogens
Authors: Clemente Tatiana M. , Angara Rajendra K. , Gilk Stacey D.
Published: August 2023

Obligate intracellular pathogens occupy one of two niches – free in the host cell cytoplasm or confined in a membrane-bound vacuole. Pathogens occupying membrane-bound vacuoles are sequestered from the innate immune system and have an extra layer of protection from antimicrobial drugs. However, this lifestyle presents several challenges. First, the bacteria must obtain membrane or membrane components to support vacuole expansion and provide space for the increasing bacteria numbers during the log phase of replication. Second, the vacuole microenvironment must be suitable for the unique metabolic needs of the pathogen. Third, as most obligate intracellular bacterial pathogens have undergone genomic reduction and are not capable of full metabolic independence, the bacteria must have mechanisms to obtain essential nutrients and resources from the host cell. Finally, because they are separated from the host cell by the vacuole membrane, the bacteria must possess mechanisms to manipulate the host cell, typically through a specialized secretion system which crosses the vacuole membrane. While there are common themes, each bacterial pathogen utilizes unique approach to establishing and maintaining their intracellular niches. In this review, we focus on the vacuole-bound intracellular niches of Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis, and Coxiella burnetii.
Particularities of coronary physiology in patients with atrial fibrillation: insights from combined pressure and flow indices measurements
Authors: Pintea Bentea Georgiana , Berdaoui Brahim , Samyn Sophie , Morissens Marielle , van de Borne Philippe , Castro Rodriguez Jose
Published: August 2023

Background

Symptoms suggestive of myocardial ischemia are frequently encountered in patients with atrial fibrillation (AF) even in the absence of obstructive coronary artery disease. Nevertheless, an in-depth characterisation of coronary physiology in patients with AF is currently lacking.

Objectives

We aim to provide an insight into the characteristics of coronary physiology in AF, by performing simultaneous invasive measurements of coronary flow- and pressure- indices in a real-life population of patients with AF and indication of coronary angiography.

Methods

This is a prospective open label study including patients with permanent or persistent AF and indication of coronary angiography showing intermediate coronary stenosis requiring routine physiological assessment (n = 18 vessels from 14 patients). We measured FFR (fractional flow reserve), and Doppler-derived coronary flow indices, including CFR (coronary flow reserve) and HMR (hyperaemic microvascular resistance).

Results

From the analysed vessels, 18/18 vessels (100%) presented a pathological CFR (<2.5), indicative of coronary microvascular dysfunction (CMD), and 3/18 (17%) demonstrated obstructive epicardial coronary disease (FFR ≤ 0.8). A large proportion of vessels (15/18; 83%) showed discordant FFR/CFR with preserved FFR and low CFR. 47% of the coronary arteries in patients with AF and non-obstructive epicardial coronary disease presented structural CMD (HMR ≥ 2.5 mmHg/cm/s), and were associated with high BMR and an impaired response to adenosine. Conversely, vessels from patients with AF and non-obstructive epicardial coronary disease with functional CMD (HMR < 2.5 mmHg/cm/s) showed higher bAPV. The permanent AF subpopulation presented increased values of HMR and BMR compared to persistent AF, while structural CMD was more often associated with persistent symptoms at 3 months, taking into account the limited sample size of our study.

Conclusion

Our findings highlight a systematically impaired CFR in patients with AF even in the absence of obstructive epicardial coronary disease, indicative of CMD. In addition, patients with AF presented more prevalent structural CMD (HMR ≥ 2.5 mmHg/cm/s), characterized by reduced hyperaemic responses to adenosine, possibly interfering with the FFR assessment.
Carbon markets, energy transition, and green development: a moderated dual-mediation model
Authors: Kong Shaohua , Li Hanzun , Tan Shuwen
Published: August 2023

Introduction: Carbon market is an important market instrument to deal with environmental problems and an important practice of the green development concept. Among the many economic sectors in China, the energy sector is the largest emitter of carbon dioxide, therefore, the transformation of the energy sector is the focus of China’s green development.

Methods: This study used data from 211 prefecture-level cities in China from 2015 to 2020 to construct carbon market, green development, energy transition (shift to clean and low-carbon energy), and financial development indices to determine how to achieve green development beginning with a carbon emissions market and investigate how carbon markets affect environmentally friendly development from a green economics perspective. Unlike previous studies, this study uses a moderated dual mediation model for analysis to examine the indirect impact of carbon markets on green development through energy efficiency and new energy use channels of energy transition. Afterward, examine how financial development influences carbon markets and green development and the mediating effect of such development in eastern, central, and western China are performed, respectively.

Results: The empirical results of this study reveal the following: first, carbon markets directly influence green development in a favorable way. Second, energy transition creates a bridge between carbon markets as well as green development; and third, financial development plays a moderating role among carbon markets, energy transition, and green development.

Discussion: Based on the empirical findings, this study provides recommendations for promoting green development, such as enhancing information disclosure and guiding green finance development.
Genome-wide association study reveals genomic loci of sex differentiation and gonadal development in Plectropomus leopardus
Authors: Gao Jin , Wang Yongbo , Liu Jinye , Chen Fuxiao , Guo Yilan , Ke Hongji , Wang Xulei , Luo Ming , Fu Shuyuan
Published: August 2023

Introduction:Plectropomus leopardus, a commercially significant marine fish, is primarily found in the Western Pacific regions and along the coast of Southeast Asia. A thorough analysis of the molecular mechanisms involved in sex differentiation is crucial for gaining a comprehensive understanding of gonadal development and improving sex control breeding. However, the relevant fundamental studies of P. leopardus are relatively lacking.

Methods: In this study, a genome-wide association study (GWAS) was conducted to investigate the genetic basis mechanism of sex differentiation and gonadal developmental traits in P. leopardus utilizing about 6,850,000 high-quality single-nucleotide polymorphisms (SNPs) derived from 168 individuals (including 126 females and 42 males) by the genome-wide efficient mixed-model association (GEMMA) algorithm.

Results: The results of these single-trait GWASs showed that 46 SNP loci (-log10p > 7) significantly associated with sex differentiation, and gonadal development traits were distributed in multiple different chromosomes, which suggested the analyzed traits were all complex traits under multi-locus control. A total of 1,838 potential candidate genes were obtained by considering a less-stringent threshold (-log10p > 6) and ±100 kb regions surrounding the significant genomic loci. Moreover, 31 candidate genes were identified through a comprehensive analysis of significant GWAS peaks, gene ontology (GO) annotations, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, including taf7, ddx6, apoeb, sgk1, a2m, usf1, hsd3b7, dll4, xbp1, tet3, esr1, and gli3. These trait-associated genes have been shown to be involved in germline development, male sex differentiation, gonad morphogenesis, hormone receptor binding, oocyte development, male gonad development, steroidogenesis, estrogen-synthetic pathway, etc.

Discussion: In the present study, multiple genomic loci of P. leopardus associated with sex differentiation and gonadal development traits were identified for the first time by using GWAS, providing a valuable resource for further research on the molecular genetic mechanism and sex control in P. leopardus. Our results also can contribute to understanding the genetic basis of the sex differentiation mechanism and gonadal development process in grouper fish.
Machine learning-based radiomics for predicting BRAF-V600E mutations in ameloblastoma
Authors: Li Wen , Li Yang , Liu Xiaoling , Wang Li , Chen Wenqian , Qian Xueshen , Zheng Xianglong , Chen Jiang , Liu Yiming , Lin Lisong
Published: August 2023

Background

Ameloblastoma is a locally invasive and aggressive epithelial odontogenic neoplasm. The BRAF-V600E gene mutation is a prevalent genetic alteration found in this tumor and is considered to have a crucial role in its pathogenesis. The objective of this study is to develop and validate a radiomics-based machine learning method for the identification of BRAF-V600E gene mutations in ameloblastoma patients.

Methods

In this retrospective study, data from 103 patients diagnosed with ameloblastoma who underwent BRAF-V600E mutation testing were collected. Of these patients, 72 were included in the training cohort, while 31 were included in the validation cohort. To address class imbalance, synthetic minority over-sampling technique (SMOTE) is applied in our study. Radiomics features were extracted from preprocessed CT images, and the most relevant features, including both radiomics and clinical data, were selected for analysis. Machine learning methods were utilized to construct models. The performance of these models in distinguishing between patients with and without BRAF-V600E gene mutations was evaluated using the receiver operating characteristic (ROC) curve.

Results

When the analysis was based on radiomics signature, Random Forest performed better than the others, with the area under the ROC curve (AUC) of 0.87 (95%CI, 0.68-1.00). The performance of XGBoost model is slightly lower than that of Random Forest, and its AUC is 0.83 (95% CI, 0.60-1.00). The nomogram evident that among younger women, the affected region primarily lies within the mandible, and patients with larger tumor diameters exhibit a heightened risk. Additionally, patients with higher radiomics signature scores are more susceptible to the BRAF-V600E gene mutations.

Conclusions

Our study presents a comprehensive radiomics-based machine learning model using five different methods to accurately detect BRAF-V600E gene mutations in patients diagnosed with ameloblastoma. The Random Forest model’s high predictive performance, with AUC of 0.87, demonstrates its potential for facilitating a convenient and cost-effective way of identifying patients with the mutation without the need for invasive tumor sampling for molecular testing. This non-invasive approach has the potential to guide preoperative or postoperative drug treatment for affected individuals, thereby improving outcomes.
Exacerbated lung inflammation following secondary RSV exposure is CD4+ T cell-dependent and is not mitigated in infant BALB/c mice born to PreF-vaccinated dams
Authors: Kosanovich Jessica L. , Eichinger Katherine M. , Lipp Madeline A. , Gidwani Sonal V. , Brahmbhatt Devarshi , Yondola Mark A. , Perkins Timothy N. , Empey Kerry M.
Published: August 2023

Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations due to bronchiolitis in children under 5 years of age. Moreover, severe RSV disease requiring hospitalization is associated with the subsequent development of wheezing and asthma. Due to the young age in which viral protection is needed and risk of vaccine enhanced disease following direct infant vaccination, current approaches aim to protect young children through maternal immunization strategies that boost neutralizing maternal antibody (matAb) levels. However, there is a scarcity of studies investigating the influence of maternal immunization on secondary immune responses to RSV in the offspring or whether the subsequent development of wheezing and asthma is mitigated. Toward this goal, our lab developed a murine model of maternal RSV vaccination and repeat RSV exposure to evaluate the changes in immune response and development of exacerbated lung inflammation on secondary RSV exposure in mice born to immunized dams. Despite complete protection following primary RSV exposure, offspring born to pre-fusion F (PreF)-vaccinated dams had exaggerated secondary ILC2 and Th2 responses, characterized by enhanced production of IL-4, IL-5, and IL-13. These enhanced type 2 cellular responses were associated with exaggerated airway eosinophilia and mucus hyperproduction upon re-exposure to RSV. Importantly, depletion of CD4+ T cells led to complete amelioration of the observed type 2 pathology on secondary RSV exposure. These unanticipated results highlight the need for additional studies that look beyond primary protection to better understand how maternal immunization shapes subsequent immune responses to repeat RSV exposure.
Th22 cells and the intestinal mucosal barrier
Authors: Chen Jieli , Yao Jun
Published: August 2023

T-helper 22 (Th22) cells represent a novel subset of CD4+ T cells that exhibit distinctive characteristics, namely the secretion of IL-22 while abstaining from secreting IL-17 and interferon-γ (IFN-γ). These cells serve as the primary source of IL-22, and both Th22 cells and IL-22 are believed to play a role in maintaining intestinal mucosal homeostasis in inflammatory bowel disease (IBD). However, the precise functions of Th22 cells and IL-22 in this context remain a subject of debate. In this work, we aimed to elucidate their impact on the integrity of the intestinal mucosal barrier by presenting an overview of the molecular structure characteristics and functional effects of Th22 cells and IL-22. Furthermore, we would explore targeted treatment approaches and potential therapeutic strategies focusing on the Th22 and IL-22 pathways.
A high proportion of caseous necrosis, abscess, and granulation tissue formation in spinal tuberculosis
Authors: Wu Runrui , Li Shanshan , Liu Yadong , Zhang Hong , Liu Dongxu , Liu Yuejiao , Chen Wen , Wang Fenghua
Published: August 2023

The special blood circulation, anatomy, and tissue structure of the spine may lead to significant differences in pathological features and drug resistance between spinal tuberculosis and pulmonary tuberculosis. Here, we collected 168 spinal tuberculosis cases and 207 pulmonary tuberculosis cases, and compared their clinical and pathological features as well as drug resistance. From the anatomical location, the highest incidence was of lumbar tuberculosis, followed by thoracic tuberculosis. PET-CT scans showed increased FDG uptake in the diseased vertebrae, discernible peripheral soft tissue shadow, visible internal capsular shadow, and an abnormal increase in FDG uptake. MRI showed infectious lesions in the diseased vertebral body, formation of paravertebral and bilateral psoas muscle abscess, and edema of surrounding soft tissues. As with control tuberculosis, the typical pathological features of spinal tuberculosis were chronic granulomatous inflammation with caseous necrosis. The incidence of granulomas was not statistically different between the groups. However, the proportions of caseous necrosis, acute inflammation, abscess, exudation, and granulation tissue formation in the spinal tuberculosis group were all significantly increased relative to the control tuberculosis group. Compared to the control tuberculosis group, the incidences of resistance to rifampicin (RFP) + isoniazid (INH) + streptomycin (STR) and INH + ethambutol (EMB) were lower in the spinal tuberculosis group, while the incidences of resistance to RFP + INH + EMB and RFP + EMB were higher. Moreover, we also found some differences in drug-resistance gene mutations. In conclusion, there are noticeable differences between spinal Mycobacterium tuberculosis and pulmonary tuberculosis in pathological characteristics, drug resistance, and drug resistance gene mutations.
Hepatitis B virus serum RNA transcript isoform composition and proportion in chronic hepatitis B patients by nanopore long-read sequencing
Authors: Vachon Alicia , Seo Grace E. , Patel Nishi H. , Coffin Carla S. , Marinier Eric , Eyras Eduardo , Osiowy Carla
Published: August 2023

Introduction

Serum hepatitis B virus (HBV) RNA is a promising new biomarker to manage and predict clinical outcomes of chronic hepatitis B (CHB) infection. However, the HBV serum transcriptome within encapsidated particles, which is the biomarker analyte measured in serum, remains poorly characterized. This study aimed to evaluate serum HBV RNA transcript composition and proportionality by PCR-cDNA nanopore sequencing of samples from CHB patients having varied HBV genotype (gt, A to F) and HBeAg status.

Methods

Longitudinal specimens from 3 individuals during and following pregnancy (approximately 7 months between time points) were also investigated. HBV RNA extracted from 16 serum samples obtained from 13 patients (73.3% female, 84.6% Asian) was sequenced and serum HBV RNA isoform detection and quantification were performed using three bioinformatic workflows; FLAIR, RATTLE, and a GraphMap-based workflow within the Galaxy application. A spike-in RNA variant (SIRV) control mix was used to assess run quality and coverage. The proportionality of transcript isoforms was based on total HBV reads determined by each workflow.

Results

All chosen isoform detection workflows showed high agreement in transcript proportionality and composition for most samples. HBV pregenomic RNA (pgRNA) was the most frequently observed transcript isoform (93.8% of patient samples), while other detected transcripts included pgRNA spliced variants, 3′ truncated variants and HBx mRNA, depending on the isoform detection method. Spliced variants of pgRNA were primarily observed in HBV gtB, C, E, or F-infected patients, with the Sp1 spliced variant detected most frequently. Twelve other pgRNA spliced variant transcripts were identified, including 3 previously unidentified transcripts, although spliced isoform identification was very dependent on the workflow used to analyze sequence data. Longitudinal sampling among pregnant and post-partum antiviral-treated individuals showed increasing proportions of 3′ truncated pgRNA variants over time.

Conclusions

This study demonstrated long-read sequencing as a promising tool for the characterization of the serum HBV transcriptome. However, further studies are needed to better understand how serum HBV RNA isoform type and proportion are linked to CHB disease progression and antiviral treatment response.
Neural correlates of the sound facilitation effect in the modified Simon task in older adults
Authors: Manelis Anna , Hu Hang , Miceli Rachel , Satz Skye , Schwalbe Marie
Published: August 2023

Introduction

The ability to resolve interference declines with age and is attributed to neurodegeneration and reduced cognitive function and mental alertness in older adults. Our previous study revealed that task-irrelevant but environmentally meaningful sounds improve performance on the modified Simon task in older adults. However, little is known about neural correlates of this sound facilitation effect.

Methods

Twenty right-handed older adults [mean age = 72 (SD = 4), 11 female] participated in the fMRI study. They performed the modified Simon task in which the arrows were presented either in the locations matching the arrow direction (congruent trials) or in the locations mismatching the arrow direction (incongruent trials). A total of 50% of all trials were accompanied by task-irrelevant but environmentally meaningful sounds.

Results

Participants were faster on the trials with concurrent sounds, independently of whether trials were congruent or incongruent. The sound effect was associated with activation in the distributed network of auditory, posterior parietal, frontal, and limbic brain regions. The magnitude of the behavioral facilitation effect due to sound was associated with the changes in activation of the bilateral auditory cortex, cuneal cortex, and occipital fusiform gyrus, precuneus, left superior parietal lobule (SPL) for No Sound vs. Sound trials. These changes were associated with the corresponding changes in reaction time (RT). Older adults with a recent history of falls showed greater activation in the left SPL than those without falls history.

Conclusion

Our findings are consistent with the dedifferentiation hypothesis of cognitive aging. The facilitatory effect of sound could be achieved through recruitment of excessive neural resources, which allows older adults to increase attention and mental alertness during task performance. Considering that the SPL is critical for integration of multisensory information, individuals with slower task responses and those with a history of falls may need to recruit this region more actively than individuals with faster responses and those without a fall history to overcome increased difficulty with interference resolution. Future studies should examine the relationship among activation in the SPL, the effect of sound, and falls history in the individuals who are at heightened risk of falls.
Xenon inhalation attenuates neuronal injury and prevents epilepsy in febrile seizure Sprague-Dawley pups
Authors: Cheng Yao , Zhai Yujie , Yuan Yi , Li Hao , Zhao Wenke , Fan Zhenhai , Zhou Ling , Gao Xue , Zhan Yan , Sun Hongliu
Published: August 2023

Background

Febrile seizures (FS) usually occur in childhood and may cause irreversible neuronal damage, cognitive functional defects, and an increase in the risk of epilepsy later in life. Anti-epileptic drugs (AEDs), currently used to treat FS in children, can relieve seizures. However, their effects in preventing the risk of developing epilepsy in later life are unsatisfactory. Moreover, AEDs may damage child brain development. Here, we evaluated the efficiency of xenon in treating prolonged FS (PFS) and preventing epilepsy in Sprague-Dawley pups.

Methods

Prolonged FS was induced by hyperthermic treatment. After 90 min of PFS, the pups in the xenon treatment group were immediately treated with 70% xenon/21% oxygen/9% nitrogen for 60 min. The levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury, seizures, learning, and memory functions were measured at specific time points.

Results

Neonatal period PFS led to spontaneous seizure, learning and memory dysfunction, accompanied by increased levels of glutamate, mitochondrial oxidative stress, mitophagy, and neuronal injury. Xenon treatment alleviated the changes caused by PFS and reduced the risk of PFS developing into epilepsy later.

Conclusion

Our results suggest that xenon inhalation could be a potential therapeutic strategy to attenuate neuronal injury and prevent epilepsy in patients with FS.
Epilepsy phenotype and gene ontology analysis of the 129 genes in a large neurodevelopmental disorders cohort
Authors: Ko Young Jun , Kim Soo Yeon , Lee Seungbok , Yoon Jihoon G. , Kim Man Jin , Jun Hyeji , Kim Hunmin , Chae Jong-Hee , Kim Ki Joong , Kim Kwangsoo , Lim Byung Chan
Published: August 2023

Objective

Although pediatric epilepsy is an independent disease entity, it is often observed in pediatric neurodevelopmental disorders (NDDs) as a major or minor clinical feature, which might provide diagnostic clues. This study aimed to identify the clinical and genetic characteristics of patients with epilepsy in an NDD cohort and demonstrate the importance of genetic testing.

Methods

We retrospectively analyzed the detailed clinical differences of pediatric NDD patients with epilepsy according to their genetic etiology. Among 1,213 patients with NDDs, 477 were genetically diagnosed by exome sequencing, and 168 had epilepsy and causative variants in 129 genes. Causative genes were classified into two groups: (i) the “epilepsy-genes” group resulting in epilepsy as the main phenotype listed in OMIM, Epi25, and ClinGen (67 patients) and (ii) the “NDD-genes” group not included in the “epilepsy-genes” group (101 patients).

Results

Patients in the “epilepsy-genes” group started having seizures, often characterized by epilepsy syndrome, at a younger age. However, overall clinical features, including treatment responses and all neurologic manifestations, showed no significant differences between the two groups. Gene ontology analysis revealed the close interactions of epilepsy genes associated with ion channels and neurotransmitters.

Conclusion

We demonstrated a similar clinical presentation of different gene groups regarding biological/molecular processes in a large NDDs cohort with epilepsy. Phenotype-driven genetic analysis should cover a broad scope, and further studies are required to elucidate integrated pathomechanisms.
Using TMS-EEG to assess the effects of neuromodulation techniques: a narrative review
Authors: Cruciani Alessandro , Mancuso Marco , Sveva Valerio , Maccarrone Davide , Todisco Antonio , Motolese Francesco , Santoro Francesca , Pilato Fabio , Spampinato Danny Adrian , Rocchi Lorenzo , Di Lazzaro Vincenzo , Capone Fioravante
Published: August 2023

Over the past decades, among all the non-invasive brain stimulation (NIBS) techniques, those aiming for neuromodulatory protocols have gained special attention. The traditional neurophysiological outcome to estimate the neuromodulatory effect is the motor evoked potential (MEP), the impact of NIBS techniques is commonly estimated as the change in MEP amplitude. This approach has several limitations: first, the use of MEP limits the evaluation of stimulation to the motor cortex excluding all the other brain areas. Second, MEP is an indirect measure of brain activity and is influenced by several factors. To overcome these limitations several studies have used new outcomes to measure brain changes after neuromodulation techniques with the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG). In the present review, we examine studies that use TMS-EEG before and after a single session of neuromodulatory TMS. Then, we focused our literature research on the description of the different metrics derived from TMS-EEG to measure the effect of neuromodulation.
Age-related decline in cognitive flexibility is associated with the levels of hippocampal neurogenesis
Authors: Amelchenko Evgeny M. , Bezriadnov Dmitri V. , Chekhov Olga A. , Anokhin Konstantin V. , Lazutkin Alexander A. , Enikolopov Grigori
Published: August 2023

Aging is associated with impairments in learning, memory, and cognitive flexibility, as well as a gradual decline in hippocampal neurogenesis. We investigated the performance of 6-and 14-month-old mice (considered mature adult and late middle age, respectively) in learning and memory tasks based on the Morris water maze (MWM) and determined their levels of preceding and current neurogenesis. While both age groups successfully performed in the spatial version of MWM (sMWM), the older mice were less efficient compared to the younger mice when presented with modified versions of the MWM that required a reassessment of the previously acquired experience. This was detected in the reversal version of MWM (rMWM) and was particularly evident in the context discrimination MWM (cdMWM), a novel task that required integrating various distal cues, local cues, and altered contexts and adjusting previously used search strategies. Older mice were impaired in several metrics that characterize rMWM and cdMWM, however, they showed improvement and narrowed the performance gap with the younger mice after additional training. Furthermore, we analyzed the adult-born mature and immature neurons in the hippocampal dentate gyrus and found a significant correlation between neurogenesis levels in individual mice and their performance in the tasks demanding cognitive flexibility. These results provide a detailed description of the age-related changes in learning and memory and underscore the importance of hippocampal neurogenesis in supporting cognitive flexibility.
Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function
Authors: Cembran Alessandro , Fernandez-Funez Pedro
Published: August 2023

Prion diseases are fatal brain disorders characterized by deposition of insoluble isoforms of the prion protein (PrP). The normal and pathogenic structures of PrP are relatively well known after decades of studies. Yet our current understanding of the intrinsic determinants regulating PrP misfolding are largely missing. A 3D subdomain of PrP comprising the β2-α2 loop and helix 3 contains high sequence and structural variability among animals and has been proposed as a key domain regulating PrP misfolding. We combined in vivo work in Drosophila with molecular dynamics (MD) simulations, which provide additional insight to assess the impact of candidate substitutions in PrP from conformational dynamics. MD simulations revealed that in human PrP WT the β2-α2 loop explores multiple β-turn conformations, whereas the Y225A (rabbit PrP-like) substitution strongly favors a 310-turn conformation, a short right-handed helix. This shift in conformational diversity correlates with lower neurotoxicity in flies. We have identified additional conformational features and candidate amino acids regulating the high toxicity of human PrP and propose a new strategy for testing candidate modifiers first in MD simulations followed by functional experiments in flies. In this review we expand on these new results to provide additional insight into the structural and functional biology of PrP through the prism of the conformational dynamics of a 3D domain in the C-terminus. We propose that the conformational dynamics of this domain is a sensitive measure of the propensity of PrP to misfold and cause toxicity. This provides renewed opportunities to identify the intrinsic determinants of PrP misfolding through the contribution of key amino acids to different conformational states by MD simulations followed by experimental validation in transgenic flies.
Levels of Bisphenol A and its analogs in nails, saliva, and urine of children: a case control study
Authors: Gálvez-Ontiveros Yolanda , Moscoso-Ruiz Inmaculada , Almazán Fernández de Bobadilla Vega , Monteagudo Celia , Giménez-Martínez Rafael , Rodrigo Lourdes , Zafra-Gómez Alberto , Rivas Ana
Published: August 2023

Introduction

A growing number of studies link the increase in overweight/obesity worldwide to exposure to certain environmental chemical pollutants that display obesogenic activity (obesogens). Since exposure to obesogens during the first stages of life has been shown to have a more intense and pronounced effect at lower doses, it is imperative to study their possible effects in childhood. The objective here was to study the association of Bisphenol A (BPA) and 11 BPA analogs in children, using three biological matrices (nails, saliva and urine), and overweight and obesity (n = 160).

Methods

In this case–control study, 59 overweight/obese children and 101 controls were included. The measuring of Bisphenols in the matrices was carried out by ultra-high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC-MS/MS). Logistic regression was used to study the association between overweight/obesity and Bisphenol exposure.

Results

The results suggested that BPF in nails is associated with overweight/ obesity in children (OR:4.87; p = 0.020). In saliva, however, the highest detected concentrations of BPAF presented an inverse association (OR: 0.06; p = 0.010) with overweight/obesity. No associations of statistical significance were detected between exposure to BPA or its other analogs and overweight/obesity in any of the biological matrices.
Neurological adverse events of mitotane in adrenocortical carcinoma: results of a pilot study
Authors: Mormando Marilda , Galiè Edvina , Bianchini Marta , Lauretta Rosa , Puliani Giulia , Tanzilli Antonio , Anceschi Umberto , Simone Giuseppe , Petreri Gianluca , Graziano Giuliana , Pace Andrea , Appetecchia Marialuisa
Published: August 2023

Introduction

Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity.

Methods

We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization.

Results

At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered.

Conclusion

The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.
Combination of clinical, radiomic, and “delta” radiomic features in survival prediction of metastatic gastroesophageal adenocarcinoma
Authors: Krishna Satheesh , Sertic Andrew , Liu Zhihui (Amy) , Liu Zijin , Darling Gail E. , Yeung Jonathon , Wong Rebecca , Chen Eric X. , Kalimuthu Sangeetha , Allen Michael J. , Suzuki Chihiro , Panov Elan , Ma Lucy X. , Bach Yvonne , Jang Raymond W. , Swallow Carol J. , Brar Savtaj , Elimova Elena , Veit-Haibach Patrick
Published: August 2023

Objectives

To identify combined clinical, radiomic, and delta-radiomic features in metastatic gastroesophageal adenocarcinomas (GEAs) that may predict survival outcomes.

Methods

A total of 166 patients with metastatic GEAs on palliative chemotherapy with baseline and treatment/follow-up (8–12 weeks) contrast-enhanced CT were retrospectively identified. Demographic and clinical data were collected. Three-dimensional whole-lesional radiomic analysis was performed on the treatment/follow-up scans. “Delta” radiomic features were calculated based on the change in radiomic parameters compared to the baseline. The univariable analysis (UVA) Cox proportional hazards model was used to select clinical variables predictive of overall survival (OS) and progression-free survival (PFS) (p-value <0.05). The radiomic and “delta” features were then assessed in a multivariable analysis (MVA) Cox model in combination with clinical features identified on UVA. Features with a p-value <0.01 in the MVA models were selected to assess their pairwise correlation. Only non-highly correlated features (Pearson’s correlation coefficient <0.7) were included in the final model. Leave-one-out cross-validation method was used, and the 1-year area under the receiver operating characteristic curve (AUC) was calculated for PFS and OS.

Results

Of the 166 patients (median age of 59.8 years), 114 (69%) were male, 139 (84%) were non-Asian, and 147 (89%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. The median PFS and OS on treatment were 3.6 months (95% CI 2.86, 4.63) and 9 months (95% CI 7.49, 11.04), respectively. On UVA, the number of chemotherapy cycles and number of lesions at the end of treatment were associated with both PFS and OS (p < 0.001). ECOG status was associated with OS (p = 0.0063), but not PFS (p = 0.054). Of the delta-radiomic features, delta conventional HUmin, delta gray-level zone length matrix (GLZLM) GLNU, and delta GLZLM LGZE were incorporated into the model for PFS, and delta shape compacity was incorporated in the model for OS. Of the treatment/follow-up radiomic features, shape compacity and neighborhood gray-level dependence matrix (NGLDM) contrast were used in both models. The combined 1-year AUC (Kaplan–Meier estimator) was 0.82 and 0.81 for PFS and OS, respectively.

Conclusions

A combination of clinical, radiomics, and delta-radiomic features may predict PFS and OS in GEAs with reasonable accuracy.
Ultrastructure for the diagnosis of primary ciliary dyskinesia in South Africa, a resource-limited setting
Authors: Birkhead Monica , Otido Samuel , Mabaso Theodore , Mopeli Keketso , Tlhapi Dorcas , Verwey Charl , Dangor Ziyaad
Published: August 2023

Introduction

International guidelines recommend a multi-faceted approach for successful diagnoses of primary ciliary dyskinesia (PCD). In the absence of a gold standard test, a combination of genetic testing/microscopic analysis of structure and function/nasal nitric oxide measurement is used. In resource-limited settings, often none of the above tests are available, and in South Africa, only transmission electron microscopy (TEM) is available in central anatomical pathology departments. The aim of this study was to describe the clinical and ultrastructural findings of suspected PCD cases managed by pediatric pulmonologists at a tertiary-level state funded hospital in Johannesburg.

Methods

Nasal brushings were taken from 14 children with chronic respiratory symptoms in keeping with a PCD phenotype. Ultrastructural analysis in accordance with the international consensus guidelines for TEM-PCD diagnostic reporting was undertaken.

Results

TEM observations confirmed 43% (6) of the clinically-suspected cases (hallmark ultrastructural defects in the dynein arms of the outer doublets), whilst 57% (8) required another PCD testing modality to support ultrastructural observations. Of these, 25% (2) had neither ultrastructural defects nor did they present with bronchiectasis. Of the remaining cases, 83% (5) had very few ciliated cells (all of which were sparsely ciliated), together with goblet cell hyperplasia. There was the apparent absence of ciliary rootlets in 17% (1) case.

Discussion

In resource-limited settings in which TEM is the only available testing modality, confirmatory and probable diagnoses of PCD can be made to facilitate early initiation of treatment of children with chronic respiratory symptoms.
The impact of medication belief on adherence to infliximab in patients with Crohn’s disease
Authors: Li Shuyan , Ma Yan , Sun Hongling , Ni Zijun , Hu Shurong , Chen Yan , Lan Meijuan
Published: August 2023

Objective: Crohn’s disease (CD) is an incurable chronic disease that requires long-term treatment. As an anti-tumor necrosis factor (TNF) agent, Infliximab (IFX) is widely used in the treatment of Crohn’s disease, while the adherence is not high. The purpose of this study was to investigate the adherence to IFX among CD patients in China and evaluate the association between medication belief and IFX adherence.

Methods: Demographic data, clinical information and patients’ medication beliefs were collected using an online questionnaire and reviewing electronic medical records (EMRs). The Beliefs about Medicines Questionnaire (BMQ)-specific was used to assess medication beliefs which contains the BMQ-specific concern score and the BMQ-specific necessity score. An evaluation of adherence factors was conducted using univariate and multidimensional logistic regression analyses.

Results: In all, 166 CD patients responded the online questionnaire among which 77 (46.39%) patients had high adherence. The BMQ-specific concern score in patients in low adherence was 30.00 and in high adherence patients was 27.50, and patients with lower BMQ-specific concern score had higher adherence (p = 0.013). The multiple regression analysis showed that the BMQ-specific concern score (OR = 0.940, 95% CI: 0.888–0.996) significantly affected the IFX adherence in CD patients. Otherwise, gender, marital status, time spent on the way (including the waiting time in infusion center) and accommodation to the center were also the influencing factors of adherence.

Conclusion: The IFX adherence to CD in China was not high. Medicine concerns may be predictive factor of adherence. Education, the duration of IFX therapy and experience of adverse effects were not significantly associated with IFX adherence. By enhancing knowledge and relieving medicine concerns, we may increase patients’ adherence to IFX.
Stroke and physiological relationships during the incremental front crawl test: outcomes for planning and pacing aerobic training
Authors: Almeida Tiago A. F. , Espada Mário C. , Massini Danilo A. , Macedo Anderson G. , Castro Eliane A. , Ferreira Cátia C. , Reis Joana F. , Pessôa Filho Dalton M.
Published: August 2023

Purpose: This study aimed to evaluate the physiological responses associated with the stroke length (SL) and stroke rate (SR) changes as swimming velocity increases during an incremental step-test. Moreover, this study also aimed to verify if SL and SR relationships toward maximal oxygen uptake (V̇O2max), gas respiratory compensation point (RCP), exchange threshold (GET), and swimming cost can be applied to the management of endurance training and control aerobic pace.

Methods: A total of 19 swimmers performed the incremental test until volitional exhaustion, with each stage being designed by percentages of the 400 m (%v400) maximal front crawl velocity. V̇O2max, GET, RCP, and the respective swimming velocities (v) were examined. Also, the stroke parameters, SL, SR, the corresponding slopes (SLslope and SRslope), and the crossing point (Cp) between them were determined.

Results: GET and RCP corresponded to 70.6% and 82.4% of V̇O2max (4185.3 ± 686.1 mL min-1), and V̇O2 at Cp, SLslope, and SRslope were observed at 129.7%, 75.3%, and 61.7% of V̇O2max, respectively. The swimming cost from the expected V̇O2 at vSLslope (0.85 ± 0.18 kJ m-1), vSRslope (0.77 ± 0.17 kJ m-1), and vCp (1.09 ± 0.19 kJ m-1) showed correlations with GET (r = 0.73, 0.57, and 0.59, respectively), but only the cost at vSLslope and vCp correlated to RCP (0.62 and 0.69) and V̇O2max (0.70 and 0.79).

Conclusion: SL and SR exhibited a distinctive pattern for the V̇O2 response as swimming velocity increased. Furthermore, the influence of SL on GET, RCP, and V̇O2max suggests that SLslope serves as the metabolic reference of heavy exercise intensity, beyond which the stroke profile defines an exercise zone with high cost, which is recommended for an anaerobic threshold and aerobic power training. In turn, the observed difference between V̇O2 at SRslope and GET suggests that the range of velocities between SL and SR slopes ensures an economical pace, which might be recommended to develop long-term endurance. The results also highlighted that the swimming intensity paced at Cp would impose a high anaerobic demand, as it is located above the maximal aerobic velocity. Therefore, SLslope and SRslope are suitable indexes of submaximal to maximal aerobic paces, while Cp’s meaning still requires further evidence.
Genome-wide association study as a powerful tool for dissecting competitive traits in legumes
Authors: Susmitha Pusarla , Kumar Pawan , Yadav Pankaj , Sahoo Smrutishree , Kaur Gurleen , Pandey Manish K. , Singh Varsha , Tseng Te Ming , Gangurde Sunil S.
Published: August 2023

Legumes are extremely valuable because of their high protein content and several other nutritional components. The major challenge lies in maintaining the quantity and quality of protein and other nutritional compounds in view of climate change conditions. The global need for plant-based proteins has increased the demand for seeds with a high protein content that includes essential amino acids. Genome-wide association studies (GWAS) have evolved as a standard approach in agricultural genetics for examining such intricate characters. Recent development in machine learning methods shows promising applications for dimensionality reduction, which is a major challenge in GWAS. With the advancement in biotechnology, sequencing, and bioinformatics tools, estimation of linkage disequilibrium (LD) based associations between a genome-wide collection of single-nucleotide polymorphisms (SNPs) and desired phenotypic traits has become accessible. The markers from GWAS could be utilized for genomic selection (GS) to predict superior lines by calculating genomic estimated breeding values (GEBVs). For prediction accuracy, an assortment of statistical models could be utilized, such as ridge regression best linear unbiased prediction (rrBLUP), genomic best linear unbiased predictor (gBLUP), Bayesian, and random forest (RF). Both naturally diverse germplasm panels and family-based breeding populations can be used for association mapping based on the nature of the breeding system (inbred or outbred) in the plant species. MAGIC, MCILs, RIAILs, NAM, and ROAM are being used for association mapping in several crops. Several modifications of NAM, such as doubled haploid NAM (DH-NAM), backcross NAM (BC-NAM), and advanced backcross NAM (AB-NAM), have also been used in crops like rice, wheat, maize, barley mustard, etc. for reliable marker-trait associations (MTAs), phenotyping accuracy is equally important as genotyping. Highthroughput genotyping, phenomics, and computational techniques have advanced during the past few years, making it possible to explore such enormous datasets. Each population has unique virtues and flaws at the genomics and phenomics levels, which will be covered in more detail in this review study. The current investigation includes utilizing elite breeding lines as association mapping population, optimizing the choice of GWAS selection, population size, and hurdles in phenotyping, and statistical methods which will analyze competitive traits in legume breeding.