bluuebunny/crossref_metadata_2025 huggingface dataset:
Mast cells are at the interface between the external environment and the inner organism
Authors: Ribatti Domenico
Published: January 2024

Mast cells localized at the level of the mucosal barrier in the skin, lung, and gastrointestinal tract, intervene in the modulation of the function of the epithelial cells and are involved in innate and adaptive defensive responses. In this context, mast cells intervene in the recognition and clearance of microbial pathogens. This mini-review article discusses the role of mast cells in these barrier systems.
Experimental promoter identification of a foodborne pathogen Salmonella enterica subsp. enterica serovar Typhimurium with near single base-pair resolution
Authors: Lee Sang-Mok , Le Hoa Thi , Taizhanova Assiya , Nong Linh Khanh , Park Joon Young , Lee Eun-Jin , Palsson Bernhard O. , Kim Donghyuk
Published: January 2024

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common foodborne pathogen which is frequently used as the reference strain for Salmonella. Investigating the sigma factor network and protomers is crucial to understand the genomic and transcriptomic properties of the bacterium. Its promoters were identified using various methods such as dRNA-seq, ChIP-chip, or ChIP-Seq. However, validation using ChIP-exo, which exhibits higher-resolution performance compared to conventional ChIP, has not been conducted to date. In this study, using the representative strain S. Typhimurium LT2 (LT2), the ChIP-exo experiment was conducted to accurately determine the binding sites of catalytic RNA polymerase subunit RpoB and major sigma factors (RpoD, RpoN, RpoS, and RpoE) during exponential phase. Integrated with the results of RNA-Seq, promoters and sigmulons for the sigma factors and their association with RpoB have been discovered. Notably, the overlapping regions among binding sites of each alternative sigma factor were found. Furthermore, comparative analysis with Escherichia coli str. K-12 substr. MG1655 (MG1655) revealed conserved binding sites of RpoD and RpoN across different species. In the case of small RNAs (sRNAs), 50 sRNAs observed their expression during the exponential growth of LT2. Collectively, the integration of ChIP-exo and RNA-Seq enables genome-scale promoter mapping with high resolution and facilitates the characterization of binding events of alternative sigma factors, enabling a comprehensive understanding of the bacterial sigma factor network and condition-specific active promoters.
Exploring the complexities of 1C metabolism: implications in aging and neurodegenerative diseases
Authors: Bou Ghanem Ayman , Hussayni Yaman , Kadbey Raghid , Ratel Yara , Yehya Shereen , Khouzami Lara , Ghadieh Hilda E. , Kanaan Amjad , Azar Sami , Harb Frederic
Published: January 2024

The intricate interplay of one-carbon metabolism (OCM) with various cellular processes has garnered substantial attention due to its fundamental implications in several biological processes. OCM serves as a pivotal hub for methyl group donation in vital biochemical reactions, influencing DNA methylation, protein synthesis, and redox balance. In the context of aging, OCM dysregulation can contribute to epigenetic modifications and aberrant redox states, accentuating cellular senescence and age-associated pathologies. Furthermore, OCM’s intricate involvement in cancer progression is evident through its capacity to provide essential one-carbon units crucial for nucleotide synthesis and DNA methylation, thereby fueling uncontrolled cell proliferation and tumor development. In neurodegenerative disorders like Alzheimer’s and Parkinson’s, perturbations in OCM pathways are implicated in the dysregulation of neurotransmitter synthesis and mitochondrial dysfunction, contributing to disease pathophysiology. This review underscores the profound impact of OCM in diverse disease contexts, reinforcing the need for a comprehensive understanding of its molecular complexities to pave the way for targeted therapeutic interventions across inflammation, aging and neurodegenerative disorders.
Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche
Authors: Jones Sherri Lee , De Braga Victoria , Caccese Christina , Lew Jimin , Elgbeili Guillaume , Castellanos-Ryan Natalie , Parent Sophie , Muckle Gina , Herba Catherine M. , Fraser William D. , Ducharme Simon , Barnwell Julia , Trasler Jacquetta , Séguin Jean R. , Nguyen Tuong-Vi , Montreuil Tina C.
Published: January 2024

Introduction

This study examined (1) whether measures of paternal anxious and depressive symptoms collected prenatally and during a follow-up assessment when the child was in middle childhood, predict child neuroendocrine outcomes, and (2) whether neuroendocrine outcomes are intermediate factors between paternal mental health and child cognitive/behavioral outcomes. Middle childhood coincides with increased autonomy as the child transitions into grade school, and with adrenarche, as the maturing adrenal gland increases secretion of dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S), hormones that are implicated in corticolimbic development which regulate emotions and cognition.

Methods

Participants were recruited from a subsample of a large prospective birth cohort study (3D study). We conducted a follow-up study when children were 6–8 years old (N = 61 families, 36 boys, 25 girls). Parental symptoms of anxiety, stress and depression were assessed via validated self-report questionnaires: prenatally using an in-house anxiety questionnaire, the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D), and at the follow up, using the Beck Anxiety and Beck Depression Inventories. Children provided salivary hormone samples, and their pituitary gland volume was measured from structural Magnetic Resonance Imaging (MRI) scans. Child behaviors were measured using the Strengths and Difficulties Questionnaire and cognitive outcomes using the WISC-V. Multiple regression analyses were used to test whether paternal mental health symptoms assessed prenatally and during childhood are associated with child neuroendocrine outcomes, adjusting for maternal mental health and child sex. Indirect-effect models assessed whether neuroendocrine factors are important intermediates that link paternal mental health and cognitive/behavioral outcomes.

Results

(1) Fathers’ prenatal anxiety symptoms predicted lower DHEA levels in the children, but not pituitary volume. (2) Higher prenatal paternal anxiety symptoms predicted higher child internalizing symptoms via an indirect pathway of lower child DHEA. No associations were detected between paternal anxiety symptoms measured in childhood, and neuroendocrine outcomes. No child sex differences were detected on any measure.

Conclusion

These results highlight the often-overlooked role of paternal factors during pregnancy on child development, suggesting that paternal prenatal anxiety symptoms are associated with child neuroendocrine function and in turn internalizing symptoms that manifest at least up to middle childhood.
The corticofugal oscillatory modulation of the cochlear receptor during auditory and visual attention is preserved in tinnitus
Authors: Donoso-San Martín Rodrigo , Leiva Alexis , Dragicevic Constantino D. , Medel Vicente , Delano Paul H.
Published: January 2024

Introduction

The mechanisms underlying tinnitus perception are still under research. One of the proposed hypotheses involves an alteration in top-down processing of auditory activity. Low-frequency oscillations in the delta and theta bands have been recently described in brain and cochlear infrasonic signals during selective attention paradigms in normal hearing controls. Here, we propose that the top-down oscillatory activity observed in brain and cochlear signals during auditory and visual selective attention in normal subjects, is altered in tinnitus patients, reflecting an abnormal functioning of the corticofugal pathways that connect brain circuits with the cochlear receptor.

Methods

To test this hypothesis, we used a behavioral task that alternates between auditory and visual top-down attention while we simultaneously measured electroencephalogram (EEG) and distortion-product otoacoustic emissions (DPOAE) signals in 14 tinnitus and 14 control subjects.

Results

We found oscillatory activity in the delta and theta bands in cortical and cochlear channels in control and tinnitus patients. There were significant decreases in the DPOAE oscillatory amplitude during the visual attention period as compared to the auditory attention period in tinnitus and control groups. We did not find significant differences when using a between-subjects statistical approach comparing tinnitus and control groups. On the other hand, we found a significant cluster in the delta band in tinnitus when using within-group statistics to compare the difference between auditory and visual DPOAE oscillatory power.

Conclusion

These results confirm the presence of top-down infrasonic low-frequency cochlear oscillatory activity in the delta and theta bands in tinnitus patients, showing that the corticofugal suppression of cochlear oscillations during visual and auditory attention in tinnitus patients is preserved.
Development of the sleep-wake switch in rats during the P2-P21 early infancy period
Authors: Patel Mainak , Joshi Badal
Published: January 2024

In early infancy, rats randomly alternate between the sleeping and waking states–from postnatal day 2–10 (P2-P10), sleep and wake bouts are both exponentially distributed with increasing means, while from P10-P21 sleep and wake bout means continue to increase, though there is a striking qualitative shift in the distribution of wake bouts from exponential to power law. The behavioral states of sleep and wakefulness correspond to the activity of sleep-active and wake-active neuronal brainstem populations, with reciprocal inhibition between the two ensuring that only one population is active at a time. The locus coeruleus (LC) forms a third component of this circuit that rises in prominence during the P10-P21 period, as experimental evidence shows that an as-of-yet undeciphered interaction of the LC with sleep-active and wake-active populations is responsible for the transformation of the wake bout distribution from exponential to power law. Interestingly, the LC undergoes remarkable physiological changes during the P10-P21 period–gap junctions within the LC are pruned and network-wide oscillatory synchrony declines and vanishes. In this work, we discuss a series of models of sleep-active, wake-active, and the LC populations, and we use these models to postulate the nature of the interaction between these three populations and how these interactions explain empirical observations of sleep and wake bout dynamics. We hypothesize a circuit in which there is reciprocal excitation between the LC and wake-active population with inhibition from the sleep-active population to the LC that suppresses the LC during sleep bouts. During the P2-P10 period, we argue that a noise-based switching mechanism between the sleep-active and wake-active populations provides a simple and natural way to account for exponential bout distributions, and that the locked oscillatory state of the LC prevents it from impacting bout distributions. From P10-P21, we use our models to postulate that, as the LC gradually shifts from a state of synchronized oscillations to a state of continuous firing, reciprocal excitation between the LC and the wake-active population is able to gradually transform the wake bout distribution from exponential to power law.
Denosumab combined with precision radiotherapy for recurrent giant cell tumor of the thoracic spine: a case report and literature review
Authors: Miao Zukang , Xu Ming , Zheng Kai , Gong Hai , Yan Ning , Chen Qian , Yu Xiuchun
Published: January 2024

Giant cell tumors of the spine have a high recurrence rate owing to their special anatomical site; hence, further treatment after recurrence is very challenging. Achieving effective tumor control and improving the long-term quality of life of the patients are the main treatment purposes to consider for recurrent giant cell tumors of the spine. A patient showing giant cell tumor recurrence of the thoracic spine after curettage received denosumab combined with precision radiotherapy, through which the tumor gained good control and the patient could regain normal functioning. A review of the relevant literature suggested that denosumab combined with radiotherapy is an effective new approach for the treatment of recurrent giant cell tumors of the spine.
Assessing risk factors associated with breakthrough early post-traumatic seizures in patients receiving phenytoin prophylaxis
Authors: Generoso Eugene , Diep Calvin , Hua Carolyn , Rader Elizabeth , Ran Ran , Lee Nathanael J. , Rivera-Lara Lucia
Published: January 2024

Objective

Post-traumatic seizure (PTS) is a well-known complication of traumatic brain injury (TBI). The objective of this study was to identify risk factors associated with breakthrough early PTS in TBI patients receiving phenytoin prophylaxis.

Methods

This was a single-centered retrospective study including adult patients admitted to the intensive care unit (ICU), had a TBI, and started on phenytoin for seizure prophylaxis within 24 h of admission. The primary outcome was the incidence and factors associated with early PTS, defined as a confirmed seizure on a continuous electroencephalogram within 7 days of TBI. Secondary outcomes included the association between early post-traumatic seizures and ICU length of stay, hospital length of stay, and in-hospital mortality.

Results

A total of 105 patients were included in the final analysis. Patients with early PTS were older (65 vs. 48 years old, p = 0.01), had a higher Marshall score (5 vs. 2, p = 0.01), were more likely to have a Marshall score > 2 (73 vs. 37%, p = 0.01), and had more neurosurgeries for hematoma evacuation (57 vs. 19%, p = 0.01). In patients with early PTS, 57% had a level at the time of seizure, and of those, 87.5% had a therapeutic level (>10 mcg/mL). Patients with early PTS had a longer ICU length of stay (14.7 vs. 5.9 days, p = 0.04) and a greater proportion of hospital mortality (21 vs. 2%, p = 0.02).

Conclusion

Patients with higher age, Marshall score, and neurosurgical procedures for hematoma evacuation had higher incidences of breakthrough early PTS despite the use of phenytoin prophylaxis. The majority of patients with early PTS had therapeutic phenytoin levels at the time of seizure when a level was available; however, approximately half (43%) did not have a level.
Palps across the tree – the neuronal innervation and development of sensory head appendages in Annelida
Authors: Kalke Paul , Linder Samira S. , Beckers Patrick , Helm Conrad
Published: January 2024

Polychaetes inhabit a wide variety of habitats and show a great morphological diversity. In this context, a key morphological structure for adapting to their individual lifestyles and ecological niches are the prominent head appendages. In the last years more and more studies focused on the mainly sensory annelid head appendages – namely the antennae, palps, buccal lips and cirri – to unravel the evolutionary origin and phylogeny of Annelida. Unfortunately, comparable data for most of the polychaete families are lacking so far, especially when it comes to features of the larval anterior nervous system and the related innervation and potential homology of these head appendages. In this study, we therefore use an integrative morphological approach including immunohistochemistry and confocal laser scanning microscopy in combination with histological serial sections and 3D-visualizations. With special focus on the palp-like appendages, our data provides a closer look into the development of the larval anterior nervous system and the related sensory structures of three polychaete families representing major groups of the annelid tree of life. Hence, we investigate members of the palaeoannelid Magelonidae as well as basally-branching Amphinomidae, and the pleistoannelid Spionidae forming a taxon deeply nested within Sedentaria. Our comparative data of larval and adult neuronal features support the homology of feeding-palps across the annelid tree. Furthermore, our observations show that larval palps gradually transform into the adult ones while keeping a very similar neuronal innervation pattern. Solely for Amphinomidae a loss of larval palps during ontogenesis has to be assumed. Therefore, our investigations uncover important and so far unknown details in terms of structural homology across Annelida and provide important results necessary for our understanding of annelid evolution.
Chip-In-Loop SNN Proxy Learning: a new method for efficient training of spiking neural networks
Authors: Liu Yuhang , Liu Tingyu , Hu Yalun , Liao Wei , Xing Yannan , Sheik Sadique , Qiao Ning
Published: January 2024

The primary approaches used to train spiking neural networks (SNNs) involve either training artificial neural networks (ANNs) first and then transforming them into SNNs, or directly training SNNs using surrogate gradient techniques. Nevertheless, both of these methods encounter a shared challenge: they rely on frame-based methodologies, where asynchronous events are gathered into synchronous frames for computation. This strays from the authentic asynchronous, event-driven nature of SNNs, resulting in notable performance degradation when deploying the trained models on SNN simulators or hardware chips for real-time asynchronous computation. To eliminate this performance degradation, we propose a hardware-based SNN proxy learning method that is called Chip-In-Loop SNN Proxy Learning (CIL-SPL). This approach effectively eliminates the performance degradation caused by the mismatch between synchronous and asynchronous computations. To demonstrate the effectiveness of our method, we trained models using public datasets such as N-MNIST and tested them on the SNN simulator or hardware chip, comparing our results to those classical training methods.
Evidence for ethnicity and location as regulators of the newborn blood metabolome: a monozygous twin study
Authors: Jiang Huimin , Han Ting-Li , Yang Jing , Yang Yang , Wang Fengdi , Chen Yuelu , Huang Nana , Mansell Toby , Craig Jeffrey M. , Scurrah Katrina J. , Novakovic Boris , Baker Philip N. , Zhang Hua , Wei Yuan , Wang Lianlian , Saffery Richard
Published: January 2024

Introduction

Monochorionic, diamniotic (MCDA) monozygotic twins share nearly all genetic variation and a common placenta in utero. Despite this, MCDA twins are often discordant for a range of common phenotypes, including early growth and birth weight. As such, MCDA twins represent a unique model to explore variation in early growth attributable primarily to in utero environmental factors.

Methods

MCDA twins with a range of within-pair birth weight discordance were sampled from the peri/postnatal epigenetic twin study (PETS, Melbourne; n = 26 pairs), Beijing twin study (BTS, Beijing; n = 25), and the Chongqing longitudinal twin study (LoTiS, Chongqing; n = 22). All PETS participants were of European-Australian ancestry, while all Chinese participants had Han ancestry. The average of the birth weight difference between the larger and smaller co-twins for all twin pairs was determined and metabolomic profiles of amino acids, TCA cycle intermediates, fatty acids, organic acids, and their derivatives generated from cord blood plasma by gas chromatograph mass spectrometry. Within and between co-twin pair analyses were performed to identify metabolites specifically associated with discordance in birth weight. Multivariable regression and pathway enrichment analyses between different regions were performed to evaluate the geographical effects on the metabolism of MCDA twin pairs.

Results

PETS twins showed a markedly different metabolic profile at birth compared to the two Chinese samples. Within-pair analysis revealed an association of glutathione, creatinine, and levulinic acid with birth weight discordance. Caffeine, phenylalanine, and several saturated fatty acid levels were uniquely elevated in PETS twins and were associated with maternal BMI and average within pair birth weight, in addition to birth weight discordance. LoTiS twins had higher levels of glutathione, tyrosine, and gamma-linolenic acid relative to PETS and BTS twins, potentially associated with eating habits.

Conclusion

This study highlights the potential role of underlying genetic variation (shared by MZ twins), in utero (non-shared by MZ twins) and location-specific (shared by MZ twins) environmental factors, in regulating the cord blood metabolome of uncomplicated MCDA twins. Future research is needed to unravel these complex relationships that may play a key role in phenotypic metabolic alterations of twins independent of genetic diversity.
Association of antioxidants use with the risk of dementia among community-dwelling adults in the United Kingdom biobank
Authors: Shang Xianwen , Liu Jiahao , Zhang Xueli , Huang Yu , Zhu Zhuoting , Tang Shulin , Wang Wei , Ge Zongyuan , Yu Honghua , He Mingguang
Published: January 2024

Background

Data regarding the association between antioxidant supplementation and incident dementia are limited.

Methods

We included 494,632 adults (54.5% females) aged 40–71 years at baseline from the United Kingdom Biobank in the final analysis. Incident dementia was ascertained using hospital inpatient and death records up to January 2021.

Results

Over a median follow-up of 11.9 years, 7,128 new cases of all-cause dementia, 2,772 cases of Alzheimer’s disease, and 1,397 cases of vascular dementia were recorded. The hazard ratio (95% CI) for incident dementia associated with zinc supplementation was 0.84 (0.74–0.96), and the association remained significant after adjusting for all confounders (0.84 (0.74–0.96)). In the full model, zinc supplementation was associated with a reduced risk of Alzheimer’s disease [HR (95% CI): 0.71 (0.57–0.88)]. There was no significant association between zinc supplementation and the risk of vascular dementia. No significant associations with incident dementia were observed for other antioxidant supplementation. The association between zinc supplementation and incident dementia was significant among individuals with [HR (95% CI): 0.34 (0.15–0.77)] and without cataract [0.87 (0.77–0.99)] but it was stronger among those with cataract (p value for interaction = 0.0271).

Conclusion

Our findings suggest that zinc supplementation may help reduce the risk of all-cause dementia and Alzheimer’s disease in middle-aged or older adults, especially among those with cataracts.
Critical assessment of wheat biofortification for iron and zinc: a comprehensive review of conceptualization, trends, approaches, bioavailability, health impact, and policy framework
Authors: Gupta Om Prakash , Singh Ajeet , Pandey Vanita , Sendhil Ramadas , Khan Mohd. Kamran , Pandey Anamika , Kumar Sunil , Hamurcu Mehmet , Ram Sewa , Singh Gyanendra
Published: January 2024

Addressing global hidden hunger, particularly in women of childbearing age and children under five, presents a significant challenge, with a focus on iron (Fe) and zinc (Zn) deficiency. Wheat, a staple crop in the developing world, is crucial for addressing this issue through biofortification efforts. While extensive research has explored various approaches to enhance Fe and Zn content in wheat, there remains a scarcity of comprehensive data on their bioavailability and impact on human and animal health. This systematic review examines the latest trends in wheat biofortification approaches, assesses bioavailability, evaluates the effects of biofortified wheat on health outcomes in humans and animals, and analyzes global policy frameworks. Additionally, a meta-analysis of per capita daily Fe and Zn intake from average wheat consumption was conducted. Notably, breeding-based approaches have led to the release of 40 biofortified wheat varieties for commercial cultivation in India, Pakistan, Bangladesh, Mexico, Bolivia, and Nepal, but this progress has overlooked Africa, a particularly vulnerable continent. Despite these advancements, there is a critical need for large-scale systematic investigations into the nutritional impact of biofortified wheat, indicating a crucial area for future research. This article can serve as a valuable resource for multidisciplinary researchers engaged in wheat biofortification, aiding in the refinement of ongoing and future strategies to achieve the Sustainable Development Goal of eradicating hunger and malnutrition by 2030.
Addressing the cumulative impacts of multiple human pressures in marine systems, for the sustainable use of the seas
Authors: Borja Angel , Elliott Michael , Teixeira Heliana , Stelzenmüller Vanessa , Katsanevakis Stelios , Coll Marta , Galparsoro Ibon , Fraschetti Simonetta , Papadopoulou Nadia , Lynam Christopher , Berg Torsten , Andersen Jesper H. , Carstensen Jacob , Leal Miguel C. , Uyarra María C.
Published: January 2024

Human activities at sea have increased, causing subsequent degradation of ocean health and affecting ecosystem services and societal goods and benefits. Climate change further exacerbates the cumulative effects of these activities and their associated pressures. Hence, effective management of these multiple activities is imperative to ensure the sustainable use of the ocean. In response to these challenges, we have developed a comprehensive conceptual framework model within an ecosystem-based approach. This framework encompasses a versatile toolbox designed to assess cumulative pressures effects and the environmental status under the European Marine Strategy Framework Directive, in compliance with the Birds and Habitats Directives requirements and the need to secure the maintenance of ecosystem services and provision of societal benefits. Although we use European examples in the current discussion, we consider that there are similar challenges in many seas worldwide and so the recommendations here are widely applicable. Our aim is to facilitate the validation, harmonization, and demonstration of this toolbox across European regional seas and several countries, at different scales, from local to regional, including overseas territories. This approach aims to foster comparability in environmental status assessments. We anticipate that the proposed methodologies will serve as a foundational benchmark against which progress can be assessed in line with expectations and policy requirements. Additionally, this work prepares the groundwork for the forthcoming evaluation of the suitability, robustness, and applicability of these solutions and tools, thereby assisting managers in achieving Good Environmental Status (GES), both in European and wider global contexts, to address challenges which are common worldwide.
A germline JAK2 exon12 mutation and a late somatic CALR mutation in a patient with essential thrombocythemia
Authors: Hao Zhuanghui , Li Juan , Gao Feng , Ren Weixiao , Lu Xiaomei , Feng Jinyi , Zhang Chen , Bian Sicheng , Xie Juan , Luo Ming , Chang Jianmei , Yang Wanfang , Hou Ruixia , Muyey Daniel Muteb , Xu Jing , Cui Jiangxia , Chen Xiuhua , Wang Hongwei
Published: January 2024

Background

It has been discovered that Janus kinase 2 (JAK2) exon12 mutations lead to the polycythemia vera (PV) phenotype, while somatic mutations of calreticulin (CALR) are associated with essential thrombocythemia (ET) or primary myelofibrosis. In this article, we report a case of ET with coexistence of JAK2 exon12 and CALR mutations. The objective of this study was to elucidate the pathogenicity mechanism of a JAK2 exon12 mutation (JAK2N533S) and the role of the coexistence of mutations on the hematological phenotype.

Methods

We designed a colony analysis of tumor cells obtained from this patient, and attempted to identify mutant genes using DNA from hair follicles. Mutation impairment prediction and conservative analysis were conducted to predict the mutation impairment and structure of JAK2N533S. In addition, we conducted a functional analysis of JAK2N533S by constructing Ba/F3 cell models.

Results

Three distinct tumor subclones, namely JAK2N533Shet+/CALRtype1het+, JAK2N533Shet+/CALRwt, and JAK2N533Shet+/CALRtype1hom+, were identified from the 17 selected erythroid and 21 selected granulocyte colonies. The analysis of hair follicles yielded positive results for JAK2N533S. According to the bioinformatics analysis, JAK2N533S may exert only a minor effect on protein function. Functional studies showed that JAK2N533S did not have a significant effect on the proliferation of Ba/F3 cells in the absence of interleukin-3 (IL-3), similar to wild-type JAK2. Notably, there were no increased phosphorylation levels of JAK2-downstream signaling proteins, including signal transducer and activator of transcription 3 (STAT3) and STAT5, in Ba/F3 cells harboring the JAK2N533S.

Conclusion

Our study revealed that the JAK2N533Shet+/CALRtype1het+ subclone was linked to a significant expansion advantage in this patient, indicating that it may contribute to the development of the ET phenotype. We further demonstrated that JAK2N533S, as a noncanonical JAK2 exon12 mutation, is a germline mutation that may not exert an effect on cell proliferation and protein function. These results and the present body of available data imply that certain noncanonical JAK2 mutations are not gain-of-function mutations leading to the development of myeloproliferative neoplasms.
Immunological characterization of an Italian PANDAS cohort
Authors: Leonardi Lucia , Lorenzetti Giulia , Carsetti Rita , Piano Mortari Eva , Guido Cristiana Alessia , Zicari Anna Maria , Förster-Waldl Elisabeth , Loffredo Lorenzo , Duse Marzia , Spalice Alberto
Published: January 2024

This cross-sectional study aimed to contribute to the definition of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) pathophysiology. An extensive immunological assessment has been conducted to investigate both immune defects, potentially leading to recurrent Group A β-hemolytic Streptococcus (GABHS) infections, and immune dysregulation responsible for a systemic inflammatory state. Twenty-six PANDAS patients with relapsing-remitting course of disease and 11 controls with recurrent pharyngotonsillitis were enrolled. Each subject underwent a detailed phenotypic and immunological assessment including cytokine profile. A possible correlation of immunological parameters with clinical-anamnestic data was analyzed. No inborn errors of immunity were detected in either group, using first level immunological assessments. However, a trend toward higher TNF-alpha and IL-17 levels, and lower C3 levels, was detected in the PANDAS patients compared to the control group. Maternal autoimmune diseases were described in 53.3% of PANDAS patients and neuropsychiatric symptoms other than OCD and tics were detected in 76.9% patients. ASO titer did not differ significantly between the two groups. A possible correlation between enduring inflammation (elevated serum TNF-α and IL-17) and the persistence of neuropsychiatric symptoms in PANDAS patients beyond infectious episodes needs to be addressed. Further studies with larger cohorts would be pivotal to better define the role of TNF-α and IL-17 in PANDAS pathophysiology.
News in pharmacology for the main medical pathologies of gestation
Authors: De Guadalupe Quintana-Coronado María , Bravo Coral , Álvarez-Mon Melchor , Ortega Miguel A. , De León-Luis Juan A.
Published: January 2024

Obstetric diseases represent a highly complex medical challenge, especially regarding its clinical approach. The use of pharmacological agents during pregnancy is one of the main therapeutic alternatives in this group of patients; however, there is a general lack of knowledge about its use, efficacy, and possible adverse effects that may occur in routine clinical practice, even among medical professionals themselves. The high percentage of pregnant women who undergo drugs at some point during pregnancy, together with the developments that have occurred in recent years in the field of pharmacology, show the need for a detailed analysis that shows the existing current knowledge and helps in the clinical decision making. In this sense, the aim of this work is to conduct a review of the available scientific literature on the novelties in pharmacology for the main medical pathologies of pregnancy. Thus, the role of this field in analgesia, antibiotic therapy, digestive, respiratory, urological, psychiatric and neurological pathologies will be detailed, evaluating the indications, precautions and considerations that must be taken into account for its use.
Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis
Authors: Wang Lei , Liu Wang-Qing , Broussy Sylvain , Han Bingnan , Fang Hongming
Published: January 2024

Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.
Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy
Authors: Zhao Yichang , Liu Huaiyuan , Xiao Chenlin , Hou Jingjing , Zhang Bikui , Li Jiakai , Zhang Min , Jiang Yongfang , Sandaradura Indy , Ding Xuansheng , Yan Miao
Published: January 2024

Introduction: The application of voriconazole in patients with liver dysfunction lacks pharmacokinetic data. In previous study, we proposed to develop voriconazole dosing regimens for these patients according to their total bilirubin, but the regimens are based on Monte Carlo simulation and has not been further verified in clinical practice. Besides, there are few reported factors that significantly affect the efficacy of voriconazole.

Methods: We collected the information of patients with liver dysfunction hospitalized in our hospital from January 2018 to May 2022 retrospectively, including their baseline information and laboratory data. We mainly evaluated the efficacy of voriconazole and the target attainment of voriconazole trough concentration.

Results: A total of 157 patients with liver dysfunction were included, from whom 145 initial and 139 final voriconazole trough concentrations were measured. 60.5% (95/157) of patients experienced the adjustment of dose or frequency. The initial voriconazole trough concentrations were significantly higher than the final (mean, 4.47 versus 3.90 μg/mL, p = 0.0297). Furthermore, daily dose, direct bilirubin, lymphocyte counts and percentage, platelet, blood urea nitrogen and creatinine seven covariates were identified as the factors significantly affect the voriconazole trough concentration. Binary logistic regression analysis revealed that the lymphocyte percentage significantly affected the efficacy of voriconazole (OR 1.138, 95% CI 1.016–1.273), which was further validated by the receiver operating characteristic curve.

Conclusion: The significant variation in voriconazole trough concentrations observed in patients with liver dysfunction necessitates caution when prescribing this drug. Clinicians should consider the identified factors, particularly lymphocyte percentage, when dosing voriconazole in this population.
The neuroprotective potential of phytochemicals in traumatic brain injury: mechanistic insights and pharmacological implications
Authors: Hasan Gulam Mustafa , Anwar Saleha , Shamsi Anas , Sohal Sukhwinder Singh , Hassan Md. Imtaiyaz
Published: January 2024

Traumatic brain injury (TBI) leads to brain damage, comprising both immediate primary damage and a subsequent cascade of secondary injury mechanisms. The primary injury results in localized brain damage, while the secondary damage initiates inflammatory responses, followed by the disruption of the blood-brain barrier, infiltration of peripheral blood cells, brain edema, and the release of various immune mediators, including chemotactic factors and interleukins. TBI disrupts molecular signaling, cell structures, and functions. In addition to physical tissue damage, such as axonal injuries, contusions, and haemorrhages, TBI interferes with brain functioning, impacting cognition, decision-making, memory, attention, and speech capabilities. Despite a deep understanding of the pathophysiology of TBI, an intensive effort to evaluate the underlying mechanisms with effective therapeutic interventions is imperative to manage the repercussions of TBI. Studies have commenced to explore the potential of employing natural compounds as therapeutic interventions for TBI. These compounds are characterized by their low toxicity and limited interactions with conventional drugs. Moreover, many natural compounds demonstrate the capacity to target various aspects of the secondary injury process. While our understanding of the pathophysiology of TBI, there is an urgent need for effective therapeutic interventions to mitigate its consequences. Here, we aimed to summarize the mechanism of action and the role of phytochemicals against TBI progression. This review discusses the therapeutic implications of various phytonutrients and addresses primary and secondary consequences of TBI. In addition, we highlighted the roles of emerging phytochemicals as promising candidates for therapeutic intervention of TBI. The review highlights the neuroprotective roles of phytochemicals against TBI and the mechanistic approach. Furthermore, our efforts focused on the underlying mechanisms, providing a better understanding of the therapeutic potential of phytochemicals in TBI therapeutics.
Frankincense preparation promotes formation of inflammation-resolving lipid mediators by manipulating lipoxygenases in human innate immune cells
Authors: Nischang Vivien , Witt Finja M. , Börner Friedemann , Gomez Mario , Jordan Paul M. , Werz Oliver
Published: January 2024

Introduction: Frankincense preparations are frequently used as traditional anti-inflammatory remedies in folk medicine with increasing popularity. Boswellic acids (BAs), especially 3-O-acetyl-11-keto-βBA (AKBA), are unique anti-inflammatory principles of frankincense, with multiple pharmacological actions and target proteins. We recently showed that AKBA favorably impacts lipid mediator (LM) networks in innate immune cells, by modulation of lipoxygenase (LOX) activities. Thus, AKBA binds to allosteric sites in 5-LOX, shifting the regiospecificity to a 12/15-lipoxygnating enzyme, and to an analogous site in 15-LOX-1, leading to enzyme activation, which favors specialized pro-resolving mediator (SPM) formation at the expense of leukotriene production.

Methods: Here, we investigated Boswellin super® (BSR), a commercially available frankincense extract with ≥30% AKBA, used as remedy that approved efficacy in osteoarthritis trials, for its ability to modulate LM pathways in human monocyte-derived macrophage (MDM) phenotypes, neutrophils, and neutrophil/platelet co-incubations. LM profiling was performed by using targeted ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS).

Results: BSR concentration-dependently (10–100 μg/ml) suppressed formation of pro-inflammatory 5-LOX products including LTB4 in exotoxin-stimulated M1-MDM and neutrophils, and strongly elevated 12/15-LOX products and SPM in activated M2-MDM and neutrophil/platelet cocultures, starting at 10 μg/mL. Also, BSR (≥10 μg/mL) induced robust 12/15-LOX product and SPM generation in resting M2-MDM, which was further markedly elevated when exogenous docosahexaenoic acid (DHA) and eicosahexaenoic acid (EPA) were supplied, and induced translocation of 15-LOX from a soluble to a particulate locale in M2 MDM.

Discussion: We conclude that BSR especially when co-added with DHA and EPA, promotes the LM class switch in innate immune cells from pro-inflammatory to pro-resolving mediators, which might be a plausible mechanism underlying the anti-inflammatory actions of BSR.
Tissue cytokines in chickens from lines selected for high or low humoral antibody responses, given supplemental Limosilactobacillus reuteri and challenged with Histomonas meleagridis
Authors: Edens Frank W. , Siegel Paul B. , Beckstead Robert B. , Honaker Christa F. , Hodgson Dellila
Published: January 2024

Histomonas meleagridis, a protozoan parasite, induces blackhead disease (histomoniasis) in poultry. During hatching, chicks from lines divergently selected for high (HAS) and low (LAS) antibody responses to sheep red blood cells were divided into two groups, each of HAS and LAS, and placed in pens with wood shavings as litter. Feed and water were allowed ad libitum. Half of the chicks from each line had Limosilactobacillus reuteri (L. reuteri) inoculated to their drinking water. On day 18, all chicks were given a transcloacal inoculation of 100,000 H. meleagridis cells. Then, 10 days later, they were euthanized, followed by collection of tissues from the brain, cecal tonsil, ceca, liver, thymus, and spleen for qPCR analyses of cytokines involved in immunological development. Changes in cytokine expressions were most numerous in the cecal tonsil, ceca, and liver. In the absence of a functional medication for control of histomoniasis, L. reuteri and/or its secretory product, reuterin, might serve, in some genetic populations, as a means to reduce the impact of histomoniasis in chickens. The data demonstrate that L. reuteri treatment had tissue specificity between the two genetic lines, in which the effects were targeted primarily toward the cecal tonsil, ceca, and liver, which are the primary tissue targets of the parasite (H. meleagridis), as well as the thymus and spleen. However, interactions among main effects reflect that responses to inflammatory markers observed in tissues for one genetic line may not be observed in another.
Expression and mutagenesis studies in the Medicago truncatula iron transporter MtVTL8 confirm its role in symbiotic nitrogen fixation and reveal amino acids essential for transport
Authors: Cai Jingya , Longo Antonella , Dickstein Rebecca
Published: January 2024

The model legume Medicago truncatula establishes a symbiosis with soil bacteria (rhizobia) that carry out symbiotic nitrogen fixation (SNF) in plant root nodules. SNF requires the exchange of nutrients between the plant and rhizobia in the nodule that occurs across a plant-derived symbiosome membrane. One iron transporter, belonging to the Vacuolar iron Transporter-Like (VTL) family, MtVTL8, has been identified as essential for bacteria survival and therefore SNF. In this work we investigated the spatial expression of MtVTL8 in nodules and addressed whether it could be functionally interchangeable with a similar nodule-expressed iron transporter, MtVTL4. Using a structural model for MtVTL8 and the previously hypothesized mechanism for iron transport in a phylogenetically-related Vacuolar Iron Transporter (VIT), EgVIT1 with known crystal structure, we identified critical amino acids and obtained their mutants. Mutants were tested in planta for complementation of an SNF defective line and in an iron sensitive mutant yeast strain. An extended phylogenetic assessment of VTLs and VITs showed that amino acids critical for function are conserved differently in VTLs vs. VITs. Our studies showed that some amino acids are essential for iron transport leading us to suggest a model for MtVTL8 function, one that is different for other iron transporters (VITs) studied so far. This study extends the understanding of iron transport mechanisms in VTLs as well as those used in SNF.
Phaseolus vulgaris mutants reveal variation in the nuclear genome
Authors: Tomlekova Nasya , Idziak-Helmcke Dominika , Franke Paula , Rojek-Jelonek Magdalena , Kwasniewska Jolanta
Published: January 2024

Phaseolus vulgaris L. (common bean) is an essential source of proteins in the human diet worldwide. Bean breeding programs to increase genetic diversity based on induced mutagenesis have a long tradition in Bulgaria. Common bean varieties with high productivity, wide environmental adaptability, good nutritional properties, and improved disease resistance have been successfully developed. In this study, we aimed to investigate selected nuclear genome features, such as the genome size, the number and chromosomal distribution of 5S and 35S rDNA loci by using the fluorescence in situ hybridization (FISH), as well as the level of DNA damage in some local Bulgarian accessions and mutants of P. vulgaris. Flow cytometry analyses revealed no significant differences in genome size between analyzed lines except for one of the analyzed mutants, M19. The value of genome size 2C DNA is about 1.37 pg2C -1 for all lines, whereas it is 1.42 pg2C-1 for M19. The chromosome number remains the same (2n=22) for all analyzed lines. Results of FISH analyses showed that the number of 5S rDNA was stable among accessions and mutant lines (four loci), while the number of 35S rDNA loci was shown as highly polymorphic, varying between ten and sixteen, and displaying differences in the size and location of 35S rDNA loci between analyzed genotypes. The cell cycle profile was different for the analyzed genotypes. The results revealed that wide variation in genome organization and size as well as DNA damage characterizes the analyzed genetic resources of the common bean.
Informed participation? An investigation of the relationship between exposure to different news channels and participation mediated through actual and perceived knowledge
Authors: Schäfer Svenja , Schemer Christian
Published: January 2024

Previous studies have found that different media channels have varying potentials for informed participation. Exposure to newspaper and TV news exposure has been shown to increase actual knowledge and participation, while social media is associated with participation based on perceived knowledge, without changes in actual knowledge. In light of these findings, we conducted an online survey (N = 1,670) in Germany to investigate the (mediated) relationships between news consumption, knowledge (perception), and participation. The study revealed that exposure to quality newspaper and public service TV news was linked to both actual and perceived knowledge, thereby impacting participation. However, tabloid newspapers and news from private TV channels were not found to be related to participation. In the case of social media, we found a relationship with online participation on social media and offline participation, but this relationship was only mediated through an increase in perceived knowledge. In other words, our findings suggest that social media use creates an illusion of knowledge that is linked to higher levels of participation. These findings highlight the democratic importance of traditional media channels, particularly public service broadcasting media. They also demonstrate how social media can lead to a false feeling of knowing, which can hinder participation processes.