bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionality of BRCA1 supports the survival of prostate cancer cells during the development of castration resistance
Authors: Sriraman Saiganesh , Virtanen Verneri , Kukkula Antti , Toriseva Mervi , Rokka Anne , Lumiainen Anni , Ahlskog Johanna K. , West Gun , Poutanen Matti , Taimen Pekka , Sundvall Maria
Published: June 2024

Androgen deprivation therapy (ADT; castration) is the main treatment option for metastatic prostate cancer (PCa), but eventually, castration-resistant prostate cancer (CRPC) develops with no curative treatments. In CRPC, more than 20% of men carry mutations in DNA damage response (DDR) genes, including BRCA1/2. In this study, we elucidated the prostate tissue-specific functional role of BRCA1 protein. Our results indicate that DDR is dynamically regulated by androgen receptor (AR) signaling, and AR activation by the natural ligand dihydrotestosterone strongly downregulates the expression of BRCA1 in multiple cell lines. Consistent with these findings, our analyses of patient samples and mouse xenografts showed that DNA damage and BRCA1 expression were sustained after ADT. With unbiased mass spectrometry and bioinformatics approaches as well as experimentally, we found that BRCA1 interacts with Raptor, an mTORC1 component, and regulates the mTOR signaling pathway and PCa growthin vitro. Furthermore, we found that mTOR inhibition reduced the recruitment of DDR proteins, BRCA1 and Rad51, to DNA damage sites, creating a vulnerability towards DNA damage-inducing androgen deprivation. Moreover, we observed that BRCA1 supported ADT-induced activation of the oxidative stress sensor NRF2. Our findings shed further light on the complex DDR–AR interplay in PCa and suggest that, during PCa progression, BRCA1 expression may be retained due to the beneficial modulation of mTORC1 signaling in the AR environment by BRCA1.

Significance

Androgen receptor activation acts as a strong suppressor of BRCA1. Consequently, androgen deprivation activates BRCA1, which in turn promotes survival in castration resistance by supporting mTOR signaling and NRF2-mediated antioxidant processes.
Characterizing and evaluating cell specialization through Gini index of gene expression: TCGA normal vs tumor case study
Authors: Cumbo Fabio , Santoni Daniele
Published: June 2024

In this work we introduce the Gini Index, commonly used as a measure of statistical dispersion to evaluate the income inequality within a nation, as an effective and reliable measure of cell specialization. In particular we use it to evaluate and compare the specialization level of normal and tumor cells according to their gene expressions. Obtained results reveal how Gini Index is able to capture information associated with cell specialization, and show that tumor cells, on average, tend to lose their specialization or in other words their capacity to be the cells they were committed to be, due to cancer.
Cocaine-Induced Gene Regulation in D1 and D2 Neuronal Ensembles of the Nucleus Accumbens Revealed by Single-Cell RNA Sequencing
Authors: Mews Philipp , Mason Autumn VA , Kirchner Emily G , Estill Molly , Nestler Eric J
Published: June 2024

Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations─or ensembles – across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.
Genetic association data are broadly consistent with stabilizing selection shaping human common diseases and traits
Authors: Koch E. , Connally N. J. , Baya N. , Reeve M. P. , Daly M. , Neale B. , Lander E. S. , Bloemendal A. , Sunyaev S.
Published: June 2024

Results from genome-wide association studies (GWAS) enable inferences about the balance of evolutionary forces maintaining genetic variation underlying common diseases and other genetically complex traits. Natural selection is a major force shaping variation, and understanding it is necessary to explain the genetic architecture and prevalence of heritable diseases. Here, we analyze data for 27 traits, including anthropometric traits, metabolic traits, and binary diseases—both early-onset and post-reproductive. We develop an inference framework to test existing population genetics models based on the joint distribution of allelic effect sizes and frequencies of trait-associated variants. A majority of traits have GWAS results that are inconsistent with neutral evolution or long-term directional selection (selection against a trait or against disease risk). Instead, we find that most traits show consistency with stabilizing selection, which acts to preserve an intermediate trait value or disease risk. Our observations also suggest that selection may reflect pleiotropy, with each variant influenced by associations with multiple selected traits.
D1-like receptor activation rescues hippocampal synaptic plasticity and cognitive impairments in the MK-801 schizophrenia model
Authors: Hernández-Frausto Melissa , Galván Emilio J , López-Rubalcava Carolina
Published: June 2024

Schizophrenia is a disorder with a higher cognitive decline in early adulthood, causing impaired retention of episodic memories. However, the physiological and behavioral functions that underlie cognitive deficits with a potential mechanism to ameliorate and improve cognitive performance are unknown. In this study, we used the MK-801 neurodevelopmental schizophrenia-like model. Rats were divided into two groups: one received MK-801, and the other received saline for five consecutive days (7-11 postnatal days, PND). Using extracellular field recordings in acute hippocampal slices and the Barnes maze task, we evaluated synaptic plasticity late-LTP and spatial memory in freely moving animals in early adolescence and young adulthood. Next, we examined D1-like activation as a mechanism to ameliorate cognitive impairments. Our results suggest that MK-801 neonatal treatment induces impairment in late-LTP expression and deficits in spatial memory retrieval in early adolescence that is maintained until young adulthood. Furthermore, we found that activation of D1-like dopamine receptors ameliorates the impairments and promotes a robust expression of late-LTP and an improved performance in the Barnes maze task, suggesting a novel and potential therapeutic role in treating cognitive impairments in schizophrenia.

Highlights

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MK-801 Schizophrenia model induces impairment in Late-LTP at early adolescence and young developmental stage.

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Barnes maze recall phase is impaired in the MK-801 Schizophrenia model.

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The activation of D1-like receptors promotes recovery and induction of the

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Late-LTP in the MK-801 schizophrenia model in adolescent and young adult rats.

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Activation of D1-like dopamine receptors improves behavioral performance in the MK-801 schizophrenia model in adolescent and young adult rats.

Graphical Abstract

Disturbances in episodic memories are observed in patients with schizophrenia and rodent models. Still, the hippocampal physiological substrates with a potential rescue mechanism related to consolidation of memories have not been elucidated. Here, in vitro electrophysiology and in vivo Barnes maze task are used at two ages in the MK-801 neurodevelopmental schizophrenia-like model. We observed a loss of hippocampal late-LTP and impaired recall phase, and the activation of dopamine D1-like receptors attenuated the impairments with a rescue of both late-LTP and recall phase, suggesting an important role of D1-like receptors activity for episodic memory in schizophrenia.
Perturbing human V1 degrades the fidelity of visual working memory
Authors: Dake Mrugank , Curtis Clayton E.
Published: June 2024

The main function of working memory is to extend the duration with which information remains available for use by a host of high-level cognitive systems1. Decades of electrophysiological studies provide compelling evidence that persistent neural activity in prefrontal cortex is a key mechanism for working memory2. Surprisingly, sophisticated human neuroimaging studies have convincingly demonstrated that the contents of working memory can be decoded from primary visual cortex (V1)3,4. The necessity of this mnemonic information remains unknown and contentious. Here, we provide causal evidence that transcranial magnetic stimulation to human V1 disrupted the fidelity of visual working memory. Magnetic stimulation during the retention interval of a visuospatial working memory task caused a systematic increase in memory errors. Errors increased only for targets that were remembered in the portion of the visual field disrupted by stimulation, and were invariant to when in the delay stimulation was applied. Moreover, concurrently measured electroencephalography confirmed that stimulation disrupted not only memory behavior, but a standard neurophysiological signature of working memory. These results change the question from whether V1 is necessary for working memory into what mechanisms does V1 use to support memory. Moreover, they point to models in which the mechanisms supporting working memory are distributed across brain regions, including sensory areas that here we show are critical for memory storage.
Glia-enriched stem-cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis
Authors: Fagiani Francesca , Pedrini Edoardo , Taverna Stefano , Brambilla Elena , Murtaj Valentina , Podini Paola , Ruffini Francesca , Butti Erica , Braccia Clarissa , Andolfo Annapaola , Magliozzi Roberta , Smirnova Lena , Kuhlmann Tanja , Quattrini Angelo , Calabresi Peter A. , Reich Daniel S. , Martino Gianvito , Panina-Bordignon Paola , Absinta Martina
Published: June 2024

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from hiPSC-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from MS patients, organoids properly mimic macroglia-microglia neuro-degenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally-resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support implementing this organoid model for drug screening to halt inflammatory neurodegeneration.
Targeted Photoactivatable Green-Emitting BODIPY Based on Directed Photooxidation Induced Activation and its Application to Live Dynamic Super-Resolution Microscopy
Authors: Saladin Lazare , Le Berruyer Valentine , Bonnevial Maxence , Didier Pascal , Collot Mayeul
Published: June 2024

Photoactivatable fluorescent probes are valuable tools in bioimaging for tracking cells down to single molecules and for single molecule localization microscopy. For the latter application, green emitting dyes are in demand. We herein developed an efficient green-emitting photoactivatable furanyl-BODIPY (PFB) and we established a new mechanism of photoactivation called Directed Photooxidation Induced Activation (DPIA) where the furan is photo-oxidized in a directed manner by the singlet oxygen produced by the probe. The efficient photoconverter (93-fold fluorescence enhancement at 510 nm, 49% yield conversion) is functionalizable and allowed targeting of several subcellular structures and organelles, which were photoactivated in live cells. Finally, we demonstrated the potential of PFB in super-resolution imaging by performing PhotoActivated Localization Microscopy (PALM) in live cells.
Whole genome sequence and 16S rRNA gene amplicon metagenomics of enhanced in-situ reductive dechlorination at a tetrachloroethene-contaminated superfund site
Authors: Reiss Rebecca A. , Guerra Peter A. , Makhnin Oleg , Kellom Matthew
Published: June 2024

The application of environmental DNA analysis techniques to guide the bioremediation strategy for tetrachloroethene-contaminated groundwater is exemplified by the North Railroad Avenue Plume (NRAP) Superfund site located in New Mexico, USA. Enhanced reductive dechlorination (ERD) was selected as the remedy due to the presence of tetrachloroethene biodegradation byproducts, organohalide respiring generaDehalococcoidesandDehalobacter, and associated reductive dehalogenase genes detected prior to remediation. DNA extracted from groundwater samples collected prior to remedy application and after four, 23 and 39 months was subjected to 16SrRNA gene amplicon and whole genome sequencing (WGS). The goals were to compare the potential of these methods as tools for environmental engineers and to highlight how advancements in DNA techniques can be used to understand ERD. The response of the indigenous NRAP microbiome to the injection and recirculation of electron donors and hydrogen sources is consistent with results obtained from microcosms, dechlorinating consortia, and other contaminated sites. WGS detects three times as many phyla and six times as many genera as 16S rRNA gene amplicons. Both techniques reveal abundance changes inDehalococcoidesandDehalobacterthat reflect organohalide form and availability. No methane was detected before remediation, its appearance after biostimulation corresponds to the increase in methanogenicArchaea. Assembly of WGS reads produced scaffolds containing reductive dehalogenase genes fromDehalococcoides,Dehalobacter, Dehalogenimonas, Desulfocarbo,andDesulfobacula. Anaerobic and aerobic cometabolic organohalide degrading microbes that increase in abundance at NRAP include methanogenicArchaea, methanotrophs,Dechloromonas, andXanthobacter, some of which contain hydrolytic dehalogenase genes. Aerobic cometabolism may be supported by oxygen gradients existing at the aquifer-soil interface or by microbes that have the potential to produce O2via chlorite dismutation. Results from next-generation sequencing-based methods are consistent with current hypotheses regarding syntrophy in environmental microbiomes and reveals novel taxa and genes that may contribute to ERD.
Rescuing impaired hippocampal-cortical interactions and spatial reorientation learning and memory during sleep in a mouse model of Alzheimer’s disease using hippocampal 40 Hz stimulation
Authors: Cushing Sarah D. , Moseley Shawn C. , Stimmell Alina C. , Schatschneider Christopher , Wilber Aaron A.
Published: June 2024

Summary/Abstract

In preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired. We reported similar impairments in 3xTg-AD mice on a virtual maze (VM) spatial-reorientation-task that requires using landmarks to navigate. Hippocampal (HPC)-cortical dysfunction during sleep (important for memory consolidation) is a potential mechanism for memory impairments in AD. We previously found deficits in HPC-cortical coordination during sleep coinciding with VM impairments the next day. Some forms of 40 Hz stimulation seem to clear AD pathology in mice, and improve functional connectivity in AD patients. Thus, we implanted a recording array targeting parietal cortex (PC) and HPC to assess HPC-PC coordination, and an optical fiber targeting HPC for 40 Hz or sham optogenetic stimulation in 3xTg/PVcremice. We assessed PC delta waves (DW) and HPC sharp wave ripples (SWRs). In sham mice, SWR-DW cross-correlations were reduced, similar to 3xTg-AD mice. In 40 Hz mice, this phase-locking was rescued, as was performance on the VM. However, rescued HPC-PC coupling no longer predicted performance as in NonTg animals. Instead, DWs and SWRs independently predicted performance in 40 Hz mice. Thus, 40 Hz stimulation of HPC rescued functional interactions in the HPC-PC network, and rescued impairments in spatial navigation, but did not rescue the correlation between HPC-PC coordination during sleep and learning and memory. Together this pattern of results could inform AD treatment timing by suggesting that despite applying 40 Hz stimulation before significant tau and amyloid aggregation, pathophysiological processes led to brain changes that were not fully reversed even though cognition was recovered.

Significance Statement

One of the earliest symptoms of Alzheimer’s disease (AD) is getting lost in space or experiencing deficits in spatial navigation, which involve navigation computations as well as learning and memory. We investigated cross brain region interactions supporting memory formation as a potential causative factor of impaired spatial learning and memory in AD. To assess this relationship between AD pathophysiology, brain changes, and behavioral alterations, we used a targeted approach for clearing amyloid beta and tau to rescue functional interactions in the brain. This research strongly connects brain activity patterns during sleep to tau and amyloid accumulation, and will aid in understanding the mechanisms underlying cognitive dysfunction in AD. Furthermore, the results offer insight for improving early identification and treatment strategies.
Effect of high sensitivity C-Reactive Protein on Uric Acid-related Cardiometabolic Risk in Patients with Coronary Artery Disease— A Large Multicenter Prospective Study
Authors: Song Ying , Cai Weiting , Jiang Lin , Xu Jingjing , Yao Yi , Xu Na , Wang Xiaozeng , Liu Zhenyu , Zhang Zheng , Zhang Yongzhen , Guo Xiaogang , Wang Zhifang , Feng Yingqing , Wang Qingsheng , Li Jianxin , Zhao Xueyan , Chen Jue , Gao Runlin , Song Lei , Han Yaling , Yuan Jinqing
Published: June 2024

Aims

Although serum uric acid (SUA) is a risk factor for cardiometabolic outcome, but it remains unclear which patients with coronary artery disease (CAD) benefit the most from SUA lowering therapy (ULT). The association of SUA level, systemic inflammation and cardiometabolic risk is still unclear. The current study is aimed to examine whether SUA-associated cardiometabolic risk is modulated by systemic inflammation in CAD patients.

Methods and Results

A total of 16,598 CAD patients with baseline high-sensitivity C-Reactive Protein (hsCRP) and SUA available were included. Baseline and follow-up data were collected. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including death, myocardial infarction and stroke. In patients with hsCRP ≥2 mg/L, increasing quintiles of SUA were significantly associated with increased rates of 2-year MACCE (adjusted p < 0.001 for trend, p = 0.037 for interaction). Each unit increase in SUA levels was associated with a 11.3% increased risk of MACCE (adjusted p < 0.001, p = 0.002 for interaction). However, in patients with hsCRP < 2mg/L, increasing quintiles of SUA were not associated with increased MACCE (adjusted p = 0.120).

Conclusion

Elevated SUA levels are related to MACCE when hsCRP levels are 2 mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of combined ULT and anti-inflammation therapy in patients with hyperuricemia and greater systemic inflammation.
Threat-Related Corticocortical Connectivity Elicited by Rapid Auditory Looms
Authors: Ignatiadis Karolina , Barumerli Roberto , Deco Gustavo , Tóth Brigitta , Baumgartner Robert
Published: June 2024

While sounds of approaching objects are generally more salient than those of receding ones, the traditional association of this auditory looming bias with threat perception is subject to debate. Differences between looming and receding sounds may also be learned through non-threatening multisensory information, or influenced by confounding stimulus characteristics. To investigate, we analyzed corticocortical connectivity patterns from electroencephalography, examining the preferential processing of looming sounds under different attentional states. To simulate rapid distance changes we used complementary distance cues, previously studied in the looming bias literature. Notably, despite the absence of conscious threat perception, we observed crucial involvement of frontal cortical regions typically associated with threat and fear responses. Our findings suggest an underlying bias towards the ventral ‘what’ stream over the dorsal ‘where’ stream in auditory information processing, even when the participants’ task was solely focused on the discrimination of movement direction. These results support the idea, that the perceptual bias towards looming sounds reflects an auditory threat detection mechanism, while offering insights into the neural function involved in processing ecologically relevant environmental cues.
Endemic transmission and international introduction of Monkeypox virus in Southern Brazil between 2022-2023
Authors: Godinho Fernanda Marques , Bermann Thales de Lima , de Oliveira Mayara Mota , Barcellos Regina Bones , Ruivo Amanda Pellenz , de Melo Viviane Horn , Machado dos Santos Franciellen , Bauermann Milena , Selayaran Taina Machado , Soares Taina dos Santos , Sesterheim Patrícia , Baethgen Ludmila Fiorenzano , Da Rocha Fernanda Maria , Amaral Karine Medeiros , Delela Fernanda Crestina Leitenski , Mondini Renata Petzhold , Vizeu Sabrina , Gregianini Tatiana Schäffer , da Veiga Ana Beatriz Gorini , Wallau Gabriel da Luz , Salvato Richard Steiner
Published: June 2024

Mpox is a zoonotic viral disease caused by the monkeypox virus (MPXV). Human cases have been mainly restricted to the African continent until the worldwide multi-country outbreak unfolded in 2022. We reconstructed epidemiological links of MPXV infections using genomic epidemiology in Rio Grande do Sul State, southern Brazil, during 2022 and 2023. We detected five well-supported clades, three representing local transmission chains that were mostly restricted to the 2022 virus spread, one supported year-long maintenance encompassing samples from 2022 and 2023, and one new importation from Europe in 2023. Our results provide new insights into the geographic extent of community transmission and its association with viral diversity during the more pronounced 2022 mpox upsurge and during the following lower incidence endemic transmission phase. These findings highlight the power of continued genomic surveillance to uncover hidden transmission chains to understand viral dynamics and inform public health responses. The detection of sustained endemic transmission in the state is important to guide targeted control measures to curtail further community and international transmission and highlight the need for strengthening genomic surveillance.
Automatic radiotherapy treatment planning with deep functional reinforcement learning
Authors: Liu Bin , Liu Yu , Li Zhiqian , Xiao Jianghong , Yin Guosheng , Lin Huazhen
Published: June 2024

Background and purpose

Intensity-modulated radiation therapy (IMRT) is a crucial radiotherapy technique, often formulated as an optimization problem. However, when the constraints are too tight to provide a feasible solution, human planners resort to relaxing the optimization parameters and re-evaluating until an acceptable solution is obtained. This process is laborious and time-consuming which has prompted attempts to automate radiotherapy through inverse planning studies using reinforcement learning. Unfortunately, these studies face two major limitations. Firstly, a separate sub-network must be designed for each organ, rendering them difficult to apply to patients with an inconsistent number of structures. Secondly, the low signal-to-noise inputs and discrete action space result in low training efficiency. To address these limitations, this study proposes a novel and effective model.

Methods

This study proposes an organ-sharing network calledFunctionalautomatictreatmentPlannIngNetwork (FatPIN), which contains a functional embedding layer to extract curve features of the dose-volume histogram (DVH). It outputs continuous actions that adjust the optimization parameters, thereby automating the radiotherapy planning process.

Results

Experiments were conducted on the cervical cancer dataset and the results show that the FatPIN is feasible and effective in real-world radiotherapy. With automatic iteration, FatPIN gradually increased the PTV dose, while reducing the dose levels of the OARs. Specifically, at step 50, theD95of the PTV reached 51.68 Gy, exceeding the clinical standard of 50.40 Gy, theV30,V40andV50of all OARs were within clinical requirements.

Conclusion

We proposed FatPIN to implement automatic radiotherapy treatment planning. Experimental assessments conducted on cases of cervical cancer demonstrate significant improvements in patient metrics facilitated by FatPIN, thus confirming its practical applicability in clinical contexts.
Assessing CT-based Volumetric Analysis via Transfer Learning with MRI and Manual Labels for Idiopathic Normal Pressure Hydrocephalus
Authors: Srikrishna Meera , Seo Woosung , Zettergren Anna , Kern Silke , Cantré Daniel , Gessler Florian , Sotoudeh Houman , Seidlitz Jakob , Bernstock Joshua D. , Wahlund Lars-Olof , Westman Eric , Skoog Ingmar , Virhammar Johan , Fällmar David , Schöll Michael
Published: June 2024

Background

Brain computed tomography (CT) is an accessible and commonly utilized technique for assessing brain structure. In cases of idiopathic normal pressure hydrocephalus (iNPH), the presence of ventriculomegaly is often neuroradiologically evaluated by visual rating and manually measuring each image. Previously, we have developed and tested a deep-learning-model that utilizes transfer learning from magnetic resonance imaging (MRI) for CT-based intracranial tissue segmentation. Accordingly, herein we aimed to enhance the segmentation of ventricular cerebrospinal fluid (VCSF) in brain CT scans and assess the performance of automated brain CT volumetrics in iNPH patient diagnostics.

Methods

The development of the model used a two-stage approach. Initially, a 2D U-Net model was trained to predict VCSF segmentations from CT scans, using paired MR-VCSF labels from healthy controls. This model was subsequently refined by incorporating manually segmented lateral CT-VCSF labels from iNPH patients, building on the features learned from the initial U-Net model. The training dataset included 734 CT datasets from healthy controls paired with T1-weighted MRI scans from the Gothenburg H70 Birth Cohort Studies and 62 CT scans from iNPH patients at Uppsala University Hospital. To validate the model’s performance across diverse patient populations, external clinical images including scans of 11 iNPH patients from the Universitätsmedizin Rostock, Germany, and 30 iNPH patients from the University of Alabama at Birmingham, United States were used. Further, we obtained three CT-based volumetric measures (CTVMs) related to iNPH.

Results

Our analyses demonstrated strong volumetric correlations (ρ=0.91, p<0.001) between automatically and manually derived CT-VCSF measurements in iNPH patients. The CTVMs exhibited high accuracy in differentiating iNPH patients from controls in external clinical datasets with an AUC of 0.97 and in the Uppsala University Hospital datasets with an AUC of 0.99.

Discussion

CTVMs derived through deep learning, show potential for assessing and quantifying morphological features in hydrocephalus. Critically, these measures performed comparably to gold-standard neuroradiology assessments in distinguishing iNPH from healthy controls, even in the presence of intraventricular shunt catheters. Accordingly, such an approach may serve to improve the radiological evaluation of iNPH diagnosis/monitoring (i.e., treatment responses). Since CT is much more widely available than MRI, our results have considerable clinical impact.
The Regular Consumption of a Food Supplement Containing Miraculin Can Contribute to Reducing Biomarkers of Inflammation and Cachexia in Malnourished Patients with Cancer and Taste Disorders: The CLINMIR Pilot Study
Authors: Álvarez-Mercado Ana Isabel , López Plaza Bricia , Plaza-Diaz Julio , Arcos Castellanos Lucía , Ruiz-Ojeda Francisco Javier , Brandimonte-Hernández Marco , Feliú-Batlle Jaime , Hummel Thomas , Palma Milla Samara , Gil Ángel
Published: June 2024

Background

Taste disorders are common in patients with cancer undergoing systemic therapy, persist during treatment and are associated with reduced food intake, increasing the risk of malnutrition. Cachectic syndrome, which is common in these patients and characterized by marked weight loss, anorexia, asthenia and anemia, is linked to the presence and growth of the tumor and leads to systemic inflammation.Synsepalum dulcificumis a plant whose berries contain miraculin, a glycoprotein that transforms sour tastes into sweet ones and could serve to ameliorate taste disorders in patients with cancer.

Objective

To evaluate the effect of the regular intake of Dried Miracle Berries (DMB), a novel food containing miraculin, on several biomarkers of inflammation and cachexia in malnourished patients with cancer and taste disorders receiving systemic antineoplastic therapy.

Materials and methods

Triple-blind, randomized, placebo-controlled clinical trial. Thirty-one patients with cancer of various etiologies receiving chemotherapy were enrolled in a pilot study and divided into three groups. The first group received a tablet containing 150 mg of DMB (standard dose); the high-dose group received a tablet of 300 mg of DMB, and the third group received a tablet with 300 mg of the placebo for three months before each main meal. Plasma levels of several molecules associated with inflammation and cancer cachexia were measured using the X-MAP Luminex multiplexing platform.

Results

The three groups showed a decrease in the plasma levels of IL-6, IL-1β, TNF-α, and PIF throughout the intervention, although the percentage change from baseline was greater in patients receiving a standard dose of DMB. In contrast, the CNTF concentration only decreased in the DMB standard-dose group. This group also presented the greatest reduction in the IL-6/ IL-10 ratio, while IL-15 and IL-10 increased in the groups treated with DMB but not in the placebo. Regardless of DMB consumption, sTNFR-II tended to decrease with treatment in patients who responsed well to the antineoplastic treatment. We did not find significant correlations between cytokines and sensory variables or dietary and nutritional status.

Conclusions

The regular consumption of a standard dose of the food supplement DMB containing miraculin along with a systemic antineoplastic treatment can contribute to reducing biomarkers of inflammation and cachexia in malnourished patients with cancer exhibiting taste disorders.
Epigenetic factors in the 22q11.2 deletion syndrome in relation to stress and schizophrenia
Authors: Jiao Chuan , Demars Fanny , Iftimovici Anton , He Qin , Kebir Oussama , Tripathi Anushree , Turbé Hugo , Demily Caroline , Krebs Marie-Odile , Jay Thérèse M , Chaumette Boris
Published: June 2024

22q11.2 deletion syndrome (22q11.2DS) stands out as one of the most significant risk factors for schizophrenia (SCZ), with approximately 40% of individuals with 22q11.2DS experiencing psychosis. The presence of discordant phenotypes among monozygotic twins, along with the involvement of environmental factors in the multiple-hit model hypothesis for psychosis onset, underscores the potential role of epigenetic modifications in the development of neuropsychiatric disorders among individuals with 22q11.2DS. To gain a deeper understanding of the underlying biological mechanisms, we conducted a translational study using three datasets: a genome-wide methylation dataset from peripheral blood of individuals with 22q11.2DS with or without SCZ, a microRNA expression dataset from the same cohort, and a second genome-wide methylation dataset obtained from a mouse model exploring gene-environment interactions. Human recruitment was carried out at a specialized center focusing on rare psychiatric disorders and included one pair of monozygotic twins discordant for SCZ. In the animal model, DNA extraction was performed from the prefrontal cortex among four groups : wild-type and Df(h22q11)/+ mice, with or without exposure to acute stress. This study identified alterations in DNA methylation and microRNA expression linked to the 22q11.2 deletion as well as SCZ within the context of the deletion in humans. The results were then compared to the effects of the corresponding deletion and stress in the mouse model. Notably, four genes (ZBTB20, SHANK3, GRAMD1B, XKR4) overlapped across all comparisons. Pathway analysis evealed epigenetic differences in the Wnt pathway associated with stress and SCZ within the context of the deletion. These findings support the hypothesis that the onset of SCZ in individuals with 22q11.2DS may be influenced by epigenetic mechanisms, both within and outside the implicated region, under the influence of environmental stressors. If replicated, these findings could be used to develop biomarkers for early diagnosis in del22q11 carriers and to explore new targeted therapeutic strategies.
Stress-mediating Inflammatory Cytokine Profiling Reveals Unique Patterns in Malaria and Typhoid Fever Patients
Authors: Bin Eric MacDonald , Netongo Palmer Masumbe , Kamdem Severin Donald , Christine Nzuno , Maxime Tchoutang Ange , Berenger Tchoupe Kamoua Eric , Buri Bongkiyung Donald , NGum Ngum Leslie , Chedjou Jean Paul , Nji Akindeh Mbu , Mbacham Wilfred Fon
Published: June 2024

Background

Malaria and typhoid fever are known to cause severe morbidity and mortality if miss-treated or left untreated. The oxidant/antioxidant and immune responses to these diseases involve a complex interplay of stress-mediating inflammatory cytokines which orchestrate a coherent response that leads to pathogen clearance and recovery. This study investigated the stress-mediated cytokine profiles in patients attending the Obala District Hospital, Yaoundé, Cameroon and diagnosed with malaria and/or typhoid fever.

Methods

In this cross-sectional observational study, we measured the levels of cortisol and stress-mediating inflammatory cytokines in peripheral blood samples collected from 55 malaria and/or typhoid fever patients, along with a healthy control group (n = 15) using commercial ELISA kits. The psychological stress of the voluntary participants over the past 30 days was assessed using a 10-item Perceived Stress Scale (PSS) questionnaire.

Results

Compared to the control group, patients with co-infection showed significant differences in anemia, thrombocytopenia, and monocytosis. Psychological stress levels were insignificantly higher in patients with typhoid fever (18.20±5.5) compared to control (15.0±2.43), malaria (15.80±4.39), and comorbidity (15.40±5.26) groups. Cortisol levels were significantly (p<0.001) higher in all patient groups compared to the control group, with the typho-malaria group showing a 2.5-fold increase. Cytokine levels were also elevated in patients with malaria and typhoid comorbidity, particularly IL-1β, IL-2, TNF-α, and IFN-γ. While IL-6 concentrations were significantly higher in patients with malaria and typho-malaria comorbidity, IL-10 levels were reduced in the typho-malaria group but still higher than in the control group. The TNF-α/IL-10 ratio was significantly higher in the co-infected group, indicating a more intense inflammatory response. Interestingly, there was a positive correlation between perceived stress scores and IL-2 (r = 0.365, p=0.002), IFN-γ (r = 0.248, p=0.03) and IL-6 (r = 0.412, p=0.0001) in the typho-malaria group. Beside IL-6, no significant correlation was found between stress index and the other anti-inflammatory cytokines IL-4 (r = 0.204, p=0.09) and IL-10 (r = 0.153, p=0.20) in coinfected individuals.

Conclusion

These results suggest that stress response may play a crucial role in shaping the inflammatory landscape during malaria and typhoid fever. Exposed to severe stressors may disrupt immune response and contribute to negative health outcomes. Understanding the immunopathogenesis of these diseases could potentially pave the way for the development of novel therapeutic strategies targeting the stress-cytokine axis.
Ethics in medical research: A quantitative analysis of the observations of Ethics Committees in research protocols
Authors: Vasco-Morales Santiago , Vasco-Toapanta Gabriel Alejandro , Vasco-Toapanta Cristhian Santiago , Toapanta-Pinta Paola
Published: June 2024

Objective

To determine the frequency of observations made by Research Ethics Committees (RECs) regarding non-compliance with ethical principles in research.

Methods

We searched for articles published up to November 30, 2023. In the databases: PubMed, Scopus and Google Scholar. Single-proportion meta-analyses were performed with the R V.3.6.1 program.

PROSPERO Registry

CRD42021291893

Results

9 publications were reviewed, including cross-sectional, retrospective cohort, and descriptive studies. Lack of adherence to the ethical principle of justice was detected in up to 100% of the protocols evaluated. In addition, 9% (95% CI: 7-12) of observations in Latin America and 15% (95% CI: 9-24) in Europe. Autonomy was observed in 26% (95% CI: 20-33) of the protocols, reaching 17% (95% CI: 13-22) in experimental studies. Beneficence, lack of adherence in the protocols evaluated from 41.17% to 77.38%, observations per protocol ranged from 5.26% to 27.11%.

Discussion

The findings highlighted disparities between regions and types of studies, reflecting cultural, interpretive, and human and institutional resource differences. RECs should ensure thorough and equitable assessments, promote fair selection, respect autonomy, and maximize benefits while minimizing risks to participants.

This study provides an assessment of ethical practices in medical research, highlighting key areas for improving compliance with fundamental ethical principles.
RNA interactome of hypervirulentKlebsiella pneumoniaereveals a small RNA inhibitor of capsular mucoviscosity and virulence
Authors: Wu Kejing , Lin Xingyu , Lu Yujie , Dong Rui , Jiang Hongnian , Svensson Sarah L , Zheng Jiajia , Shen Ning , Camilli Andrew , Chao Yanjie
Published: June 2024

HypervirulentKlebsiella pneumoniae(HvKP) is an emerging bacterial pathogen causing invasive infection in immune-competent humans. The hypervirulence is strongly linked to the overproduction of hypermucovisous capsule, but the underlining regulatory mechanism of hypermucoviscosity (HMV) has been elusive, especially at the post-transcriptional level mediated by small noncoding RNAs (sRNAs). Using a recently developed RNA interactome profiling approach, we interrogate the Hfq-associated sRNA regulatory network and establish the intracellular RNA-RNA interactome in HvKP. Our data reveal numerous interactions between sRNAs and HMV-related mRNAs, and identify a plethora of sRNAs that repress or promote HMV. One of the strongest repressors of HMV is ArcZ, which is activated by catabolite regulator CRP and targets many HMV-related genes includingmlaAandfbp. We discover that MlaA and its function in phospholipid transport is crucial for capsule retention and HMV, inactivation of which abolishedKlebsiellavirulence in mice. ArcZ overexpression significantly reduced bacterial burden in mice and reduced HMV in multiple carbapenem-resistant and hypervirulent clinical isolates with diverse genetic background, indicating it is a potent RNA inhibitor of bacterial pneumonia with therapeutic potential. In summary, our work unravels a comprehensive map of the RNA-RNA interaction network of HvKP and identifies a novel CRP-ArcZ-MlaA regulatory circuit of HMV, providing mechanistic insights into the posttranscriptional virulence control in a superbug of global concern.

HIGHLIGHTS

Global RNA-RNA interactome map in hypervirulentKlebsiella pneumoniae

Hfq and multiple small RNAs regulate capsular hypermucoviscosity

ArcZ targetsmlaAthat is required for lipid transport, hypermucoviscosity and virulence

Crp is a transcriptional activator of ArcZ governing a new virulence circuit
Exploring the potential causal effects of myopia: A phenome-wide Mendelian randomization association study
Authors: Hu Di , Jiang Junhong , Zhang Qi , Lin Zenan
Published: June 2024

Myopia is a leading cause of visual impairment worldwide, whose pathogenesis remains poorly understood. We comprehensively performed phenome-wide Mendelian randomization analysis (MR-PheWAS) to explore causal factors and potential therapeutic targets for myopia in participants from the UK Biobank study. The analysis revealed that 55 robust associations (1 disease, 2 employment, 3 cognitive functions, 4 sex-specific factor, 4 mental health, 5 lifestyle and environment, 10 sociodemographic, 12 physical measures and 14 ocular measures/conditions phenotypes) were significantly causally correlated with myopia. The results indicate that myopia may be influenced by several factors, such as serum metabolic traits, fatty acids intake, fat-related indexes, mental health, as well as some previously acknowledged risk factors. Future clinical trials are needed to verify our results.
Questions of flavor physics and neutrino mass from a flipped hypercharge
Authors: Van Loi Duong , Van Dong Phung , Duy N. T. , Thao Nguyen Huy
Published: June 2024

The flavor structure of quarks and leptons is not yet fully understood, but it hints a more fundamental theory of nonuniversal generations. We therefore propose a simple extension of the Standard Model by flipping (i.e., enlarging) the hypercharge U(1)Y to U(1)X⊗U(1)N for which both X and N depend on generations of both quark and lepton. By anomaly cancellation, this extension not only explains the existence of just three fermion generations as observed but also requires the presence of a right-handed neutrino per generation, which motivates seesaw neutrino mass generation. Furthermore, in its minimal version with a scalar doublet and two scalar singlets, the model naturally generates the measured fermion-mixing matrices while it successfully accommodates several flavor anomalies observed in the neutral meson mixings,

B

-meson decays, lepton-flavor-violating processes of charged leptons, as well as satisfying constraints from particle colliders.

Published by the American Physical Society
2024
Entanglement and Bell inequalities with boosted
tt¯
Authors: Dong Zhongtian , Gonçalves Dorival , Kong Kyoungchul , Navarro Alberto
Published: June 2024

The Large Hadron Collider provides a unique opportunity to study quantum entanglement and violation of Bell inequalities at the highest energy available today. In this paper, we will investigate these quantum correlations with top quark pair production, which represents a system of two-qubits. The semileptonic top pair channel has a factor of 6 increase in statistics and easier reconstruction with respect to the dileptonic channel. Although measuring the spin polarization of the hadronic top quark is known to be challenging, our study indicates that it is feasible to reconstruct the spin density matrix of the two-qubit system using an optimal hadronic polarimeter. This is achieved with the aid of jet substructure techniques and NN-inspired reconstruction methods, which improve the mapping between subjets and quarks. We find that entanglement can already be observed at more than the 5σ level with existing data, and violation of Bell inequalities may be probed above the 4σ level at the HL-LHC with 3  ab−1 of data.

Published by the American Physical Society
2024
Axionlike dark matter from the type-II seesaw mechanism
Authors: Chao Wei , Jin Mingjie , Li Hai-Jun , Peng Ying-Quan , Wang Yue
Published: June 2024

Although axionlike particles (ALPs) are popular dark matter candidates, their mass generation mechanisms as well as cosmic thermal evolutions are unclear. In this paper, we propose a new mass generation mechanism of an ALP during the electroweak phase transition in the presence of the type-II seesaw mechanism. In this scenario, the ALP gets mass uniquely at the electroweak scale, so there is a cutoff scale on the ALP oscillation temperature that is irrelevant to the specific mass of the ALP, serving as a distinctive feature of this scenario. Interactions of the ALP have been systematically studied, which shows that the ALP does not couple to diphotons. Instead, it couples to active neutrinos as well as the electron. Therefore, it can be boosted by cosmic rays and can be tested in proposed direct detection experiments with various condensed matter materials as targets.

Published by the American Physical Society
2024
Half the Schwarzschild entropy from Strominger-Vafa black holes
Authors: Heidmann Pierre
Published: June 2024

We construct a regular bound state of two extremal black holes in type IIB supergravity with opposite charges. The bound state resembles the Schwarzschild black hole from the asymptotics to the photon ring and has the same mass and charges as the Schwarzschild black hole. On the one hand, we show that the bound-state entropy admits a microscopic description in terms of branes and antibranes in string theory. On the other hand, we demonstrate that the entropy approaches half of the Schwarzschild entropy as the mass becomes significantly larger than the Kaluza-Klein scales used to regularize the geometry. This opens up the possibility of a brane/antibrane interpretation of the Schwarzschild entropy in string theory.

Published by the American Physical Society
2024
Behavioural intention to adopt mobile wallets at the bottom of the pyramid: a developing economy perspective
Authors: Sodhay Sumit , Kathuria Lalit Mohan , Kaur Tanveen , Kaur Gurpreet
Published: June 2024

Purpose

The study aims to investigate the factors influencing the behavioural intention of bottom-of-the-pyramid (BOP) consumers in developing economies, such as India, to adopt mobile wallets, drawing upon the framework of the uses and gratification theory. Furthermore, the study also examines the moderating effect of gender.

Design/methodology/approach

To achieve the objective, primary data were collected from a sample of 220 respondents using the survey method. The reliability and validity of the survey instrument were demonstrated through confirmatory factor analysis. Subsequently, structural equation modelling (SEM) was used for hypotheses testing.

Findings

The study revealed that only convenience and social influence have a positive significant influence on the behavioural intention to adopt mobile wallets whereas, innovativeness, trust and compatibility have no significant relationship with behavioural intention to adopt mobile wallets among the BOP consumers. Further, gender moderates the relationship between compatibility and behavioural intention to adopt mobile wallets in India.

Originality/value

This study contributes to the underexplored area of research concerning the behavioural intention to adopt mobile wallets among BOP consumers in a developing economy. It introduces a novel approach by using the uses and gratifications theory to uncover the underlying motivations behind adoption behaviour.