Miracle-dz/UniFAR-FTUs huggingface dataset:
Cullin-5 Adaptor SPSB1 Controls NF-κB Activation Downstream of Multiple Signaling Pathways

Cullin-RING E3 ubiquitin ligases (CRLs) have emerged as critical regulators of many cellular functions including innate immunity and inflammation. CRLs form multiprotein complexes in which specific adaptor proteins recruit the substrates to be ubiquitylated. Here, we systematically depleted all predicted SOCS-box proteins – the substrate adaptors for the CRL5 family - and assessed the impact on the activation of the NF-κB pathway. Depletion of SPSB1 resulted in a significant increase in NF-κB activation, indicating the importance of SPSB1 as an NF-κB negative regulator. In agreement, overexpression of SPSB1 suppressed NF-κB activity in a potent, dose-dependent manner in response to various agonists. Conversely, the activation of IRF-3, AP-1 and STATs was unaffected by SPSB1, showing its specificity for NF-κB. Mechanistically, SPSB1 suppressed NF-κB activation induced via multiple pathways including Toll-like receptors and RNA and DNA sensing adaptors, but was unable to prevent the phosphorylation and degradation of IκB nor the translocation of p65 into the nucleus. This indicated that SPSB1 exerts its inhibitory activity downstream, or at the level, of the NF-κB heterodimer and in agreement, SPSB1 was found to co-precipitate with p65. Additionally, A549 cells stably expressing SPSB1 presented lower cytokine levels including type I interferon in response to cytokine stimulation and virus infection. Taken together, our results reveal novel regulatory mechanisms in inflammation and innate immune signalling and identify the prominent role of SPSB1 in controlling NF-κB activation, thus providing new opportunities for the therapeutic targeting of NF-κB transcriptional activity.
Top-Down and Bottom-Up Controls on Microeukaryotic Diversity (i.e., Amplicon Analyses of SAR Lineages) and Function (i.e., Metatranscriptome Analyses) Assessed in Microcosm Experiments

The availability of high-throughput sequencing (HTS) has transformed our understanding of the diversity of microbial eukaryotes (i.e., protists) across diverse habitats. Yet relating this biodiversity to function remains a challenge, particularly in the context of microbial food webs. Here we perform a set of microcosm experiments to evaluate the impact of changing predator and prey concentrations on a marine protist community, focusing on SAR (Stramenopila, Alveolata, and Rhizaria) lineages. We combine an estimate of taxonomic diversity through analysis of SSU-rDNA amplicons with metatranscriptomics, a proxy for function. We assess changes in a community sampled from New England waters with varying concentrations of predators (copepods) and prey (phytoplankton <15 μm in size). The greatest impact observed is on the diversity and function of the small plankton (2–10 μm, nanoplankton) community in the presence of high prey abundance (i.e., bloom conditions). Many SAR taxa in the nanosized fraction decrease with increasing phytoplankton abundance, while ciliates (from both the nano- and microsized fractions) increase. A large number of transcripts and function estimates in the nanoplankton decreased during our simulated phytoplankton bloom. We also find evidence of an interaction between increasing phytoplankton and copepod abundances on the microsized planktonic community, consistent with the hypothesis that phytoplankton and copepods exert bottom-up control and top-down control on the microsized protists, respectively. Together our analyses suggest that community function [i.e., diversity of gene families (GFs)] remains relatively stable, while the functions at the species level (i.e., transcript diversity within GFs) show a substantial reduction of function under bloom conditions. Our study demonstrated that interactions within plankton food webs are complex, and that the relationships between diversity and function for marine microeukaryotes remain poorly understood.
Assessment of Spoilage Bacterial Communities in Food Wrap and Modified Atmospheres-Packed Minced Pork Meat Samples by 16S rDNA Metagenetic Analysis

Although several studies have focused on the dynamics of bacterial food community, little is known about the variability of batch production and microbial changes that occur during storage. The aim of the study was to characterize the microbial spoilage community of minced pork meat samples, among different food production and storage, using both 16S rRNA gene sequencing and classical microbiology. Three batches of samples were obtained from four local Belgian facilities (A–D) and stored until shelf life under food wrap (FW) and modified atmosphere packaging (MAP, CO2 30%/O2 70%), at constant and dynamic temperature. Analysis of 288 samples were performed by 16S rRNA gene sequencing in combination with counts of psychrotrophic and lactic acid bacteria at 22°C. At the first day of storage, different psychrotrophic counts were observed between the four food companies (Kruskal-Wallist test, p-value < 0.05). Results shown that lowest microbial counts were observed at the first day for industries D and A (4.2 ± 0.4 and 5.6 ± 0.1 log CFU/g, respectively), whereas industries B and C showed the highest results (7.5 ± 0.4 and 7.2 ± 0.4 log CFU/g). At the end of the shelf life, psychrotrophic counts for all food companies was over 7.0 log CFU/g. With metagenetics, 48 OTUs were assigned. At the first day, the genus Photobacterium (86.7 and 19.9% for food industries A and C, respectively) and Pseudomonas (38.7 and 25.7% for food companies B and D, respectively) were dominant. During the storage, a total of 12 dominant genera (>5% in relative abundance) were identified in MAP and 7 in FW. Pseudomonas was more present in FW and this genus was potentially replaced by Brochothrix in MAP (two-sided Welch’s t-test, p-value < 0.05). Also, a high Bray-Curtis dissimilarity in genus relative abundance was observed between food companies and batches. Although the bacteria consistently dominated the microbiota in our samples are known, results indicated that bacterial diversity needs to be addressed on the level of food companies, batches variation and food storage conditions. Present data illustrate that the combined approach provides complementary results on microbial dynamics in minced pork meat samples, considering batches and packaging variations.
Association Between Dietary Patterns and Fluorosis in Guizhou, China

Objective: Many studies have explored the effects of individual foods or nutrients on fluorosis, but no studies have focused on dietary patterns. This study examined the relationship between dietary patterns and coal-burning fluorosis in Guizhou, China. Methods: This 1:1 matched case-control study was conducted in Zhijin County of Guizhou province with a sample size of 200 cases of fluorosis and 200 age and gender matched controls. Habitual dietary intake was assessed by face-to-face interviews, using a validated 75-item food frequency questionnaire (FFQ) and various covariates using structured questionnaires. The dietary patterns were identified by factor analysis. Results: The factor analysis identified three major dietary patterns which were labeled healthy, easy-to-roast and high protein. After adjusting for various confounding factors, a decreased risk for fluorosis was observed in the highest tertile of the healthy dietary pattern relative to the lowest tertile (OR = 0.47, 95% CI = 0.27–0.84, P-trend = 0.003) and a positive association was observed between the easy-to-roast dietary pattern and fluorosis risk (OR = 2.05, 95% CI = 1.15–3.66), with a significant linear trend (P = 0.017). We did not find an association between fluorosis risk and the high protein dietary pattern. The relationships remained significant when the analyses were stratified by gender and fluorosis subtypes. Conclusion: The healthy dietary pattern may lower coal-burning fluorosis risk; in contrast, the easy-to-roast dietary pattern significantly increases the risk of coal-burning fluorosis.
Ovarian Cancer Targeted Theranostics

Ovarian cancer is a leading cause of death from gynecological malignancies. Although the prognosis is quite favorable if detected at an early stage, the vast majority of cases are diagnosed at an advanced stage, when 5-year survival rates are only 30–40%. Most recurrent ovarian tumors are resistant to traditional therapies underscoring the need for new therapeutic options. Theranostic agents, that combine diagnostic and therapeutic capabilities, are being explored to better detect, diagnose and treat ovarian cancer. To minimize morbidity, improve survival rates, and eventually cure patients, new strategies are needed for early detection and for delivering specifically anticancer therapies to tumor sites. In this review we will discuss various molecular imaging modalities and targets that can be used for imaging, therapeutic and theranostic agent development for improved diagnosis and treatment of ovarian cancer.
Abnormal Pyramidal Decussation and Bilateral Projection of the Corticospinal Tract Axons in Mice Lacking the Heparan Sulfate Endosulfatases, Sulf1 and Sulf2

The corticospinal tract (CST) plays an important role in controlling voluntary movement. Because the CST has a long trajectory throughout the brain toward the spinal cord, many axon guidance molecules are required to navigate the axons correctly during development. Previously, we found that double-knockout (DKO) mouse embryos lacking the heparan sulfate endosulfatases, Sulf1 and Sulf2, showed axon guidance defects of the CST owing to the abnormal accumulation of Slit2 protein on the brain surface. However, postnatal development of the CST, especially the pyramidal decussation and spinal cord projection, could not be assessed because DKO mice on a C57BL/6 background died soon after birth. We recently found that Sulf1/2 DKO mice on a mixed C57BL/6 and CD-1/ICR background can survive into adulthood and therefore investigated the anatomy and function of the CST in the adult DKO mice. In Sulf1/2 DKO mice, abnormal dorsal deviation of the CST fibers on the midbrain surface persisted after maturation of the CST. At the pyramidal decussation, some CST fibers located near the midline crossed the midline, whereas others located more laterally extended ipsilaterally. In the spinal cord, the crossed CST fibers descended in the dorsal funiculus on the contralateral side and entered the contralateral gray matter normally, whereas the uncrossed fibers descended in the lateral funiculus on the ipsilateral side and entered the ipsilateral gray matter. As a result, the CST fibers that originated from 1 side of the brain projected bilaterally in the DKO spinal cord. Consistently, microstimulation of 1 side of the motor cortex evoked electromyogram responses only in the contralateral forelimb muscles of the wild-type mice, whereas the same stimulation evoked bilateral responses in the DKO mice. The functional consequences of the CST defects in the Sulf1/2 DKO mice were examined using the grid-walking, staircase, and single pellet-reaching tests, which have been used to evaluate motor function in mice. Compared with the wild-type mice, the Sulf1/2 DKO mice showed impaired performance in these tests, indicating deficits in motor function. These findings suggest that disruption of Sulf1/2 genes leads to both anatomical and functional defects of the CST.
Central Neuropathic Pain and Profiles of Quantitative Electroencephalography in Multiple Sclerosis Patients

Pain has a significant impact on the quality of life of patients with multiple sclerosis (MS). However, the neurophysiological mechanisms of central neuropathic pain in a MS course are not known. We hypothesized that changes in power spectral density (PSD) that take place in the electroencephalography (EEG) of MS patients with and without the central neuropathic pain (CNP) would differ. The study aimed to assess the features of quantitative EEG using the PSD indicator along with peak frequencies in the standard frequency bands in MS patients with and without CNP. We have analyzed the quantitative spectral content of the EEG at a resting state in 12 MS patients with CNP, 12 MS patients without CNP, and 12 gender- and age-matched healthy controls using fast Fourier transformation. Based on the ANOVA, at the group level, the theta band absolute and relative PSD showed an increase, whereas alpha band relative PSD showed a decrease in MS patients both with and without CNP. However, only in MS with CNP group, the absolute and relative PSD in the beta1 and beta2 bands increased and exceeded that in patients without pain. Only MS patients with CNP demonstrated the significantly increased absolute PSD for the theta, beta1, and beta2 frequency bands in most regions of interest. In the theta band, MS patients with CNP displayed the increase in absolute spectral power for the mid-temporal derivation of the right hemisphere and the increase in relative spectral power for the prefrontal derivation of this hemisphere. In the beta1 band, the increase in absolute spectral power was observed for the three temporal derivations of the right hemisphere, whereas in the beta2 band, for the occipital, parietal, and temporal lobes of both hemispheres. In the alpha band, only a relative spectral power decrease was revealed for the occipital lobes of both hemispheres and parietal lobe of the right hemisphere. In MS patients with CNP, the frequencies of the dominant spectral power (peak frequencies) in the high-frequency beta band were higher than in the healthy control in posterior areas of the left hemisphere. Data could represent central nervous system alterations related to central neuropathic pain in MS patients that lead to the disturbances in cortical communication.
Plasma and Serum Alpha-Synuclein as a Biomarker of Diagnosis in Patients With Parkinson's Disease

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, and α-synuclein plays a critical role in the pathogenesis of PD. Studies have revealed controversial results regarding the correlation between motor severity and α-synuclein levels in peripheral blood from patients with PD. Objective: We examined α-synuclein levels in plasma or serum in patients with PD and investigated the relationship between plasma or serum α-synuclein level and motor symptom severity. Methods: We recruited 88 participants (48 patients with PD and 40 healthy controls). Clinical information was collected, and venous blood was drawn from each participant to be processed to obtain plasma or serum. The plasma or serum α-synuclein level was detected using monoclonal antibodies with magnetic nanoparticles, and was measured through immunomagnetic reduction. Plasma or serum α-synuclein levels were quantitatively detected. Results: In patients with PD, the means of plasma and serum α-synuclein level were 3.60 ± 2.53 and 0.03 ± 0.04 pg/mL, respectively. The areas under the receiver operating characteristic curve of plasma and serum α-synuclein for distinguishing patients with PD from healthy controls were 0.992 and 0.917, respectively. The serum α-synuclein level also showed a significant correlation with patients in H-Y stages 1–3 (r = 0.40, p = 0.025), implying that the serum α-synuclein level may be a potential marker of motor symptom severity in patients with early PD. Conclusions: Our data suggest that the α-synuclein level in serum or plasma can differentiate between healthy controls and patients with PD. Serum α-synuclein levels moderately correlate with motor severity in patients with early PD.
BIGDOSE: software for 3D personalized targeted radionuclide therapy dosimetry.

Background Advance 3D quantitative radionuclide imaging techniques boost the accuracy of targeted radionuclide therapy (TRT) dosimetry to voxel level. The goal of this work is to develop a comprehensive 3D dosimetric software, BIGDOSE, with new features of image registration and virtual CT for patient-specific dosimetry. Methods BIGDOSE includes a portable graphical user interface written in Python, integrating (I) input of sequential ECT/CT images; (II) segmentation; (III) non-rigid image registration; (IV) curve fitting and voxel-based integration; (V) dose conversion and (VI) 3D dose analysis. The accuracy of the software was evaluated using a simulation study with 9 XCAT phantoms. We simulated SPECT/CT acquisitions at 1, 12, 24, 72 and 144-hrs post In-111 Zevalin injection with inter-scans misalignments using an analytical projector for medium energy general purpose (MEGP) collimator, modeling attenuation, scatter and collimator-detector response. The SPECT data were reconstructed using quantitative OS-EM method. A CT organ-based registration was performed before the dose calculation. Organ absorbed doses for the corresponding Y-90 therapeutic agent were calculated on target organs and compared with those obtained from OLINDA/EXM, using dose measured from GATE as the gold standard. One patient with In-111 DTPAOC injection as well as two patients with Y-90 microsphere embolization were used to demonstrate the clinical effectiveness of our software. Results In the simulation, the organ dose errors of BIGDOSE were -9.59%±9.06%, -8.36±5.82%, -23.41%±6.67%, -6.05%±2.06% for liver, spleen, kidneys and lungs, while they were -25.72%±12.52%, -14.93%±10.91%, -28.63%±12.97% and -45.30%±5.84% for OLINDA/EXM. Cumulative dose volume histograms, dose maps and iso-dose contours provided 3D dose distribution information on the simulated and patient data. Conclusions BIGDOSE provides a one-stop platform for voxel-based dose estimation with enhanced functions. It is a promising tool to streamline the current clinical TRT dosimetric practice with high accuracy, incorporating 3D personalized imaging information for improved treatment outcome.
Fetal heart rate monitoring practices at a public hospital in Northern Uganda – what health workers document, do and say

ABSTRACT Background: In Uganda, perinatal mortality is 38 per 1000 pregnancies. One-third of these deaths are due to birth asphyxia. Adequate fetal heart rate (FHR) monitoring during labor may detect birth asphyxia but little is known about monitoring practices in low resource settings. Objective: To explore FHR monitoring practices among health workers at a public hospital in Northern Uganda. Methods: A sequential explanatory mixed methods study was conducted by reviewing 251 maternal records and conducting 11 interviews and two focus group discussions with health workers complemented by observations of 42 women in labor until delivery. Quantitative data were summarized using frequencies and percentages. Content analysis was used for qualitative data. Results: FHR was assessed in 235/251 (93.6%) of records at admission. Health workers documented the FHR at least once in 175/228 (76.8%) of cases during the first stage of labor compared to observed 17/25 (68.0%) cases. Median intervals between FHR monitoring were 30 (IQR 30–120) minutes in patients’ records versus 139 (IQR 87–662) minutes according to observations. Observations suggested no monitoring of FHR during the second stage of labor but records indicated monitoring in 3.2% of cases. Reported barriers to adequate FHR monitoring were inadequate number of staff and monitoring devices, institutional challenges such as few beds, documentation problems and perceived non-compliant women not reporting for repeated checks during the first stage of labor. Health workers demonstrated knowledge of national FHR monitoring guidelines and acknowledged that practice was different. Conclusions: When compared to national and international guidelines, FHR monitoring is sub-optimal in the studied setting. Approximately one in four women was not monitored during the first stage of labor. Barriers to appropriate FHR monitoring included shortage of staff and devices, institutional challenges and mother’s negative attitudes. These barriers need to be addressed in order to reduce neonatal mortality.
Paramedic Global Impression of Change During Prehospital Evaluation and Transport for Acute Stroke

Background and Purpose— The prehospital setting is a promising site for therapeutic intervention in stroke, but current stroke screening tools do not account for the evolution of neurological symptoms in this early period. We developed and validated the Paramedic Global Impression of Change (PGIC) Scale in a large, prospective, randomized trial. Methods— In the prehospital FAST-MAG (Field Administration of Stroke Therapy-Magnesium) randomized trial conducted from 2005 to 2013, EMS providers were asked to complete the PGIC Scale (5-point Likert scale values: 1-much improved, 2-mildly improved, 3-unchanged, 4-mildly worsened, 5-much worsened) for neurological symptom change during transport for consecutive patients transported by ambulance within 2 hours of onset. We analyzed PGIC concurrent validity (compared with change in Glasgow Coma Scale, Los Angeles Motor Scale), convergent validity (compared with National Institutes of Health Stroke Scale severity measure performed in the emergency department), and predictive validity (of neurological deterioration after hospital arrival and of final 90-day functional outcome). We used PGIC to characterize differential prehospital course among stroke subtypes. Results— Paramedics completed the PGIC in 1691 of 1700 subjects (99.5%), among whom 635 (37.5%) had neurological deficit evolution (32% improvement, 5.5% worsening) during a median prehospital care period of 33 (IQR, 27–39) minutes. Improvement was associated with diagnosis of cerebral ischemia rather than intracranial hemorrhage, milder stroke deficits on emergency department arrival, and more frequent nondisabled and independent 3-month outcomes. Conversely, worsening on the PGIC was associated with intracranial hemorrhage, more severe neurological deficits on emergency department arrival, more frequent treatment with thrombolytic therapy, and poor disability outcome at 3 months. Conclusions— The PGIC scale is a simple, validated measure of prehospital patient course that has the potential to provide information useful to emergency department decision-making. Registration— URL: https://www.clinicaltrials. gov. Unique identifier: NCT00059332.
Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3

Abstract Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINC02657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors. LASTR is upregulated in several types of epithelial cancers due to the activation of the stress-induced JNK/c-JUN pathway. Using a mass-spectrometry based approach, we identified the RNA-splicing factor SART3 as a LASTR-interacting partner. We found that LASTR promotes splicing efficiency by controlling SART3 association with the U4 and U6 small nuclear ribonucleoproteins (snRNP) during spliceosome recycling. Intron retention induced by LASTR depletion downregulates expression of essential genes, ultimately decreasing the fitness of cancer cells.