Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular biomarkers in the neurological ICU: is there a role?

PURPOSE OF REVIEW The aim of the article is to summarize recent advances in the field of molecular biomarkers in neurocritical care. RECENT FINDINGS Advances in ultrasensitive immunoassay technology have made it possible to measure brain-derived proteins that are present at subfemtomolar concentrations in blood. These assays have made it possible to measure neurofilament light chain (NfL) in serum or plasma, and early studies indicate that NfL is a promising prognostic and pharmacodynamic biomarker across a broad range of neurologic disorders, including cardiac arrest and traumatic brain injury. However, as acquired brain injury is a complex and heterogeneous disorder, it is likely that assays of panels of biomarkers will ultimately be needed to maximally impact practice. Micro-RNAs are a novel but exciting class of molecules that also show potential to provide clinically actionable information. SUMMARY Although not yet ready for adoption into routine clinical practice, several molecular biomarkers are on the cusp of clinical validation. The availability of such tests likely will revolutionize the practice of neurocritical care.
Chlamydia trachomatis is associated with medically indicated preterm birth and preeclampsia in young pregnant women.

BACKGROUND Studies on Chlamydia trachomatis associated pregnancy outcomes are largely conflicting, ignoring the heterogeneous natures of pregnancy complications and potential effect modification by maternal age. This study determined if prenatal Chlamydia trachomatis infection is associated with preterm birth (PTB) and preeclampsia subtypes. METHODS A retrospective cohort study was conducted using 22,772 singleton pregnancies with a prenatal C. trachomatis diagnostic test. Spontaneous and medically indicated preterm births, term and preterm preeclampsia were outcomes. Modified Poisson regression calculated relative risk (RR) and 95% confidence intervals (CI) with propensity score adjustments stratified by maternal age <25 and ≥25. RESULTS Overall, C. trachomatis was significantly associated with term preeclampsia (RRadj=1.88 95% CI 1.38-2.57). Among young women (age<25), C. trachomatis was significantly associated with medically indicated preterm birth (RRadj=2.29 CI 95% 1.38-3.78) and term preeclampsia (RRadj=1.57 CI 95% 1.05-2.36) in propensity adjusted models. No significant associations in older women were detected. CONCLUSION C. trachomatis was associated with medically indicated preterm birth and term preeclampsia in young women. Associations between chlamydia and perinatal outcomes may depend on the subtype of preterm birth and preeclampsia, which should be investigated through mechanistic studies.
CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression.

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The extensively validated 30% of positive CLL cells cut-off value is able to separate CLL patients into two subgroups with different prognosis, but it does not consider the pattern of CD49d expression. In the present study, we analysed a cohort of 1,630 CLL samples and identified the presence of ~20% of CLL cases (n=313) characterized by a bimodal expression of CD49d, i.e. concomitant presence of a CD49dpos sub-population and a CD49dneg sub-population. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49dpos sub-population over time after therapy. The CD49dpos sub-population from CD49d bimodal CLL displayed higher levels of proliferation compared to the CD49dneg cells, was more highly represented in the bone marrow compared to peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49dpos sub-population exceeded or not the 30% cut-off, experienced a clinical behavior similar to CD49dpos CLL, both in the chemo-immunotherapy (n=1,522) and in the ibrutinib (n=158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should be also considered to improve the prognostic impact of this biomarker in CLL.
Physical Principles Underlying the Complex Biology of Intracellular Phase Transitions.

Many biomolecular condensates appear to form via spontaneous or driven processes that have the hallmarks of intracellular phase transitions. This suggests that a common underlying physical framework might govern the formation of functionally and compositionally unrelated biomolecular condensates. In this review, we summarize recent work that leverages a stickers-and-spacers framework adapted from the field of associative polymers for understanding how multivalent protein and RNA molecules drive phase transitions that give rise to biomolecular condensates. We discuss how the valence of stickers impacts the driving forces for condensate formation and elaborate on how stickers can be distinguished from spacers in different contexts. We touch on the impact of sticker- and spacer-mediated interactions on the rheological properties of condensates and show how the model can be mapped to known drivers of different types of biomolecular condensates. Expected final online publication date for the Annual Review of Biophysics, Volume 49 is May 6, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Opioid-free and opioid-sparing anesthesia

In light of the current opioid crisis, there has been a movement to reduce opioid use in the perioperative period. Opioid-free anesthesia (OFA) is a practice that completely excludes the use of intraoperative systemic, neuraxial, or intracavitary opioids. A related but less restrictive technique is opioid-sparing anesthesia, where small amounts of opioids are used intraoperatively. Both opioid-free and opioid-sparing techniques have shown particular value in certain patient populations. Patients with obstructive sleep apnea and those undergoing bariatric surgery are at high risk for opioid-related respiratory complications in the postoperative period. Patients suffering from chronic postsurgical pain, complex regional pain syndrome, cancer-related pain, and other opioid-tolerant patients may also benefit from opioid-free and opioid-sparing anesthetic approaches.
Elemental bioimaging shows mercury and other toxic metals in normal breast tissue and in breast cancers

Objective Exposure to toxic metals such as mercury has been proposed to be a risk factor for the development of breast cancer since some metals can promote genetic mutations and epigenetic changes. We sought to find what toxic metals are present in normal breast tissue and in the tumours of women who had mastectomies for invasive ductal breast carcinoma. Materials and methods Formalin-fixed paraffin-embedded blocks from mastectomies for breast carcinoma were examined from 50 women aged 34–69 years. Paraffin blocks selected for elemental analysis were from breast tissue not involved by carcinoma and from the carcinoma itself. Seven micrometer-thick sections were stained with autometallography to demonstrate the presence of mercury, and subjected to laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to confirm the presence of mercury and to detect other toxic metals. Results Autometallography-detected mercury was seen in intraductal secretions and some luminal epithelial cells of normal breast lobules in 26 (55%) of the 47 samples where lobules were present, and in 10 (23%) of carcinomas from the 44 samples where carcinoma was present. In eight samples ductal carcinoma in situ was present and one of these contained mercury. LA-ICP-MS confirmed the presence of mercury in samples that stained with autometallography, and detected lead, iron, nickel, aluminium, chromium and cadmium in some samples. Conclusions Mercury was present in normal breast lobules in more than half of mastectomy samples that contained an invasive carcinoma, and in a smaller proportion of carcinomas and ductal carcinomas in situ. Other toxic metals that may interact synergistically with mercury could be detected in some samples. These findings do not provide direct evidence that toxic metals such as mercury play a role in the pathogenesis of breast cancer, but suggest that future molecular biological investigations on the role of toxic metals in breast cancer are warranted.
An untargeted metabolomics study of blood pressure: findings from the Bogalusa Heart Study.

OBJECTIVE To identify novel and confirm previously reported metabolites associated with SBP, DBP, and hypertension in a biracial sample of Bogalusa Heart Study (BHS) participants. METHODS We employed untargeted, ultra-high performance liquid chromatography tandem mass spectroscopy metabolomics profiling among 1249 BHS participants (427 African-Americans and 822 whites) with BP and covariable data collected during the 2013 to 2016 visit cycle. A total of 1202 metabolites were tested for associations with continuous and binary BP phenotypes using multiple linear and logistic regression models, respectively, in overall and race-stratified analyses. RESULTS A total of 24 novel metabolites robustly associated with BP, achieving Bonferroni-corrected P less than 4.16 × 10 in the overall analysis and consistent effect sizes across race groups. The identified metabolites included three amino acid and nucleotide metabolites from histidine, pyrimidine, or tryptophan metabolism sub-pathways, seven cofactor and vitamin or xenobiotic metabolites from the ascorbate and aldarate metabolism, bacterial/fungal, chemical, and food component sub-pathways, 10 lipid metabolites from the eicosanoid, phosphatidylcholine, phosphatidylethanolamine, and sphingolipid metabolism sub-pathways, and four still unnamed metabolites. Six previously described metabolites were robustly confirmed by our study (Bonferroni-corrected P < 4.95 × 10 and consistent effect directions across studies). Furthermore, previously reported metabolites for SBP, DBP, and hypertension demonstrated 5.92-fold, 4.77-fold, and 4.54-fold enrichment for nominally significant signals in the BHS (P = 3.08 × 10, 5.93 × 10, and 2.30 × 10, respectively). CONCLUSION In aggregate, our study provides new information about potential molecular mechanisms underlying BP regulation. We also demonstrate reproducibility of findings across studies despite differences in study populations and metabolite profiling methods.
Distinctive and common features of moderate aplastic anaemia

The therapy algorithm for severe aplastic anaemia (sAA) is established but moderate AA (mAA), which likely reflects a more diverse pathogenic mechanism, often represents a treatment/management conundrum. A cohort of AA patients (n = 325) was queried for those with non‐severe disease using stringent criteria including bone marrow hypocellularity and chronic persistence of moderately depressed blood counts. As a result, we have identified and analyzed pathological and clinical features in 85 mAA patients. Progression to sAA and direct clonal evolution (paroxysmal nocturnal haemoglobinuria/acute myeloid leukaemia; PNH/AML) occurred in 16%, 11% and 1% of mAA cases respectively. Of the mAA patients who received immunosuppressive therapy, 67% responded irrespective of time of initiation of therapy while conservatively managed patients showed no spontaneous remissions. Genomic analysis of mAA identified evidence of clonal haematopoiesis with both persisting and remitting patterns at low allelic frequencies; with more pronounced mutational burden in sAA. Most of the mAA patients have autoimmune pathogenesis similar to those with sAA, but mAA contains a mix of patients with diverse aetiologies. Although progression rates differed between mAA and sAA (P = 0·003), cumulative incidences of mortalities were only marginally different (P = 0·095). Our results provide guidance for diagnosis/management of mAA, a condition for which no current standard of care is established.
Tobacco Smoking in People Is Not Associated with Altered 18-kDa Translocator Protein Levels: A PET Study

The effects of tobacco smoking on the immune system of the brain are not well elucidated. Although nicotine is immunosuppressive, other constituents in tobacco smoke have inflammatory effects. PET imaging of the 18-kDa translocator protein (TSPO) provides a biomarker for microglia, the primary immunocompetent cells of the brain. This work compared brain TSPO levels in 20 tobacco smokers (abstinent for at least 2 h) and 20 nonsmokers using a fully quantitative modeling approach for the first time, to our knowledge. Methods: 11C-PBR28 (N-((2-(methoxy-11C)-phenyl)methyl)-N-(6-phenoxy-3-pyridinyl)acetamide) PET scans were acquired with arterial blood sampling to estimate the metabolite-corrected input function. 11C-PBR28 volumes of distribution were estimated throughout the brain with multilinear analysis. Results: Statistical analyses revealed no evidence of significant differences in regional 11C-PBR28 volumes of distribution between smokers and nonsmokers (whole-brain Cohen d = 0.09) despite adequate power to detect medium effect sizes. Conclusion: These findings inform previous PET studies reporting lower TSPO radiotracer concentrations in the brain (measured as SUV) for tobacco smokers than for nonsmokers by demonstrating the importance of accounting for radiotracer concentrations in plasma. These findings suggest that nonsmokers and smokers have comparable TSPO levels in the brain. Additional work with other biomarkers is needed to fully characterize the effects of tobacco smoking on the brain immune system.
Gender differences in related influential factors of regular exercise behavior among people in Taiwan in 2007: A cross-sectional study

Purpose The purpose was to explore the exercise behavior of the Taiwanese population during leisure time and to examine the gender differences in related influential factors. Methods The Leisure Time and Sport Questionnaire (LTSQ) conducted by the Academia Sinica in 2007 was used for analysis. Participants were drawn from the Taiwanese population aged over 18 years old. Multinomial logistic regression models were used to test the association between the frequency of exercise and related factors in all the participants, male, and female participants, respectively. Results In the total 2,147 participants, 47.8% reported they regularly exercised, 34.1% irregularly exercised, and 18.1% never exercised. There were no significant gender differences in the frequency of exercise, but a significant gender difference was found in the types of exercise most often practiced. Participants in one of following conditions, over 65 and under 40 years old, living in the city, having higher education levels, having a spouse or partner, enjoying exercise, feeling worthwhile to spend money on exercise, and not having to take care of others, were more likely to be engaged in regular exercise in the total population. The “enjoyment” in exercise was a significant influential factor for both sexes. Women were more likely to exercise regularly if they were aged 40–64 years old compared with those over 65 years old, have lower self-rated health scores, felt it was more worthwhile to spend money on exercise and did not have to care for another, whereas men who have higher education level and did not feel a lack of time were more likely to exercise regularly. Conclusions There are gender differences in regular exercise behavior during leisure time and related influential factors among Taiwanese adults. The findings of the present study can be used when designing gender-specific health promotion programs.
Treatment options for glucocorticoid-induced osteoporosis

ABSTRACT Introduction Glucocorticoid (GC) induced osteoporosis (GIOP) is the most common form of secondary osteoporosis. It develops in a dose and time dependent manner, due to a rapid and transient increase in bone resorption, followed by the inhibition of bone formation. Areas covered In this review, the authors summarize the pathophysiology of GIOP and give discussion to the clinical management of patients taking GCs, focusing on the currently available drugs that have antiresorptive or anabolic activity on bone. Expert opinion Despite the widespread use of GCs and their well-established detrimental skeletal effects, GIOP remains an under-diagnosed and under-treated condition. Indeed, the clinical management of GIOP is still debated, so that the recent guidelines differ in their indications for pharmacological intervention. Either bone mineral density (BMD) or algorithms such as FRAX do not completely account for the remarkable and rapid increase in fracture risk of most GC-treated patients. Moreover, while oral bisphosphonates remain the most used and cost-effective option, the potential increased benefits of more potent antiresorptive agents (e.g. denosumab and zoledronate) or anabolic compounds (e.g. teriparatide) warrant further investigation. Despite the above limitations, the assessment of fracture risk is recommended for all individuals committed to receiving oral GCs for 3 months or longer.
Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next.

Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease's phenotype-genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively. This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Effects of magnesium isoglycyrrhizinate on immunological liver damage induced by D-galactosamine and Freund's complete adjuvant in mice

Objective:To investigate the effects of magnesium isoglycyrrhizinate(MgIG) on immunological liver damage induced by D-galactosamine(D-Gal) and Freund's complete adjuvant(FCA) in mice.Methods: The immunological liver damage of C57L/6J mice was induced by intraperitoneal injection of D-Gal 1 500 mg·kg-1 and subcutaneous injection of FCA 5 mL·kg-1 simultaneously,once a week for 13 weeks.Two hours after injection of D-Gal/FCA,mice were treated with intraperitoneal injections of MgIG(50,100,200 mg·kg-1),respectively,once daily for 13 weeks.Then,mice were sacrificed.The blood sample was obtained for biochemical test and NO assay;the liver tissue was isolated for pathological examination;the spleen weight was measured.Results: MgIG dose-dependently inhibited the increased aminotransferase activity,decreased plasma NO level,attenuated liver injure,and reduced death rate after D-Gal/FCA-induced liver damage in mice.Conclusion: MgIG is effective in treating immunological liver damage induced by D-Gal/FCA in mice.
Selective targeting of nanomedicine to inflamed cerebral vasculature to enhance the blood–brain barrier

Significance Drug delivery to the brain is a challenging and elusive goal. Conjugating with ligands of target molecules including transferrin receptor modestly enhances cerebral accumulation of drugs and drug carriers. We found that conjugating with ligands of VCAM-1 provides order(s) of magnitude higher cerebral accumulation of nanocarriers, especially in the inflamed brain. VCAM-1 targeted nanocarriers loaded with messenger RNA encoding endothelial glycoprotein thrombomodulin cause expression of the transgene in the lumen of cerebral vasculature. This alleviates pathological permeability of the blood–brain barrier in mouse model of neurovascular inflammation. These results provide a basis for precise and effective molecular interventions in the cerebral vasculature. Drug targeting to inflammatory brain pathologies such as stroke and traumatic brain injury remains an elusive goal. Using a mouse model of acute brain inflammation induced by local tumor necrosis factor alpha (TNFα), we found that uptake of intravenously injected antibody to vascular cell adhesion molecule 1 (anti-VCAM) in the inflamed brain is >10-fold greater than antibodies to transferrin receptor-1 and intercellular adhesion molecule 1 (TfR-1 and ICAM-1). Furthermore, uptake of anti-VCAM/liposomes exceeded that of anti-TfR and anti-ICAM counterparts by ∼27- and ∼8-fold, respectively, achieving brain/blood ratio >300-fold higher than that of immunoglobulin G/liposomes. Single-photon emission computed tomography imaging affirmed specific anti-VCAM/liposome targeting to inflamed brain in mice. Intravital microscopy via cranial window and flow cytometry showed that in the inflamed brain anti-VCAM/liposomes bind to endothelium, not to leukocytes. Anti-VCAM/LNP selectively accumulated in the inflamed brain, providing de novo expression of proteins encoded by cargo messenger RNA (mRNA). Anti-VCAM/LNP-mRNA mediated expression of thrombomodulin (a natural endothelial inhibitor of thrombosis, inflammation, and vascular leakage) and alleviated TNFα-induced brain edema. Thus VCAM-directed nanocarriers provide a platform for cerebrovascular targeting to inflamed brain, with the goal of normalizing the integrity of the blood–brain barrier, thus benefiting numerous brain pathologies.