Previous studies have suggested that Lingzhi (Ganoderma lucidum) has antioxidant effects and possibly beneficial effects on blood pressure, plasma lipids and glucose, but these have not been ...confirmed in subjects with mild hypertension or hyperlipidaemia. The objective of the present study was to assess the cardiovascular, metabolic, antioxidant and immunomodulatory responses to therapy with Lingzhi in patients with borderline elevations of blood pressure and/or cholesterol in a controlled cross-over trial. A total of twenty-six patients received 1·44 g Lingzhi daily or matching placebo for 12 weeks in a randomised, double-blind, cross-over study with placebo-controlled run-in and cross-over periods. Body weight, blood pressure, metabolic parameters, urine catecholamines and cortisol, antioxidant status and lymphocyte subsets were measured after each period. Lingzhi was well tolerated and data from twenty-three evaluable subjects showed no changes in BMI or blood pressure when treated with Lingzhi or placebo. Plasma insulin and homeostasis model assessment-insulin resistance were lower after treatment with Lingzhi than after placebo. TAG decreased and HDL-cholesterol increased with Lingzhi but not with placebo in the first treatment period, but significant carry-over effects prevented complete analysis of these parameters. Urine catecholamines and cortisol, plasma antioxidant status and blood lymphocyte subsets showed no significant differences across treatments. Results indicate that Lingzhi might have mild antidiabetic effects and potentially improve the dyslipidaemia of diabetes, as shown previously in some animal studies. Further studies are desirable in patients with hyperglycaemia.
Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of ...IBCs.
The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes.
DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007).
These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.
Although tuberculosis (TB) is a reemerging disease that affects people in developing countries and immunocompromised populations in developed countries, the current diagnostic methods are far from ...optimal. Metabolomics is increasingly being used for studies on infectious diseases. We performed metabolome profiling of plasma samples to identify potential biomarkers for diagnosing TB. We compared the plasma metabolome profiles of TB patients (n = 46) with those of community-acquired pneumonia (CAP) patients (n = 30) and controls without active infection (n = 30) using ultrahigh-performance liquid chromatography-electrospray ionization-quadrupole time of flight mass spectrometry (UHPLC-ESI-QTOFMS). Using multivariate and univariate analyses, four metabolites, 12R-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid 12(R)-HETE, ceramide (d18:1/16:0), cholesterol sulfate, and 4α-formyl-4β-methyl-5α-cholesta-8-en-3β-ol, were identified and found to have significantly higher levels in TB patients than those in CAP patients and controls. In a comparison of TB patients and controls, the four metabolites demonstrated area under the receiver operating characteristic curve (AUC) values of 0.914, 0.912, 0.905, and 0.856, sensitivities of 84.8%, 84.8%, 87.0%, and 89.1%, specificities of 90.0%, 86.7%, 86.7%, and 80.0%, and fold changes of 4.19, 26.15, 6.09, and 1.83, respectively. In a comparison of TB and CAP patients, the four metabolites demonstrated AUC values of 0.793, 0.717, 0.802, and 0.894, sensitivities of 89.1%, 71.7%, 80.4%, and 84.8%, specificities of 63.3%, 66.7%, 70.0%, and 83.3%, and fold changes of 4.69, 3.82, 3.75, and 2.16, respectively. 4α-Formyl-4β-methyl-5α-cholesta-8-en-3β-ol combined with 12(R)-HETE or cholesterol sulfate offered ≥70% sensitivity and ≥90% specificity for differentiating TB patients from controls or CAP patients. These novel plasma biomarkers, especially 12(R)-HETE and 4α-formyl-4β-methyl-5α-cholesta-8-en-3β-ol, alone or in combination, are potentially useful for rapid and noninvasive diagnosis of TB. The present findings may offer insights into the pathogenesis and host response in TB.
The DIALS diffraction‐modeling software package has been applied to serial crystallography data. Diffraction modeling is an exercise in determining the experimental parameters, such as incident beam ...wavelength, crystal unit cell and orientation, and detector geometry, that are most consistent with the observed positions of Bragg spots. These parameters can be refined by nonlinear least‐squares fitting. In previous work, it has been challenging to refine both the positions of the sensors (metrology) on multipanel imaging detectors such as the CSPAD and the orientations of all of the crystals studied. Since the optimal models for metrology and crystal orientation are interdependent, alternate cycles of panel refinement and crystal refinement have been required. To simplify the process, a sparse linear algebra technique for solving the normal equations was implemented, allowing the detector panels to be refined simultaneously against the diffraction from thousands of crystals with excellent computational performance. Separately, it is shown how to refine the metrology of a second CSPAD detector, positioned at a distance of 2.5 m from the crystal, used for recording low‐angle reflections. With the ability to jointly refine the detector position against the ensemble of all crystals used for structure determination, it is shown that ensemble refinement greatly reduces the apparent nonisomorphism that is often observed in the unit‐cell distributions from still‐shot serial crystallography. In addition, it is shown that batching the images by timestamp and re‐refining the detector position can realistically model small, time‐dependent variations in detector position relative to the sample, and thereby improve the integrated structure‐factor intensity signal and heavy‐atom anomalous peak heights.
For XFEL data, simultaneous refinement of multi‐panel detector geometry with thousands of crystal models in the program DIALS improves the integrated signal quality and helps to reduce non‐isomorphism
Many environmental pollutants are known to have disproportionate effects on Black, Indigenous and People of Color (BIPOC) as well as communities of low-income and wealth. The reasons for these ...disproportionate effects are complex and involve hundreds of years of systematic oppression kept in place through structural racism and classism in the USA. Here we analyze the available literature and existing datasets to determine the extent to which disparities in exposure and harm exist for one of the most widespread pollutants in the world - pesticides. Our objective was to identify and discuss not only the historical injustices that have led to these disparities, but also the current laws, policies and regulatory practices that perpetuate them to this day with the ultimate goal of proposing achievable solutions. Disparities in exposures and harms from pesticides are widespread, impacting BIPOC and low-income communities in both rural and urban settings and occurring throughout the entire lifecycle of the pesticide from production to end-use. These disparities are being perpetuated by current laws and regulations through 1) a pesticide safety double standard, 2) inadequate worker protections, and 3) export of dangerous pesticides to developing countries. Racial, ethnic and income disparities are also maintained through policies and regulatory practices that 4) fail to implement environmental justice Executive Orders, 5) fail to account for unintended pesticide use or provide adequate training and support, 6) fail to effectively monitor and follow-up with vulnerable communities post-approval, and 7) fail to implement essential protections for children. Here we've identified federal laws, regulations, policies, and practices that allow for disparities in pesticide exposure and harm to remain entrenched in everyday life for environmental justice communities. This is not simply a pesticides issue, but a broader public health and civil rights issue. The true fix is to shift the USA to a more just system based on the Precautionary Principle to prevent harmful pollution exposure to everyone, regardless of skin tone or income. However, there are actions that can be taken within our existing framework in the short term to make our unjust regulatory system work better for everyone.
To investigate the contribution of the gut microbiota to the pathogenesis of uveitis.
Experimental autoimmune uveitis (EAU) in B10.RIII mice was induced using interphotoreceptor binding protein ...peptide. Mice were treated with oral or intraperitoneal (IP) antibiotics. Effector (Teff) and regulatory (Treg) T lymphocytes were identified using flow cytometry; 16S rRNA gene sequencing and qPCR were performed on gastrointestinal (GI) contents.
Broad-spectrum (four antibiotics given simultaneously) oral, but not IP, antibiotics reduced mean uveitis clinical scores significantly compared with water-treated animals (0.5 vs. 3.0, P < 0.0001 for oral; 3.4 vs. 3.4, P > 0.99 for IP). Both oral metronidazole (P = 0.02) and vancomycin (P < 0.0001) alone decreased inflammation, whereas neomycin (P = 0.7) and ampicillin (P = 0.4) did not change mean uveitis scores. Oral broad-spectrum antibiotics increased Tregs in the GI lamina propria of EAU animals at 1 week, and in extraintestinal lymphoid tissues later, whereas Teff and inflammatory cytokines were reduced. 16S sequencing of GI contents revealed altered microbiota in immunized mice compared with nonimmunized mice, and microbial diversity clustering in EAU mice treated with uveitis-protective antibiotics. Experimental autoimmune uveitis mice also demonstrated gut microbial diversity clustering associated with clinical score severity.
Oral antibiotics modulate the severity of inducible EAU by increasing Tregs in the gut and extraintestinal tissues, as well as decreasing effector T cells and cytokines. 16S sequencing suggests that there may be protective and, conversely, potentially uveitogenic, gut microbiota. These findings may lead to a better understanding of how uveitis can be treated or prevented by modulating the gut microbiome.
This study examines teachers' conceptions of assessment and related contextual factors at the classroom, school and national levels. A representative survey of Singaporean secondary school teachers ...resulted in a final sample consisting of 229 teachers from 9 secondary schools. Findings on that, teachers endorse views of assessment for school accountability, student accountability and student improvement, but little endorsement of assessment as irrelevance. Teachers report feeling capable and qualified to use assessments, but concerned about how much they are trusted as assessors at school and national levels. Follow-up latent class analysis identified groups of teachers based on their responses to the irrelevance of assessment; teachers who found assessment irrelevant were present across all schools and subjects, but showed lower sense of preparation for assessment, school-level support and importance of academic success in society.
Abstract Early diagnosis of acute community-acquired pneumonia (CAP) is important in patient triage and treatment decisions. To identify biomarkers that distinguish patients with CAP from non-CAP ...controls, we conducted an untargeted global metabolome analysis for plasma samples from 142 patients with CAP (CAP cases) and 97 without CAP (non-CAP controls). Thirteen lipid metabolites could discriminate between CAP cases and non-CAP controls with area-under-the-receiver-operating-characteristic curve of >0.8 ( P ≤ 10−9 ). The levels of glycosphingolipids, sphingomyelins, lysophosphatidylcholines and L-palmitoylcarnitine were higher, while the levels of lysophosphatidylethanolamines were lower in the CAP cases than those in non-CAP controls. All 13 metabolites could distinguish CAP cases from the non-infection, extrapulmonary infection and non-CAP respiratory tract infection subgroups. The levels of trihexosylceramide (d18:1/16:0) were higher, while the levels of lysophosphatidylethanolamines were lower, in the fatal than those of non-fatal CAP cases. Our findings suggest that lipid metabolites are potential diagnostic and prognostic biomarkers for CAP.
Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists and protein engineers because conformational dynamics are essential for complex ...functions such as enzyme catalysis and allosteric regulation. Time-resolved crystallography offers a window into protein motions, yet without a universal perturbation to initiate conformational changes the method has been limited in scope. Here we couple a solvent-based temperature jump with time-resolved crystallography to visualize structural motions in lysozyme, a dynamic enzyme. We observed widespread atomic vibrations on the nanosecond timescale, which evolve on the submillisecond timescale into localized structural fluctuations that are coupled to the active site. An orthogonal perturbation to the enzyme, inhibitor binding, altered these dynamics by blocking key motions that allow energy to dissipate from vibrations into functional movements linked to the catalytic cycle. Because temperature jump is a universal method for perturbing molecular motion, the method demonstrated here is broadly applicable for studying protein dynamics.
PDF
