Free-flowing rivers (FFRs) support diverse, complex and dynamic ecosystems globally, providing important societal and economic services. Infrastructure development threatens the ecosystem processes, ...biodiversity and services that these rivers support. Here we assess the connectivity status of 12 million kilometres of rivers globally and identify those that remain free-flowing in their entire length. Only 37 per cent of rivers longer than 1,000 kilometres remain free-flowing over their entire length and 23 per cent flow uninterrupted to the ocean. Very long FFRs are largely restricted to remote regions of the Arctic and of the Amazon and Congo basins. In densely populated areas only few very long rivers remain free-flowing, such as the Irrawaddy and Salween. Dams and reservoirs and their up- and downstream propagation of fragmentation and flow regulation are the leading contributors to the loss of river connectivity. By applying a new method to quantify riverine connectivity and map FFRs, we provide a foundation for concerted global and national strategies to maintain or restore them.
Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify ...MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1–MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysisshowed expression of
MRP1,
MRP2,
MRP3,
MRP4, and
MRP5 mRNA, whereas
MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs.
The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer ...(TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy.
We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR).
Median TMB was 1.52 mut/Mb (range 0.02–7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 95% confidence intervals (CI) 1.33–3.20, P = 0.001 among all patients, 1.77 (95% CI 1.00–3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21–6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP.
TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.
•Tumor mutational burden (TMB) predicts pCR after neoadjuvant treatment in early triple negative breast cancer.•The predictive value of TMB was found both for immune checkpoint inhibition with chemotherapy and for chemotherapy alone.•Both TMB and an immune gene expression profile add independent value for pCR prediction in multivariate analysis.
Inflammatory cardiomyopathy diagnosed by endomyocardial biopsy (EMB) is common in non-ischemic heart failure (HF) and might be associated with adverse outcome. We aimed to identify markers predicting ...myocardial inflammation in HF. We screened 517 patients with symptomatic non-ischemic HF who underwent EMB; 397 patients (median age 54 IQR 43/64, 28.7% females) were included in this study. 230 patients were diagnosed with myocardial inflammation, defined as ≥ 7.0 CD3
lymphocytes/mm
and/or ≥ 35.0 Mac1 macrophages/mm
and were compared to 167 inflammation negative patients. Patients with myocardial inflammation were more often smokers (52.4% vs. 39.8%, p = 0.013) and had higher C-reactive protein (CRP) levels (5.4 mg/dl vs. 3.7 mg/dl, p = 0.003). In logistic regression models CRP ≥ 8.15 mg/dl (OR 1.985 95%CI 1.160-3.397; p = 0.012) and Troponin I (TnI) ≥ 136.5 pg/ml (OR 3.011 1.215-7.464; p = 0.017) were independently associated with myocardial inflammation, whereas no association was found for elevated brain natriuretic peptide (OR 1.811 0.873-3.757; p = 0.111). In prognostic performance calculation the highest positive predictive value (90%) was detected for the combination of Global longitudinal strain (GLS) ≥ -13.95% and TnI ≥ 136.5 pg/ml (0.90 (0.74-0.96)). Elevated CRP, TnI and GLS in combination with TnI can be useful to detect myocardial inflammation. Smoking seems to predispose for myocardial inflammation.
Gene-targeted mice lacking the AMPA receptor subunit GluR1 (GluR-A) have deficits in hippocampal CA3-CA1 long-term potentiation. We now report that they showed normal spatial reference learning and ...memory, both on the hidden platform watermaze task and on an appetitively motivated Y-maze task. In contrast, they showed a specific spatial working memory impairment during tests of non-matching to place on both the Y-maze and an elevated T-maze. In addition, successful watermaze and Y-maze reference memory performance depended on hippocampal function in both wild-type and mutant mice; bilateral hippocampal lesions profoundly impaired performance on both tasks, to a similar extent in both groups. These results suggest that different forms of hippocampus-dependent spatial memory involve different aspects of neural processing within the hippocampus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:To investigate the association of collaboration between intensive care unit (ICU) physicians and nurses and patient outcome.
DESIGN:Prospective, descriptive, correlational study using ...self-report instruments.
SETTINGS:A community teaching hospital medical ICU, a university teaching hospital surgical ICU, and a community non-teaching hospital mixed ICU, all in upstate New York.
SUBJECTS:Ninety-seven attending physicians, 63 resident physicians, and 162 staff nurses.
PROCEDURE:When patients were ready for transfer from the ICU to an area of less intensive care, questionnaires were used to assess care providers' reports of collaboration in making the transfer decision. After controlling for severity of illness, the association between interprofessional collaboration and patient outcome was assessed. Unit-level organizational collaboration and patient outcomes were ranked.
MEASURES:Healthcare providers' reported levels of collaboration, patient severity of illness and individual risk, patient outcomes of death or readmission to the ICU, unit-level collaboration, and unit patient risk of negative outcome.
MAIN RESULTS:Medical ICU nurses' reports of collaboration were associated positively with patient outcomes. No other associations between individual reports of collaboration and patient outcome were found. There was a perfect rank order correlation between unit-level organizational collaboration and patient outcomes across the three units.
CONCLUSIONS:The study offered some support for the importance of physician-nurse collaboration in ICU care delivery, a variable susceptible to intervention and further study.
Heavy-fermion systems share some of the strange metal phenomenology seen in other unconventional superconductors, providing a unique opportunity to set strange metals in a broader context. Central to ...understanding heavy-fermion systems is the interplay of localization and itinerancy. These materials acquire high electronic masses and a concomitant Fermi volume increase as the f electrons delocalize at low temperatures. However, despite the wide-spread acceptance of this view, a direct microscopic verification has been lacking. Here we report high-resolution angle-resolved photoemission measurements on CeCoIn5, a prototypical heavy-fermion compound, which spectroscopically resolve the development of band hybridization and the Fermi surface expansion over a wide temperature region. Unexpectedly, the localized-to-itinerant transition occurs at surprisingly high temperatures, yet f electrons are still largely localized even at the lowest temperature. These findings point to an unanticipated role played by crystal-field excitations in the strange metal behavior of CeCoIn5. Our results offer a comprehensive experimental picture of the heavy-fermion formation, setting the stage for understanding the emergent properties, including unconventional superconductivity, in this and related materials.
In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such ...as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy.
Male Sprague–Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4weeks, rats were unilaterally nephrectomized and randomized for 24weeks of treatment with carnosine, lisinopril or both.
Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria.
Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.
•Carnosine treatment has renoprotective function in diabetic rats.•Renoprotection differs from the effect of the ACE inhibitor lisinopril.•Carnosinase activity correlates with anserine levels in the kidney.•Carnosine and lisinopril together combine the effect of single treatment.
Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or ...clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".
•Rare, medium and common variants in at least 20 genes are associated with AD.•Multiple genes affect processing of APP and production of Aβ peptide.•Others relate to immunity, inflammation, vesicular trafficking, and lipid metabolism.•These genes reflect steps in a complex metabolic/signalling cascade.•Nodal points in these pathways may represent potential therapeutic targets.
Abstract
We report on the realization of an extremely sensitive x-ray polarization microscope, allowing to detect tiniest polarization changes of 1 in 100 billion (10
−11
) with a
μ
m-size focused ...beam. The extreme degree of polarization purity places the most stringent requirements on the orientation of the polarizer and analyzer crystals as well as the composition and the form fidelity of the lenses, which must not exhibit any birefringence. The results show that these requirements are currently only met by polymer lenses. Highly sensitive scanning x-ray polarization microscopy thus is established as a new method. It can provide new insights in a wide range of applications ranging from quantum electrodynamics and quantum optics to x-ray spectroscopy, materials research, and laser physics.
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