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In 1989, the need for reliable gridded land surface precipitation data sets, in view of the large uncertainties in the assessment of the global energy and water cycle, has led to the establishment of the Global Precipitation Climatology Centre (GPCC) at Deutscher Wetterdienst on invitation of the WMO. The GPCC has calculated a precipitation climatology for the global land areas for the target period 1951–2000 by objective analysis of climatological normals of about 67,200 rain gauge stations from its data base. GPCC's new precipitation climatology is compared to several other station-based precipitation climatologies as well as to precipitation climatologies derived from the GPCP V2.2 data set and from ECMWF's model reanalyses ERA-40 and ERA-Interim. Finally, how GPCC's best estimate for terrestrial mean precipitation derived from the precipitation climatology of 786 mm per year (equivalent to a water transport of 117,000 km³) is fitting into the global water cycle context is discussed.

Background Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E 2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, recent genome-wide association studies (GWAS) have identified five risk alleles for AS in PTGER4 , the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS. Methods Th17 cells from patients with AS were analyzed for the transcriptional expression of prostaglandin receptor genes by quantitative RT-PCR. Th17 cells from patients with rheumatoid arthritis (RA) and from healthy individuals served as controls. EP4 receptor expression in Th17 cells was assessed ex vivo by flow cytometry and by western blot. Functional analysis using EP4-specific agonists was performed to reveal how EP4 regulates Th17 cells. Results EP4 is significantly overexpressed in Th17 cells from patients with AS compared to Th17 cells from healthy individuals or patients with RA or psoriatic arthritis (PsA). EP4 upregulation is unique to Th17 cells and is not found in other CD4 + T cell subsets. Specific activation of EP4 drives Th17 cell development and promotes EP4 expression in a positive feedback loop in AS but not in RA or PsA. Mechanistically, EP4 acts via upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORγt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. Increased EP4 expression levels in Th17 cells from AS patients correlate with high disease activity as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 ( r  = 0.7591, p  = 0.0016). Conclusions EP4 is a potential marker of disease activity in patients with AS. Aberrant EP4 expression might contribute to pathogenic Th17 cell accumulation and represent a new target for the treatment of AS.

Glucosylceramide and glucosylsphingosine are the two major storage products in Gaucher disease (GD), an inherited metabolic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The build-up of glucosylceramide in the endoplasmic reticulum and prominent accumulation in cell lysosomes of tissue macrophages results in decreased blood cell and platelet counts, and skeletal abnormalities. The pathological role of the deacylated form of glucosylceramide, glucosylsphingosine (lyso-Gb1), a recently identified sensitive and specific biomarker for GD, is not well investigated. We established a long-term infusion model in C57BL/6JRj mice to examine the effect of lyso-Gb1 on representative hallmark parameters of GD. Mice received lyso-Gb1 at a dosage of 10 mg·kg−1 per day as a continuous subcutaneous administration, and were routinely checked for blood lyso-Gb1 levels using liquid chromatography-multiple reaction monitoring mass spectrometry (LC/MRM-MS) measurements at four-weekly intervals throughout treatment. The C57BL/6JRj mice showed a stable increase of lyso-Gb1 up to->500-fold greater than the normal reflecting concentrations seen in moderately to severely affected patients. Furthermore, lyso-Gb1 accumulated in peripheral tissues. The mice developed hematological symptoms such as reduced hemoglobin and hematocrit, increased spleen weights and a slight inflammatory tissue response after eight weeks of treatment. The above findings indicate a measurable visceral and hematological response in treated mice that suggests a role for lyso-Gb1 in the development of peripheral signs of GD.

The 2015 release of the precipitation climatology from the Global Precipitation Climatology Centre (GPCC) for 1951–2000, based on climatological normals of about 75,100 rain gauges, allows for quantification of mean land surface precipitation as part of the global water cycle. In GPCC’s 2011-release, a bulk climatological correction was applied to compensate for gauge undercatch. In this paper we derive an improved correction approach based on the synoptic weather reports for the period 1982–2015. The compared results show that the climatological approach tends to overestimate the correction for Central and Eastern Europe, especially in the northern winter, and in other regions throughout the year. Applying the mean weather-dependent correction to the GPCC’s uncorrected precipitation climatology for 1951–2000 gives a value of 854.7 mm of precipitation per year (excluding Antarctica) or 790 mm for the global land surface. The warming of nearly 1 K relative to pre-industrial temperatures is expected to be accompanied by a 2%–3% increase in global (land and ocean) precipitation. However, a comparison of climatology for 30-year reference periods from 1931–1960 up to 1981–2010 reveals no significant trend for land surface precipitation. This may be caused by the large variability of precipitation, the varying data coverage over time and other issues related to the sampling of rain-gauge networks. The GPCC continues to enlarge and further improve the quality of its database, and will generate precipitation analyses with homogeneous data coverage over time. Another way to reduce the sampling issues is the combination of rain gauge-based analyses with remote sensing (i.e., satellite or radar) datasets.

MRI-targeted prostate biopsy improves detection of clinically significant prostate cancer (PCa). However, up to 70% of PCa lesions display intralesional tumor heterogeneity. Current target sampling strategies do not yet adequately account for this finding. This prospective study included 118 patients who underwent transperineal robotic assisted biopsy of the prostate. We identified a total of 58 PCa-positive PI-RADS lesions. We compared diagnostic accuracy of a target-saturation biopsy strategy to accuracy of single, two, or three randomly selected targeted biopsy cores and analysed potential clinical implications. Intralesional detection of clinically significant cancer (ISUP ≥ 2) was 78.3% for target-saturation biopsy and 39.1%, 52.2%, and 67.4% for one, two, and three targeted cores, respectively. Target-saturation biopsies led to a more accurate characterization of PCa in terms of Gleason score and reduced rates of significant cancer missed. Compared to one, two, and three targeted biopsy cores, target-saturation biopsies led to intensified staging procedures in 21.7%, 10.9, and 8.7% of patients, and ultimately to a potential change in therapy in 39.1%, 26.1%, and 10.9% of patients. This work presents the concept of robotic-assisted target saturation biopsy. This technique has the potential to improve diagnostic accuracy and thus individual staging procedures and treatment decisions.

We present a new global land-based daily precipitation dataset from 1950 using an interpolated network of in situ data called Rainfall Estimates on a Gridded Network – REGEN. We merged multiple archives of in situ data including two of the largest archives, the Global Historical Climatology Network – Daily (GHCN-Daily) hosted by National Centres of Environmental Information (NCEI), USA, and one hosted by the Global Precipitation Climatology Centre (GPCC) operated by Deutscher Wetterdienst (DWD). This resulted in an unprecedented station density compared to existing datasets. The station time series were quality-controlled using strict criteria and flagged values were removed. Remaining values were interpolated to create area-average estimates of daily precipitation for global land areas on a 1∘ × 1∘ latitude–longitude resolution. Besides the daily precipitation amounts, fields of standard deviation, kriging error and number of stations are also provided. We also provide a quality mask based on these uncertainty measures. For those interested in a dataset with lower station network variability we also provide a related dataset based on a network of long-term stations which interpolates stations with a record length of at least 40 years. The REGEN datasets are expected to contribute to the advancement of hydrological science and practice by facilitating studies aiming to understand changes and variability in several aspects of daily precipitation distributions, extremes and measures of hydrological intensity. Here we document the development of the dataset and guidelines for best practices for users with regards to the two datasets.

Background Pediatric acute liver failure (PALF) is an uncommon, devastating illness with significant mortality. Liver transplantation remains the mainstay of treatment for irreversible PALF. The purpose of this study was to determine the etiology and prognostic factors associated with outcome of PALF in South Africa and to evaluate prognostic scoring systems used. Methods Records of 45 pediatric patients younger than 16 years of age who presented with PALF from 1 January 2015 till 31 October 2020 were analysed. Patients were divided into two groups with one group consisting of patients with spontaneous recovery of the liver with supportive treatment (6/45:13.3%) and the second group consisting of patients with poor outcomes who demised (19/45: 42%) or underwent liver transplantation (20/45: 44%). Results The median age of presentation was 3.3 years (IQR 1.8–6.9) with the 1–5 years age group constituting majority of patients (55.6%). Median time to follow up was 6.1 months (IQR 0.2–28.8). Higher liver injury unit scores were observed in patients who had poorer outcomes ( P  = 0.008) with a threshold of greater than 246 having a sensitivity of 84% and specificity of 83% ( P  < 0.001). Higher peak PELD/MELD ( P  = 0.006) and admission UKELD ( P  = 0.002) scores, were found in patients with poorer outcomes. Kings College Hospital criteria (KCHC) was useful in predicting which patients would die without liver transplantation ( P  = 0.002). Liver transplantation was performed in 20/45 (44%) patients with a post transplantation 1 year patient and graft survival of 80%. Conclusion Although, survival of PALF patients was lower than high and other low-middle income countries, outcomes post transplantation were good. Our study demonstrates the utility of dynamic scoring systems in PALF patients, it underscores the need for early referral and clinical monitoring in a tertiary center once the criteria for PALF have been met.

Neurodegenerative diseases are often accompanied by olfactory deficits. Here we use a rare neurovisceral lipid storage disorder, Niemann-Pick disease C1 (NPC1), to illustrate disease-specific dynamics of olfactory dysfunction and its reaction upon therapy. Previous findings in a transgenic mouse model ( showed severe morphological and electrophysiological alterations of the olfactory epithelium (OE) and the olfactory bulb (OB) that ameliorated under therapy with combined 2-hydroxypropyl-ß-cyclodextrin (HPßCD)/allopregnanolone/miglustat or HPßCD alone. A buried pellet test was conducted to assess olfactory performance. qPCR for olfactory key markers and several olfactory receptors was applied to determine if their expression was changed under treatment conditions. In order to investigate the cell dynamics of the OB, we determined proliferative and apoptotic activities using a bromodeoxyuridine (BrdU) protocol and caspase-3 (cas-3) activity. Further, we performed immunohistochemistry and western blotting for microglia (Iba1), astroglia (GFAP) and tyrosine hydroxylase (TH). The buried pellet test revealed a significant olfactory deterioration in mice, which reverted to normal levels after treatment. At the OE level, mRNA for olfactory markers showed no changes; the mRNA level of classical olfactory receptor (ORs) was unaltered, that of unique ORs was reduced. In the OB of untreated mice, BrdU and cas-3 data showed increased proliferation and apoptotic activity, respectively. At the protein level, Iba1 and GFAP in the OB indicated increased microgliosis and astrogliosis, which was prevented by treatment. Due to the unique plasticity especially of peripheral olfactory components the results show a successful treatment in NPC1 condition with respect to normalization of olfaction. Unchanged mRNA levels for olfactory marker protein and distinct olfactory receptors indicate no effects in the OE in mice. Olfactory deficits are thus likely due to central deficits at the level of the OB. Further studies are needed to examine if olfactory performance can also be changed at a later onset and interrupted treatment of the disease. Taken together, our results demonstrate that olfactory testing in patients with NPC1 may be successfully used as a biomarker during the monitoring of the treatment.

The essay explores the themes of linguistic manipulation and power as portrayed in George Orwell’s (1949), drawing connections with contemporary discourse on disinformation and political language. Through the lens of Teun A. Van Dijk’s critical discourse analysis and Michel Foucault’s concept of panopticism, the study examines Orwell’s depiction of a dystopian society where language serves as a central tool for consolidating totalitarian power. In particular, the fictional language of is analyzed as an instrument designed to restrict critical thought, aligning with Orwell’s broader critique of language manipulation as a mechanism of cognitive and societal control. By exploring the intersections of language, power, and social structure, this essay highlights how Orwell’s warnings remain relevant in today’s world of pervasive digital disinformation and propaganda, underscoring the importance of safeguarding linguistic integrity as a defense of independent thought.

Introduction: Olfactory impairment is one of the earliest symptoms in neurodegenerative disorders that has also been documented in Niemann-Pick disease type C1 (NPC1). NPC1 is a very rare, neurovisceral lipid storage disorder, characterized by a deficiency of Npc1 gene function that leads to progressive neurodegeneration. Here, we compared the pathologic effect of defective Npc1 gene on the vomeronasal neuroepithelium (VNE) with that of the olfactory epithelium (OE) in an NPC1 mouse model. Methods: Proliferation in the VNE and OE was assessed by applying a bromodeoxyuridine (BrdU) protocol. We further compared the immunoreactivities of anti-olfactory marker protein (OMP), and the lysosomal marker cathepsin-D in both epithelia. To investigate if degenerative effects of both olfactory systems can be prevented or reversed, some animals were treated with a combination of miglustat/allopregnanolone/2-hydroxypropyl-cyclodextrin (HPβCD), or a monotherapy with HPβCD alone. Results: Using BrdU to label dividing cells of the VNE, we detected a proliferation increase of 215% ± 12% in Npc1−/− mice, and 270% ± 10% in combination- treated Npc1−/− animals. The monotherapy with HPβCD led to an increase of 261% ± 10.5% compared to sham-treated Npc1−/− mice. Similar to the OE, we assessed the high regenerative potential of vomeronasal progenitor cells. OMP reactivity in the VNE of Npc1−/− mice was not affected, in contrast to that observed in the OE. Concomitantly, cathepsin-D reactivity in the VNE was virtually absent. Conclusion: Vomeronasal receptor neurons are less susceptible against NPC1 pathology than olfactory receptor neurons. Compared to control mice, however, the VNE of Npc1−/− mice displays an increased neuroregenerative potential, indicating compensatory cell renewal.