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An integrative taxonomic approach, combining new morphological data with the analysis of partial COI sequences (DNA-barcodes) is used to describe Lebertia litoralis Zawal & Szenejko sp. nov. from lake habitats in Poland and Norway. The obtained DNA-barcodes of Polish and Norwegian specimens differ only slightly (k = 4.142, Π = 0.006). Morphologically, the new species is most similar to Lebertia porosa Thor, 1900 and L. obscura Thor, 1900, from which it differs by a slenderer shape of the first leg and the position of the distoventral setae of p-4, inserted rather far away from the distal segment edge.http://zoobank.org/urn:lsid:zoobank.org:pub:27F6FFD0-CA98-4FAD-BC16-58FA654E36ED

Scarce data are currently available about the distribution of the Mediterranean medicinal leech Hirudo verbana in Italy, and most of the known occurrence localities are based on records collected in the nineteenth and the first half of the twentieth century, which were not confirmed in the last decades, mostly due to a lack of surveys. Accordingly, the available knowledge on the distribution of the species is far from being updated and representative, although a significant negative trend of H. verbana throughout the country is supposed. The lack of sound distribution data is a significant shortfall, which hinders the implementation of the monitoring of the species as required by the Article 17 of the “Habitats Directive” on the species of Union concern. To provide recent, validated distributional data for the Mediterranean medicinal leech in Italy to be used as baseline data for further surveys and monitoring, we present herein a set of unpublished observations collected in the last decades in peninsular Italy, Sicily, and Sardinia. Moreover, we report observation of H. verbana feeding on amphibians, a feeding habit to date poorly documented for the Mediterranean medicinal leech. Based on both published and novel data, H. verbana is characterised by a large but fragmented distribution in Italy. Therefore, dedicated monitoring programs and the collection of validated occasional observations are highly desirable to get a clearer picture of the real distribution of the species.

Abstract Background Documentation on water mites in Spain is scarce, as is information on the parasite-host relationship between certain water mite species and representatives of the dipteran family Simuliidae. The discomfort caused to humans and animals by black flies seems to be increasing in recent years. In this context, an investigation of parasitic water mites is of great importance, not only from the point of view of biodiversity, but also in terms of their potential to control black fly populations. Methods Rivers across a wide region of eastern Spain were sampled to determine the specific richness of simuliid dipterans and to investigate their possible parasites, such as water mites, mermithid nematodes and microsporidia (fungal microbes). Data on environmental variables, abundance, prevalence and intensity of parasitism on the collected specimens were analyzed. Results In 10 streams, 15,396 simuliid pupae were collected and checked for the presence of water mite larvae; 426 pupae in seven streams were found to be associated with water mite larvae. Of the 21 simuliid species identified based on morphological characters, eight were found to be associated with water mite larvae. Water mite infection was not equally distributed among black fly species. Also, the prevalence of parasitism was low and differed among simuliid species, ranging from one to 13 water mites per black fly pupa. Variation at the intra- and interspecific levels was detected in terms of the number of water mites inside the black fly cocoons. Free-living deutonymphal and adult water mites representing 15 different species of six genera and five families were morphologically identified. The taxonomic identity of the parasitic mite larvae is unclear at present. Morphologically, they fit descriptions of larval Sperchon (Hispidosperchon) algeriensis Lundblad, 1942, but the possibility cannot be excluded that they represent Sperchon algeriensis, the most abundant species at the adult stage in this study and unknown at the larval stage, or even another species of the genus. A molecular analysis produced for the first time cytochrome oxidase I gene sequences for S. algeriensis. Conclusions Our results contribute to current knowledge on Spanish Hydrachnidia and their relationships with simuliids as hosts. However, further research is needed to evaluate the diversity, distribution, bioecology and prevalence of this parasitism. Graphical Abstract

Background: Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods: We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients’ Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results: The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model (0.86 vs. 0.69, P

Initial analyses of DNA barcode data from Norwegian populations attributed to the water mite Lebertia porosa Thor, 1900 revealed large genetic divergence and potentially cryptic species-level diversity. We used one mitochondrial (COI) and two nuclear markers (18S and 28S) as well as comparative morphological analysis to redefine Lebertia porosa, and to further investigate the species boundaries of Norwegian populations of its close relatives. Our results show that Lebertia porosa, as currently defined, consists of multiple species that can be separated by molecular and morphological characteristics. Although we document the presence of the endosymbiotic bacteria Wolbachia in two out of eight screened genetic lineages, we find no evidence of intraspecific genetic divergence caused by Wolbachia infections. The assignment of one of the genetic lineages to the nominal species could be made through morphological comparisons of specimens from the L. porosa type locality with the syntypes of L. obscura Thor, 1900. Thus, the diagnosis of L. porosa is emended and a neotype is defined. Two of the remaining genetic lineages could be assigned to existing names previously regarded as junior synonyms of L. porosa, namely L. obscura (lectotype defined here) and L. gibbosa Lundblad, 1926, which are both redescribed. The outstanding genetic lineages are unnamed, but from our work we conclude that the taxa Lebertia porosa britannica Thor, 1906, L. porosa dorsalis Thor, 1906, and L. porosa italica Thor, 1906 are nomina dubia that cannot be considered junior synonyms of L. porosa as proposed by K. Viets (1956). We also consider L. vigintimaculata Thor, 1900 a nomen dubium, probably identical to L. obscura.

As a follow-up to the project “Springs in the Bavarian National Parks as Indicators of Climate Change (SpringNPB)”, a standard methodology for using springs as sentinel environments of climate change was transferred to the UNESCO Rhön Biosphere Reserve and other Bavarian middle-elevation mountain ranges. We studied diatoms from fifteen springs selected in the UNESCO Biosphere Reserve (9) and Steigerwald Nature Park (6). A total of 127 species belonging to 40 genera were found sampling 3 microhabitat types (lithic materials, hygrophilous or aquatic vegetation, and surface sediments). The cumulative percentage of endangered species according to the Red List was 41.5%. These very shaded, low–medium conductivity, low-discharge forest springs are fed by small surficial aquifers. As a consequence, the discharge fluctuates widely, and some springs even occasionally fall dry. Our results could contribute to the use of diatoms as indicators of discharge variability/desiccation in springs: springs affected by discharge variability have lower diatom species richness and distinct diatom communities; diatom indicators and metrics can be validated using invertebrates; larger databases will be necessary to identify the most suitable diatom indicators.

Ten-eleven translocation proteins (TET1-3) are dioxygenases that oxidize 5-methyldeoxycytosine, thus taking part in passive and active demethylation. TETs have shown to be involved in immune cell development, affecting from self-renewal of stem cells and lineage commitment to terminal differentiation. In fact, dysfunction of TET proteins have been vastly associated with both myeloid and lymphoid leukemias. Recently, there has been accumulating evidence suggesting that TETs regulate immune cell function during innate and adaptive immune responses, thereby modulating inflammation. In this work, we pursue to review the current and recent evidence on the mechanistic aspects by which TETs regulate immune cell maturation and function. We will also discuss the complex interplay of TET expression and activity by several factors to modulate a multitude of inflammatory processes. Thus, modulating TET enzymes could be a novel pharmacological approach to target inflammation-related diseases and myeloid and lymphoid leukemias, when their activity is dysregulated.

Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity of α-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116 IDH1R132H/+ (harbouring a mutated IDH1 allele) and the parental cells HCT116 IDH1+/+ (wild type IDH1). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumour suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment of IDH1/2 mutated cancers.

Abstract Background Water mites are among the most diverse organisms inhabiting freshwater habitats and are considered as substantial part of the species communities in springs. As parasites, Hydrachnidia influence other invertebrates and play an important role in aquatic ecosystems. In Europe, 137 species are known to appear solely in or near springheads. New species are described frequently, especially with the help of molecular species identification and delimitation methods. The aim of this study was to verify the mainly morphology-based taxonomic knowledge of spring-inhabiting water mites of central Europe and to build a genetic species identification library. Methods We sampled 65 crenobiontic species across the central Alps and tested the suitability of mitochondrial (cox1) and nuclear (28S) markers for species delimitation and identification purposes. To investigate both markers, distance- and phylogeny-based approaches were applied. The presence of a barcoding gap was tested by using the automated barcoding gap discovery tool and intra- and interspecific genetic distances were investigated. Furthermore, we analyzed phylogenetic relationships between different taxonomic levels. Results A high degree of hidden diversity was observed. Seven taxa, morphologically identified as Bandakia concreta Thor, 1913, Hygrobates norvegicus (Thor, 1897), Ljania bipapillata Thor, 1898, Partnunia steinmanni Walter, 1906, Wandesia racovitzai Gledhill, 1970, Wandesia thori Schechtel, 1912 and Zschokkea oblonga Koenike, 1892, showed high intraspecific cox1 distances and each consisted of more than one phylogenetic clade. A clear intraspecific threshold between 5.6–6.0% K2P distance is suitable for species identification purposes. The monophyly of Hydrachnidia and the main superfamilies is evident with different species clearly separated into distinct clades. cox1 separates water mite species but is unsuitable for resolving higher taxonomic levels. Conclusions Water mite species richness in springs is higher than has been suggested based on morphological species identification alone and further research is needed to evaluate the true diversity. The standard molecular species identification marker cox1 can be used to identify species but should be complemented by a nuclear marker, e.g. 28S, to resolve taxonomic relationships. Our results contribute to the taxonomical knowledge on spring inhabiting Hydrachnida, which is indispensable for the development and implementation of modern environment assessment methods, e.g. metabarcoding, in spring ecology.

Background: Since the publication of the reports by the Commission on Social Determinants of Health (CSDH), many research papers have documented inequities, explaining causal pathways in order to inform policy and programmatic decision-making. At the international level, the sustainable development goals (SDGs) reflect an attempt to bring together these themes and the complexities involved in defining a comprehensive development framework. However, to date, much less has been done to address the monitoring challenges, that is, how data generation, analysis and use are to become routine tasks. Objective: To test proposed indicators of social determinants of health (SDH), gender, equity, and human rights with respect to their relevance in tracking progress in universal health coverage and population health (level and distribution). Design: In an attempt to explore these monitoring challenges, indicators covering a wide range of social determinants were tested in four country case studies (Bangladesh, Brazil, South Africa, and Vietnam) for their technical feasibility, reliability, and validity, and their communicability and usefulness to policy-makers. Twelve thematic domains with 20 core indicators covering different aspects of equity, human rights, gender, and SDH were tested through a review of data sources, descriptive analyses, key informant interviews, and focus group discussions. To test the communicability and usefulness of the domains, domain narratives that explained the causal pathways were presented to policy-makers, managers, the media, and civil society leaders. Results: For most countries, monitoring is possible, as some data were available for most of the core indicators. However, a qualitative assessment showed that technical feasibility, reliability, and validity varied across indicators and countries. Producing understandable and useful information proved challenging, and particularly so in translating indicator definitions and data into meaningful lay and managerial narratives, and effectively communicating links to health and ways in which the information could improve decision-making. Conclusions: This exercise revealed that for monitoring to produce reliable data collection, analysis, and discourse, it will need to be adapted to each national context and institutionalised into national systems. This will require that capacities and resources for this and subsequent communication of results are increased across countries for both national and international monitoring, including the successful implementation of the SDGs.

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60–70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84–1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741)

After extensive exploratory investigations into crenic habitats at the beginning of the 1990s, a number of springs were selected and long-term ecological research programmes independently initiated in the Berchtesgaden National Park (north-eastern Alps, Bavaria) and the Adamello-Brenta Nature Park (south-eastern Alps, Trentino). Following more than a decade of standardized work, this paper presents a selection of results from both sides of the Alps, with a focus on zoobenthos in Bavaria and on pro- and eukaryotic algae in Trentino. In order to test the assumption that permanent springs are particularly suitable habitats for long-term ecological research, the following topics are addressed: (1) taxonomic diversity and relationships between diversity and spring typology; (2) transverse gradients in crenic habitats, hygrophilous terrestrial invertebrates and xerotolerant algae; (3) possibilities of documenting changes in species composition over decadal time scales ("medium-term") based on emergence traps, benthos, and benthic algae. The data obtained show that: (1) crenic habitats support particularly high biological diversity (but a thorough documentation of insect diversity is impossible without emergence studies); (2) helocrenes are the most species-rich habitats, for both invertebrates and diatoms; (3) dynamic (unstable) and occasionally-impacted springs show identifiable signs of medium-term change, whilst particularly complex and stable crenic habitats seem to be controlled by internal processes. Our results suggest that: (1) the meiofauna is likely to react directly to environmental change, while emergers and the hygrophilous terrestrial fauna are indirectly affected, and (2) diatoms react both to direct effects of environmental change, e.g. discharge and hydrochemistry, and to indirect effects on the surroundings of the spring. Based on our results, long-term research strategies are discussed. For long-term studies, we propose a focus on meiofauna and diatoms, with target-oriented emergence studies and macroscopic benthic algal analyses. This could form the basis for an integrated and uniform approach to studies of these habitats worldwide.

The distribution patterns of Alpine crenic meiofauna were studied using a standardised sampling procedure at 110 springs, evenly distributed across both carbonate and siliceous rocks in Trentino (northern Italy). Spring altitude ranges between 170 and 2800 m a.s.l. One hundred and thirty-eight taxa (mainly identified at species level), belonging to the Annelida (39), freshwater Acari (57), Copepoda (24), and Ostracoda (18) were found in springs of the investigated area. Using Canonical Correspondence Analysis, spatial patterns of meiofaunal assemblages at the regional scale were best explained by altitude, water chemistry (mainly related to geology) and water-flow regime; the role of microhabitat structure and anthropogenic disturbance as environmental descriptors was of minor importance.

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16.

Corroles are a developing class of tetrapyrrole-based molecules with significant chemical potential and relatively unexplored photophysical properties. We combined femtosecond broadband fluorescence up-conversion and fs broadband Vis-pump Vis-probe spectroscopy to comprehensively characterize the photoreaction of 5,10,15-tris-pentafluorophenyl-corrolato-antimony(V)-trans-difluoride (Sb-tpfc-F2). Upon fs Soret band excitation at ~400 nm, the energy relaxed almost completely to Q band electronic excited states with a time constant of 500 ± 100 fs; this is evident from the decay of Soret band fluorescence at around 430 nm and the rise time of Q band fluorescence, as well as from Q band stimulated emission signals at 600 and 650 nm with the same time constant. Relaxation processes on a time scale of 10 and 20 ps were observed in the fluorescence and absorption signals. Triplet formation showed a time constant of 400 ps, with an intersystem crossing yield from the Q band to the triplet manifold of between 95% and 99%. This efficient triplet formation is due to the spin-orbit coupling of the antimony ion.

Exercise has been demonstrated to potently protect substantia nigra pars compacta (SN) dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. One mechanism proposed to account for this neuroprotection is the upregulation of neurotrophic factors. Several neurotrophic factors, including Brain Derived Neurotrophic Factor (BDNF), have been shown to upregulate in response to exercise. In order to determine if exercise-induced neuroprotection is dependent upon BDNF, we compared the neuroprotective effects of voluntary exercise in mice heterozygous for the BDNF gene (BDNF+/-) with strain-matched wild-type (WT) mice. Stereological estimates of SNpc DA neurons from WT mice allowed 90 days exercise via unrestricted running demonstrated complete protection against the MPTP-induced neurotoxicity. However, BDNF+/- mice allowed 90 days of unrestricted exercise were not protected from MPTP-induced SNpc DA neuron loss. Proteomic analysis comparing SN and striatum from 90 day exercised WT and BDNF+/- mice showed differential expression of proteins related to energy regulation, intracellular signaling and trafficking. These results suggest that a full genetic complement of BDNF is critical for the exercise-induced neuroprotection of SNpc DA neurons.

Temporal trends and concentrations of dioxins and polybrominated diphenyl ethers in the Swiss environment are presented.

In spite of being one of the main components in the longitudinal zonation of lotic systems, spring habitats have received much less attention than lakes and streams/rivers, and are still widely understudied...