Chironomid-inferred summer temperature development during the late Rissian glacial, Eemian interglacial and earliest Würmian glacial at Füramoos, southern Germany

Eemian pollen records from central Europe describe a transition from thermophilous tree taxa in the early Eemian to boreal tree taxa in the late Eemian with forest opening in the subsequent stadial. Available summer-temperature reconstructions for the mid- to late Eemian transition show decreasing values during that time. We present a new chironomid record from southern Germany that covers the mid-Eemian to the end of the first Würmian stadial ( c . 125-105 ka) and also parts of the late Rissian glaciation and early Brörup interstadial of the early Würmian glaciation. Based on this record we describe lake development in the former Füramoos palaeolake and quantitatively reconstruct July air temperature during the examined interval. Late Rissian sediments are dominated by two chironomid taxa, Sergentia coracina -type and Micropsectra radialis -type, indicating very cold conditions. Following an uncertain interval, probably including a hiatus at the late Rissian/Eemian transition, mid-Eemian sediments contain Tanytarsus glabrescens -type and Tanytarsus mendax -type suggesting relatively high July air temperatures. During the late Eemian, typically thermophilic taxa such as Tanytarsus glabrescens -type disappear, suggesting decreasing temperatures. Stadial A is associated with increases in Microtendipes pedellus -type suggesting more oligotrophic conditions. Early Brörup sediments contain Tanytarsus glabrescens -type, suggesting a slight increase in July air temperature. Reconstructed July air temperatures show temperatures of 7-8 °C during the late Rissian and a decline from ~15.5-12 °C during the mid- to late Eemian associated with decreasing Northern Hemisphere July insolation. July air temperature values vary between 12 and 14 °C in the late Eemian, while reconstructed temperatures remain within 12-13.5 °C during Stadial A. Our new chironomid-based temperature reconstruction provides valuable corroboration and new quantification of temperature development from the mid-Eemian to the early Brörup interstadial as well as for sections of the late Rissian from the alpine foreland of southern Germany

Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes

Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics

The Influence of Aging on Perceptual Grouping in Haptic Search

Perceptual grouping speeds up haptic search. This has particularly been shown for grouping of distractors by similarity and good continuation [1]. Here, we investigated the effect of aging on grouping in haptic search. We reasoned that because older adults have less cognitive resources available for processing perceptual information, they would benefit more from grouping as compared to younger adults. We tested this hypothesis in a haptic search task in which proximity, similarity and good continuation of the distractors were manipulated. We found that older adults indeed show a larger effect of distractor similarity on search times as compared to younger adults, where similar dis- tractors were processed faster than dissimilar distractors. However, older adults showed an opposite effect of grouping by proximity, where items that were further apart were processed faster. This may be caused by a strong bowed spatial position effect in older adults: stimuli that are closer to each other are more difficult to discriminate. We conclude that haptic perceptual grouping by similarity has larger benefits in elderly as compared to younger adults

Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage

A Literature Review on Cloud Computing Adoption Issues in Enterprises

Part 3: Creating Value through ApplicationsInternational audienceCloud computing has received increasing interest from enterprises since its inception. With its innovative information technology (IT) services delivery model, cloud computing could add technical and strategic business value to enterprises. However, cloud computing poses highly concerning internal (e.g., Top management and experience) and external issues (e.g., regulations and standards). This paper presents a systematic literature review to explore the current key issues related to cloud computing adoption. This is achieved by reviewing 51 articles published about cloud computing adoption. Using the grounded theory approach, articles are classified into eight main categories: internal, external, evaluation, proof of concept, adoption decision, implementation and integration, IT governance, and confirmation. Then, the eight categories are divided into two abstract categories: cloud computing adoption factors and processes, where the former affects the latter. The results of this review indicate that enterprises face serious issues before they decide to adopt cloud computing. Based on the findings, the paper provides a future information systems (IS) research agenda to explore the previously under-investigated areas regarding cloud computing adoption factors and processes. This paper calls for further theoretical, methodological, and empirical contributions to the research area of cloud computing adoption by enterprises

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria‐dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full‐length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+/K+‐ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified