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A 43-year-old woman presented with a presumed lower respiratory tract infection, with symptoms of persistent cough, lethargy, fevers and night sweats. Initial general practitioner assessment revealed raised C reactive protein and a leucocytosis comprising both a neutrophilia and an eosinophilia. The patient was initially treated for bacterial pneumonia. Despite treatment, the patient’s condition did not improve and hospital admission was arranged for further investigation. Initial physical examination was unremarkable. A chest X-ray revealed bilateral, symmetrical, peripheral consolidation with an upper zone predominance. Subsequently, endobronchial washings revealed abundant eosinophils. A diagnosis of idiopathic chronic eosinophilic pneumonia was made, and the patient responded well to oral corticosteroids with complete resolution of radiological appearances 1 month later.

We present a case of piriformis syndrome in a woman in her 30’s following low energy trauma, presenting with unilateral lower limb weakness, altered sensation and urinary retention. CT imaging revealed a bulky piriformis muscle which was further clarified on MRI as an intramuscular haematoma within the left piriformis causing compression of the left lumbosacral plexus. Haematoma formation was exacerbated due to use of an antiplatelet medication the patient was taking for Moyamoya disease, which carries an increased risk of cerebrovascular accident. Surgical exploration of the piriformis and sciatic nerve was undertaken and confirmed a haematoma within the piriformis. A full release of the piriformis tendon was undertaken, and the sciatic nerve was inspected, no further abnormality was found. After review in clinic post-discharge, the patient reported normal sensation and normal muscle power in her feet.

A 45-year-old woman presented with a left-sided neck swelling following treatment a year prior for cervical spine chordoma. She had initially been managed surgically with a cervical vertebrectomy and a course of proton beam therapy. Although there had been a degree of residual tissue, her disease remained stable radiologically and clinically. Repeat MRI demonstrated an increasing left paravertebral mass and a head of pancreas metastasis, which shared pathological characteristics with chordoma. Given the advanced metastatic nature of her disease, imatinib was offered with a palliative intent. While waiting for treatment she developed a spinal cord compression, managed with radiotherapy. She commenced imatinib and her disease remained stable for 9 months before progressing clinically and radiologically. This case demonstrates an unusual pattern of metastatic chordoma and provides further rationale for imatinib in such patients.

Intensive care units (ICUs) may disrupt sleep. Quantitative ICU studies of concurrent and continuous sound and light levels and timings remain sparse in part due to the lack of ICU equipment that monitors sound and light. Here, we describe sound and light levels across three adult ICUs in a large urban United States tertiary care hospital using a novel sensor. The novel sound and light sensor is composed of a Gravity Sound Level Meter for sound level measurements and an Adafruit TSL2561 digital luminosity sensor for light levels. Sound and light levels were continuously monitored in the room of 136 patients (mean age = 67.0 (8.7) years, 44.9% female) enrolled in the Investigation of Sleep in the Intensive Care Unit study (ICU-SLEEP; Clinicaltrials.gov: #NCT03355053), at the Massachusetts General Hospital. The hours of available sound and light data ranged from 24.0 to 72.2 hours. Average sound and light levels oscillated throughout the day and night. On average, the loudest hour was 17:00 and the quietest hour was 02:00. Average light levels were brightest at 09:00 and dimmest at 04:00. For all participants, average nightly sound levels exceeded the WHO guideline of < 35 decibels. Similarly, mean nightly light levels varied across participants (minimum: 1.00 lux, maximum: 577.05 lux). Sound and light events were more frequent between 08:00 and 20:00 than between 20:00 and 08:00 and were largely similar on weekdays and weekend days. Peaks in distinct alarm frequencies (Alarm 1) occurred at 01:00, 06:00, and at 20:00. Alarms at other frequencies (Alarm 2) were relatively consistent throughout the day and night, with a small peak at 20:00. In conclusion, we present a sound and light data collection method and results from a cohort of critically ill patients, demonstrating excess sound and light levels across multiple ICUs in a large tertiary care hospital in the United States. ClinicalTrials.gov, #NCT03355053. Registered 28 November 2017, https://clinicaltrials.gov/ct2/show/NCT03355053.

Tujuan pada penelitian ini adalah untuk mengetahui pengaruh pengembangan karir (perlakuan yang adil, kepedulian atasan, informasi, minat dan kepuasan) terhadap kinerja karyawan pada PT Adidaya Andalan Asia cabang Samarinda. Jenis penelitian ini adalah penelitian kuantitaif dengan sampel sebanyak 52 responden. Teknik pengambilan sampel adalah menggunakan Incidental sampling. Uji instrument menggunakan uji validitas (product moment)dan uji reliabilitas (Alpha Cronbach) serta uji korelasi (r) dan uji koefisien determinasi. Adapun uji hipotesis dengan menggunakan regresi linier berganda, uji t dan uji F dengan alat bantu SPSS 22.0. Hasil penelitian menunjukkan bahwa secara parsial pada taraf 5% variabel perlakuan yang adil (X1), kepedulian atasan (X2), informasi (X3), minat (X4), kepuasan (X5) berpengaruh signifikan terhadap kinerja karyawan. Kemudian secara simultan pada taraf 5% variabel perlakuan yang adil (X1), kepedulian atasan (X2), informasi (X3), minat (X4), kepuasan (X5) berpengaruh signifikan terhadap kinerja karyawan dengan persentase pengaruh sebesar 36,80%.

Gut microflora dysbiosis affects the majority of individuals after COVID-19, contributing to both gastro-intestinal (GI) and non-GI symptoms. Natural phytochemicals have reported anti-viral properties and favourable effects on inflammatory and oxidative pathways, both important for tissue damage post-viral pneumonia. This study involved 147 participants with symptomatic COVID-19, randomised to receive a placebo (P) or a phytochemical-rich concentrated food capsule (PC) in addition to a pre/probiotic lactobacillus capsule. Participants taking the PC had an almost two-fold reduction in mean fatigue scores compared to P [p = 0.02], a three-fold reduction in cough score and more than a double improvement in overall well-being scores [p = 0.02]. Two (1.5%) participants reported mild, increased bloating which they felt was attributable to the capsules, although GI symptoms improved in 25 of 31 participants (82%) who reported them at baseline. Sedentary, older, previously hospitalised men with GI symptoms had a statistically significantly improvement among those given the probiotic. Although some participants with early disease would have improved spontaneously, such a rapid improvement observed in the majority of participants, who had been suffering for an average of 108 days, was clinically relevant and welcomed, especially among those more likely to have pre-existing gut dysbiosis. We are now evaluating whether this blend could also enhance antibody titres post-COVID-19 vaccination.

Food fortification is an effective approach to improve vitamin D (VD) concentrations in foods. Eggs are a useful food vehicle for enrichment with VD via its hydroxylated metabolite, 25-hydroxyvitamin D (25-D3), in hen feed. This study determined the impact of time of lay, storage conditions (ambient and refrigeration) and common cooking methods (boiling, frying, scrambling, poaching and microwaving) on the vitamin D metabolite concentration of eggs enriched with 25-D3. Processed samples were freeze-dried and analysed for D3 and 25-D3 using an HPLC-MS(/MS) method. The results indicated that storage and cooking practices influence VD metabolites, with 25-D3 showing true retention of 72–111% and concentrations of 0.67–0.96 µg/100 g of whole egg. Vitamin D3 showed true retention of 50–152% and concentrations of 0.11–0.61 µg/100 g of whole egg. Depending on the storage and method of cooking applied, the calculated total VD activity of enriched eggs ranged from 3.45 to 5.43 µg/100 g of whole egg and was 22–132% higher in comparison to standardised VD content for non-enriched British eggs. The study suggests that 25-D3 is a stable metabolite in eggs following storage and cooking, and that 25-D3-enriched eggs may serve as a potent dietary source of VD.

Background and objectives According to data from large national registries, almost 20 to 25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. Design, setting, participants, and measurements ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. Results We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded respectively the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES ‘first’ eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (p = 0.02) and in patients with a family history of kidney disease (p Conclusion Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome ‘first’ may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Supplementary Tables S1-S5.

Purpose: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response.Experimental Design: Both in vitro and in vivo assays, using the human TT RETC634W MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients.Results: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2.Conclusions: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients. Clin Cancer Res; 17(7); 2044–54. ©2011 AACR.

Supplementary Table 2 from Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

Supplementary Movie 1 from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

We have reported previously that the interaction of αE(CD103)β7 integrin, expressed on a CD8+ tumor-infiltrating lymphocyte (TIL) clone but not on a peripheral blood lymphocyte (PBL) counterpart, with the epithelial marker E-cadherin on human lung tumor cells plays a crucial role in T-cell receptor–mediated cytotoxicity. We show here that both TIL and PBL clones are able to migrate toward autologous tumor cells and that chemokine receptor CCR5 is involved in this process. Adoptive transfer of the PBL clone in the cognate tumor engrafted in nonobese diabetic/severe combined immunodeficient mice and subsequent coengagement of T-cell receptor and transforming growth factor-β1 receptor triggers CD103 expression on T-cell surface resulting in strong potentiation of antitumor lytic function. Moreover, interaction of αEβ7 integrin with E-cadherin, but not lymphocyte function-associated antigen-1 with intercellular adhesion molecule-1, promotes CCR5 recruitment at the immunologic synapse formed between TIL and tumor cells, leading to inhibition of T-cell sensitivity to CCL5 chemotactic gradient. These results provide evidence for a role of tumor microenvironment, namely MHC class I–restricted antigen presentation and transforming growth factor-β1 secretion, in regulating the effector phase of tumor-specific CTL response. They also suggest a unique role of CD103 in T-cell retention at the tumor site by a CCR5-dependent mechanism. [Cancer Res 2009;69(15):6249–55]

Supplementary Figure 1 from Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

Non–small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g., T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G1 cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g., caspase-2, caspase-3, caspase-7, and caspase-9), but not in the extrinsic (e.g., caspase-8), pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and caspase-independent effector mechanisms. Transcriptome analyses revealed the up-regulation of proapoptotic (e.g., Bim, Puma) and cell cycle inhibitory (e.g., p27Kip1, p57Kip2) factors, as well as the down-regulation of antiapoptotic (e.g., Mcl1), heat shock (e.g., HSP40, HSP70, HSP90), and cell cycle promoting [e.g., cyclins B1, D1, and D3; cyclin-dependent kinase 1 (CDK1); MCM family proteins; proliferating cell nuclear antigen (PCNA)] proteins. BMS-690514–induced death of H1975 cells was modified in a unique fashion by a panel of small interfering RNAs targeting apoptosis modulators. Down-regulation of components of the nuclear factor-κB survival pathway (e.g., p65, Nemo/IKKγ, TAB2) sensitized cells to BMS-690514, whereas knockdown of proapoptotic factors (e.g., Puma, Bax, Bak, caspase-2, etc.) and DNA damage–related proteins (e.g., ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC. [Cancer Res 2007;67(13):6253–62]

Supplementary Figures 1-6 from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

Supplementary Table 1 from A Novel Epidermal Growth Factor Receptor Inhibitor Promotes Apoptosis in Non–Small Cell Lung Cancer Cells Resistant to Erlotinib

Supplementary Figure, Table and Movie Legends from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

Supplementary Figure 2 from Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

Supplementary Tables 1-4 from miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death

Supplementary Table 1 from Intratumoral Induction of CD103 Triggers Tumor-Specific CTL Function and CCR5-Dependent T-Cell Retention

Supplementary Methods and Materials from A Novel Epidermal Growth Factor Receptor Inhibitor Promotes Apoptosis in Non–Small Cell Lung Cancer Cells Resistant to Erlotinib

The anterior cerebral artery (ACA) and the anterior communicating artery (AComA) are important arteries of the telencephalon and are prominent location for cerebral aneurysms. Their embryological development is closely linked, and explains the possible variants seen in adults. In this paper, we present details related to the development of these two arteries, focusing on some variants such as the infra-optic course of the ACA, the unpaired ACA, and the persistent primitive olfactory artery.

In the field of production automation, IO-Link Wireless (IOLW) offers energy-efficient and cost-effective solutions for networking wireless sensors and actuators close to the machines on the industrial shop-floor. In this paper, a concept is presented to enhance IOLW with security-for-safety and safety features in order to make safety critical systems in industrial environments with performance characteristics dedicated to demanding applications feasible. As data security is of paramount importance, security mechanisms already implemented in other wireless protocols are investigated and security-for-safety mechanisms for IOLW are introduced. Potential cryptographic algorithms are evaluated for IOLW with respect to energy consumption and timing. Taking performance parameters into account, which are crucial for industrial manufacturing processes, a safety protocol data unit (SPDU) is described and evaluated for different payload length and cycle times. Finally, an outlook towards the implementation of a demonstrator setup completes this work.

Background Some herbal natural products play an important role in protecting organisms from the toxic effect of some xenobiotics. The present study was designed to evaluate the potential therapeutic effects of Ottelione A (OTTE) against carbon tetrachloride(CCl4)-induced toxicity in mice. Methods Adult male Swiss albino mice were divided into six groups: group I was used as a normal control received olive oil; group II received DMSO; group III received OTTE; group IV received CCl4 in olive oil, (injected i.p) 3 times/week for 6 weeks; group V received the same CCl4 regimen as group IV followed by OTTE injected for 15 days, and group VI first received OTTE injected for 15 days followed by the same CCl4 regimen as group IV. Some biochemical and histological parameters were investigated. Results Our results showed that the administration of CCl4 caused hepatotoxicity, as monitored by the significant increase in biochemical parameters concerning the olive oil group. Treatment with OTTE appeare d to be effective against hepatotoxic and liver changes induced by CCl4, as evidenced by the improvement of the same parameters. Conclusion Ottelione A (OTTE) has good antioxidant and therapeutic properties, which can help in preventing CCl4-induced hepatotoxicity in both pre-treatment and post-treatment modes. Graphical Abstract

Understanding and mitigating optical loss is critical to the development of high-performance photonic integrated circuits (PICs). Especially in high refractive index contrast compound semiconductor (III-V) PICs, surface absorption and scattering can be a significant loss mechanism, and needs to be suppressed. Here, we quantify the optical propagation loss due to surface state absorption in a suspended GaAs photonic integrated circuits (PIC) platform, probe its origins using X-ray photoemission spectroscopy (XPS) and spectroscopic ellipsometry (SE), and show that it can be mitigated by surface passivation using alumina ($Al_{2}O_{3}$). We also explore potential routes towards achieving passive device performance comparable to state-of-the-art silicon PICs, Comment: 8 pages, 8 figures, Comments welcome !!! v2: fixed typo in equation 1, minor edits in text

The results of this study indicate that the SST evaluation does not provide a validated objective indicator for handling quality on a large sample of the population. As of yet, such indicator remains to be identified.

This thesis examines how injustice towards the intellectually disabled can be challenged and argues that the current literature on social change cannot be straightforwardly applied. I discuss how the barriers intellectual disability presents can be overcome and argue that a focus on intellectual disability reveals the crucial role virtue plays within social movements.

Supplementary information file

AI tools increasingly shape how we discover, make and experience music. While these tools can have the potential to empower creativity, they may fundamentally redefine relationships between stakeholders, to the benefit of some and the detriment of others. In this position paper, we argue that these tools will fundamentally reshape our music culture, with profound effects (for better and for worse) on creators, consumers and the commercial enterprises that often connect them. By paying careful attention to emerging Music AI technologies and developments in other creative domains and understanding the implications, people working in this space could decrease the possible negative impacts on the practice, consumption and meaning of music. Given that many of these technologies are already available, there is some urgency in conducting analyses of these technologies now. It is important that people developing and working with these tools address these issues now to help guide their evolution to be equitable and empower creativity. We identify some potential risks and opportunities associated with existing and forthcoming AI tools for music, though more work is needed to identify concrete actions which leverage the opportunities while mitigating risks., Presented at Cultures in AI/AI in Culture workshop at NeurIPS 2022

BackgroundNephrosclerosis is one of the histopathological consequences of severe or malignant hypertension (MH), some of the pathophysiology of which has been extrapolated from essential polygenetic arterial hypertension. Despite our recent description of unsuspected ciliopathies with MH, causes of MH in young patients with severe renal impairment are poorly understood.MethodsTo refine and better describe the MH phenotype, we studied clinical and prognostic factors in young patients receiving a kidney biopsy following their first episode of MH. Patients were identified retrospectively and prospectively from eight centres over a 35-year period (1985–2020). Keywords were used to retrospectively enrol patients irrespective of lesions found on renal biopsy.ResultsA total of 114 patients were included, 77 (67%) of whom were men, average age 34 years, 35% Caucasian and 34% African origin. An isolated clinical diagnosis of severe nephrosclerosis was suggested in only 52% of cases, with 24% primary glomerulopathies. Only 7% of patients had normal renal function at diagnosis, 25% required emergency dialysis and 21% were eventually transplanted. Mortality was 1% at the last follow-up. Independent prognostic factors significantly associated with renal prognosis (6-month dialysis) and predictive of end-stage renal disease were serum creatinine on admission {odds ratio [OR] 1.56 [95% confidence interval (CI) 1.34–1.96], P 30% [OR 10.70 (95% CI 1.53–112.03), P = .03]. Astonishingly, the presence of any thrombotic microangiopathy lesion on renal biopsy was an independent, protective factor [OR 0.14 (95% CI 0.02–0.60), P = .01]. The histopathological hallmark of nephrosclerosis was found alone in only 52% of study patients, regardless of ethnicity.ConclusionsThis suggests that kidney biopsy might be beneficial in young patients with MH.

Social Enterprises are becoming a significant force of social as well as economic good despite facing many difficulties that are brought about by their unique characteristics. Chief among these is the question of their perceived legitimacy that impinges upon their ability to gain funding, acquire contracts and appear as capable organisations to potential partnering institutions. This study explores the means by which Social Enterprises are legitimized through participation in the Social Enterprise Place (SEP) programme in the UK. By examining the Boundary Objects (BO) that span the intersections of the incumbent social groups it identifies three pillars upon which SEPs have facilitated SE legitimacy. These pillars comprise (i) the place-based language (syntactic BO), that enables the identification of (ii) common social goals (semantic BOs), and thereby enables the (iii) mobilization of resources toward their resolution (pragmatic BOs). This research provides insight into the facilitation of legitimacy for Social Enterprises that are engaged in a place-based initiative. By responding to Peterson’s (2016) call for macromarketers to take more note of meso level marketing dynamics in different industries the paper highlights the potential for place to facilitate the legitimacy of SEs. In addition, it reveals a further macromarketing dimension to Boundary Object plasticity whereby they may evolve through syntactic, semantic and pragmatic forms over time.

International audience; Background and objectives Kidney impairment of ANCA-associated vasculitides can lead to kidney failure. Patients with kidney failure may suffer from vasculitis relapses but are also at high risk of infections and cardiovascular events, which questions the maintenance of immunosuppressive therapy. Design, setting, participants, & measurements Patients with ANCA-associated vasculitides initiating long-term dialysis between 2008 and 2012 in France registered in the national Renal Epidemiology and Information Network registry and paired with the National Health System database were included. We analyzed the proportion of patients in remission off immunosuppression over time and overall and event-free survival on dialysis (considering transplantation as a competing risk). We compared the incidence of vasculitis relapses, serious infections, cardiovascular events, and cancers before and after dialysis initiation. Results In total, 229 patients were included: 142 with granulomatous polyangiitis and 87 with microscopic polyangiitis. Mean follow-up after dialysis initiation was 4.6±2.7 years; 82 patients received a kidney transplant. The proportion of patients in remission off immunosuppression increased from 23% at dialysis initiation to 62% after 5 years. Overall survival rates on dialysis were 86%, 69%, and 62% at 1, 3, and 5 years, respectively. Main causes of death were infections (35%) and cardiovascular events (26%) but not vasculitis flares (6%). The incidence of vasculitis relapses decreased from 57 to seven episodes per 100 person-years before and after dialysis initiation ( P =0.05). Overall, during follow-up, 45% of patients experienced a serious infection and 45% had a cardiovascular event, whereas 13% experienced a vasculitis relapse. Conclusions The proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increases with time spent on dialysis. In this cohort, patients were far less likely to relapse from their vasculitis than to display serious infectious or cardiovascular events. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN03190321.mp3

International audience; Polycyclic heterocycles such as 1- and 2-aminothioxanthones are important precursors to molecules endowed with different properties and original syntheses are always required. Here, 1-aminothioxanthone was obtained either in four steps from commercially available thioxanthone, or in five steps from 3-fluoroaniline. As for 2-aminothioxanthone, direct N-arylation using commercial 2-chlorothioxanthone gave its Boc-protected derivative. From 1-aminothioxanthone, original 10-methylbenzothiopyrano[4,3,2-de]indolo[2,3-b]quinoline was synthesized by tandem N-arylation-cyclization using 2-iodo-N-methylindole in the presence of copper. However, this approach being less efficient with 2-iodobenzothiophene, we also studied another strategy. Our efforts were next concentrated on the synthesis of benzofuro-, benzothieno- and indolo[2,3-b]benzothiopyrano[4,3,2-de]1,8-naphthyridines which are original hexacycles of helical nature. Different approaches were designed and we achieved our goal from 2-chloro-4-fluoropyridine, in five steps. The original polycyclic compounds obtained were evaluated as protein kinase inhibitors, and the results were rationalized by molecular modeling experiments. Finally, their photophysical properties were measured for the purpose of structure-property relationships.

Meiosis requires the formation of programmed DNA double strand breaks (DSBs), essential for fertility and for generating genetic diversity. In male and female meiotic cells, DSBs are induced by the catalytic activity of the TOPOVIL complex formed by SPO11 and TOPOVIBL. To ensure genomic integrity, DNA cleavage activity is tightly regulated, and several accessory factors (REC114, MEI4, IHO1, and MEI1) are needed for DSB formation in mice. How and when these proteins act is not understood. Here, we show that REC114 is a direct partner of TOPOVIBL, and identified their conserved interacting domains by structural analysis. We then analysed the role of this interaction by monitoring meiotic DSBs in female and male mice carrying point mutations in TOPOVIBL that decrease or disrupt its binding to REC114. In these mutants, DSB activity was strongly reduced genome-wide in oocytes, but only in sub-telomeric regions in spermatocytes. In addition, in mutant spermatocytes, DSB activity was delayed in autosomes. These results provide evidence that REC114 is a key member of the TOPOVIL catalytic complex, and that the REC114/TOPOVIBL interaction ensures the efficiency and timing of DSB activity by integrating specific chromosomal features.

In human movement analysis, multibody models are an indispensable part of the process both for marker-based and video-based markerless approaches. Constituents (segments, joint constraints, body segment inertial parameters etc.) of such models and modeler’s choice play an important role in the accuracy of estimated results (segmental and joint kinematics, segmental and whole-body center of mass positions etc.). For marker-based method, although standard models exist, particularly for the lower extremity (e.g., Conventional Gait Model or models embedded in OpenSim), there seems to be a lack of consolidated explanation on the constituents of the whole-body model. For the markerless approach, multibody kinematic models (e.g., the Theia3D model) have been in use lately. However, there is no clear explanation on the estimated quantities (e.g., joint centers, body surface landmarks etc.) and their relation to the underlying anatomy. This also motivates the need for a description of the markerless multibody model. Moreover, comparing markerless results to those of classical marker-based method is currently the most commonly used approach for evaluation of markerless approaches. This study first aims to develop and describe a whole-body marker-based model ready to be used for human movement analysis. Second, the markerless multibody model embedded in Theia3D is described and inertial parameters are redefined. We also report assessment of the markerless approach compared to marker-based method for a static T-pose performed by 15 subjects. Finally, we disseminate the marker-based and markerless multibody models for their use in Visual3D.

Background: Rheopheresis is a double-filtration plasmapheresis that removes a defined spectrum of high-molecular-weight proteins to lower plasma viscosity and improves microcirculation disorders. This technique can be performed in hemodialysis (HD) patients with severe microischemia. Interestingly, some studies showed that rheopheresis sessions improve endothelial function. Methods: Our study evaluated the inflammatory and endothelial biomarker evolution in 23 HD patients treated or not with rheopheresis. A p value ≤ 0.001 was considered statistically significant. Results: Thirteen HD patients treated by rheopheresis either for a severe peripheral arterial disease (N = 8) or calciphylaxis (N = 5) were analyzed. Ten control HD patients were also included in order to avoid any misinterpretation of the rheopheresis effects in regard to the HD circuit. In the HD group without rheopheresis, the circulating endothelial adhesion molecules, cytokines, angiogenic factor concentrations, and circulating levels were not modified. In the HD group with rheopheresis, the circulating endothelial adhesion molecules (sVCAM-1, sP-selectin, and sE-selectin) experienced a significant reduction, except sICAM-1. Among the pro-inflammatory cytokines, TNF-α was significantly reduced by 32.6% [(−42.2)–(−22.5)] (p < 0.0001), while the anti-inflammatory cytokine IL-10 increased by 674% (306–1299) (p < 0.0001). Among the angiogenic factors, only sEndoglin experienced a significant reduction. The CEC level trended to increase from 13 (3–33) cells/mL to 43 (8–140) cells/mL (p = 0.002). We did not observe any difference on the pre-session values of the molecules of interest between the first rheopheresis session and the last rheopheresis session. Conclusion: Rheopheresis immediately modified the inflammation balance and the endothelial injury biomarkers. Further studies are needed to understand the mechanisms underlying these biological observations.

In dieser Arbeit werden die Grundlagen für einen neuartigen robotergestützten Fertigungsprozess erarbeitet, bei dem duroplastisch vorimprägnierte, glasfaserverstärkte Faserverbundhalbzeuge lokal auf metallische Bauteile gepresst und ausgehärtet werden, um mit geringem Materialeinsatz deren Eigenschaftsniveau wesentlich zu steigern. Diese Technologie ist nach aktuellem Stand einzigartig und ermöglicht erstmals das voll-automatisierte Fertigen von Metall-Faserverbund-Hybridstrukturen im automobilen Großserienmaßstab. Diese Arbeit verfolgt auf Grund der hohen Komplexität der Aufgabenstellung einen durchgängigen Ansatz von der Materialauswahl und Prozessbeschreibung über die Struktur- und Prozesssimulation bis zur Bewertung der Eigenschaften am komplexen Bauteil. Als Randbedingung ist in Anlehnung an eine bestehende Karosseriefertigung eine Taktzeit unter 60 s festgelegt. Weiterhin muss aufgrund der begrenzten Presskraft der Industrieroboter und der vorgesehenen Applikationsfläche der notwendige Pressdruck gegenüber dem Stand der Technik wesentlich reduziert werden. Durch die ganzheitliche Betrachtungsweise der Problemstellung von der Materialauswahl und dessen Fertigungsparametern über die simulative Betrachtung des Herstellungsprozesses und den strukturellen Material- und Bauteileigenschaften hin zur Bewertung wesentlicher Einflussfaktoren wie Temperatur und Korrosionsbeständigkeit auf die mechanischen Eigenschaften, werden grundlegende Fragestellungen hinsichtlich der Machbarkeit dieser neuartigen robotergestützten Technologie beantwortet. Weiterhin wird durch die industrielle Umsetzung des Fertigungsprozesses im Rahmen einer vollautomatisierten robotergestützten Applikationszelle ein wesentlicher Schritt in Richtung Großserienfähigkeit von Faserverbundstrukturen bewältigt.:1 Einleitung 1 1.1 Motivation und Zielstellung 1.2 Anforderung an Material und Prozess 1.3 Vorgehensweise und Methodik 2 Grundlagen 2.1 Faserverbundwerkstoffe im Automobil 2.2 Metall-Faserverbund-Hybridbauweisen: Stand der Technik 2.3 Verwendete Werkstoffe und Halbzeuge 2.4 Literaturüberblick 3 Materialspezifikation und Herstellungsprozess 3.1 Probekörper, Fertigungsvorrichtungen und Prüfmethoden 3.2 Bewertung ausgewählter Prepregs und Auswahl einer Vorzugsvariante 3.3 Ermittlung von Fertigungsparametern zur Erzeugung einer ausreichenden Laminatqualität 3.4 Haftfestigkeit hybrider Verbunde in Abhängigkeit der Fertigungsparameter 3.5 Bewertung des Einflusses eines zusätzlichen Klebstoffs 3.6 Potenzialbewertung von Metall-Faserverbund-Hybridbauteilen 3.7 Bewertung der Lagenanzahl der Faserverbundverstärkung 4 Modellbildung und Struktursimulation 4.1 Strukturanalyse des Faserverbundmaterials 4.2 Strukturanalyse der Grenzschicht zwischen Metall und Faserverbund 4.3 Strukturanalyse des Hutprofils im 3-Punkt-Biegeversuch 5 Modellbildung und Prozesssimulation 5.1 Mathematische Beschreibung der Reaktivität der Matrix 5.2 Thermo-chemische Kopplung der Materialkennwerte 5.3 Thermo-chemo-mechanische Kopplung der Materialkennwerte 5.4 Simulation des Herstellungsprozesses der Faserverbundplatte 5.5 Simulation des Herstellungsprozesses des Metall-Kunststoff-Hybrid-Streifenprobekörpers 5.6 Sensitivitätsanalyse der Materialkennwerte 5.7 Simulation des Herstellungsprozesses des hybriden Hutprofils 6 Ergänzende Bewertung automobilspezifischer Einflüsse 6.1 Prüftemperatur 6.2 Belastungsgeschwindigkeit 6.3 Klimawechsel und Korrosion 7 Robotergestützter Applikationsprozess 7.1 Konzeptionierung, Aufbau und Inbetriebnahme des Fertigungsprozesses 7.2 Prüfung der hybriden Hutprofile, hergestellt im robotergestützten Applikationsprozess 7.3 Ermittlung der Zykluszeit und Abschätzung für den Serienprozess 8 Zusammenfassung und Ausblick Literaturverzeichnis Anhang A Grundlagen B Materialspezifikation und Herstellungsprozess C Modellbildung und Struktursimulation D Prozessmodellierung und Simulation E Bewertung automobilrelevanter Einflüsse

Three series of our lead CLK1 inhibitor

The kidney-specific gene

Security is an essential requirement of Industrial Control System (ICS) environments and its underlying communication infrastructure. Especially the lowest communication level within Supervisory Control and Data Acquisition (SCADA) systems - the field level - commonly lacks security measures. Since emerging wireless technologies within field level expose the lowest communication infrastructure towards potential attackers, additional security measures above the prevalent concept of air-gapped communication must be considered. Therefore, this work analyzes security aspects for the wireless communication protocol IO-LinkWireless (IOLW), which is commonly used for sensor and actuator field level communication. A possible architecture for an IOLW safety layer has already been presented recently [1]. In this paper, the overall attack surface of IOLW within its typical environment is analyzed and attack preconditions are investigated to assess the effectiveness of different security measures. Additionally, enhanced security measures are evaluated for the communication systems and the results are summarized. Also, interference of security measures and functional safety principles within the communication are investigated, which do not necessarily complement one another but may also have contradictory requirements. This work is intended to discuss and propose enhancements of the IOLW standard with additional security considerations in future implementations., 8 pages

For many years, most studies on administrative justice were written from a doctrinal legal perspective. More recently, however, administrative justice has also become the subject of a growing body of empirical research. This chapter provides an overview of empirical administrative justice research in three fields: administrative decision-making, redress mechanisms, and the impact of redress mechanisms on administrative practice. In legal doctrine, ‘legal instrumentalism’ has become central to thinking about administrative justice. However, the findings from empirical research provide little support for the underlying assumptions of instrumentalism. In this way, empirical legal research forces us to rethink the relationship between administrative law and administrative justice. The chapter concludes that while in some cases law and legal institutions may be an effective instrument to promote administrative justice in other cases, the direct impact of law is severely limited and law may even have a negative effect on the quality of administrative justice.