Passive Reciprocal high-pass/low-pass 4-bit phase shifter at 2.45 GHz

This paper presents the design, fabrication and measurement of a low cost, reciprocal 4-bit phase shifter at 2.45 GHz ISM band using COTS components. High-pass/low-pass filters in π configuration are used to implement the phase shifter bit sections. SPDT switches are realized with BAP51 dual PIN diodes, with resonant inductors in the off-state to provide high isolation. The driver circuit consisting of 74AHC240 octal buffer/inverter was implemented to switch the PIN diodes and control the phase states. A compact layout of the 4-bit phase shifter and driver circuitry was fabricated on a 4-layer FR4 substrate. The total size of the PCB board was 4.9×5.3 cm. The measurement results showed an RMS phase error better than 4.1°, insertion loss better than 8.8 dB and return loss better than 13 dB. The maximum power consumption of the 4-bit phase shifter was 80 mW

Reduced Life- and Healthspan in Mice Carrying a Mono-Allelic BubR1 MVA Mutation

Mosaic Variegated Aneuploidy (MVA) syndrome is a rare autosomal recessive disorder characterized by inaccurate chromosome segregation and high rates of near-diploid aneuploidy. Children with MVA syndrome die at an early age, are cancer prone, and have progeroid features like facial dysmorphisms, short stature, and cataracts. The majority of MVA cases are linked to mutations in BUBR1, a mitotic checkpoint gene required for proper chromosome segregation. Affected patients either have bi-allelic BUBR1 mutations, with one allele harboring a missense mutation and the other a nonsense mutation, or mono-allelic BUBR1 mutations combined with allelic variants that yield low amounts of wild-type BubR1 protein. Parents of MVA patients that carry single allele mutations have mild mitotic defects, but whether they are at risk for any of the pathologies associated with MVA syndrome is unknown. To address this, we engineered a mouse model for the nonsense mutation 2211insGTTA (referred to as GTTA) found in MVA patients with bi-allelic BUBR1 mutations. Here we report that both the median and maximum lifespans of the resulting BubR1(+/GTTA) mice are significantly reduced. Furthermore, BubR1(+/GTTA) mice develop several aging-related phenotypes at an accelerated rate, including cataract formation, lordokyphosis, skeletal muscle wasting, impaired exercise ability, and fat loss. BubR1(+/GTTA) mice develop mild aneuploidies and show enhanced growth of carcinogen-induced tumors. Collectively, these data demonstrate that the BUBR1 GTTA mutation compromises longevity and healthspan, raising the interesting possibility that mono-allelic changes in BUBR1 might contribute to differences in aging rates in the general population

Senescent cells in the development of cardiometabolic disease

Purpose of review Senescent cells have recently been identified as key players in the development of metabolic dysfunction. In this review, we will highlight recent developments in this field and discuss the concept of targeting these cells to prevent or treat cardiometabolic diseases. Recent findings Evidence is accumulating that cellular senescence contributes to adipose tissue dysfunction, presumably through induction of low-grade inflammation and inhibition of adipogenic differentiation leading to insulin resistance and dyslipidaemia. Senescent cells modulate their surroundings through their bioactive secretome and only a relatively small number of senescent cells is sufficient to cause persistent physical dysfunction even in young mice. Proof-of-principle studies showed that selective elimination of senescent cells can prevent or delay the development of cardiometabolic diseases in mice. Summary The metabolic consequences of senescent cell accumulation in various tissues are now unravelling and point to new therapeutic opportunities for the treatment of cardiometabolic diseases

Quick Scan Streefbeeld Aal

Het gaat slecht met de aal in Europa, de aalpopulatie en aalvangsten zijn sterk teruggelopen. De huidige intrek van glasaal is slechts 1-5% van de intrek in de 60-70-er jaren (ICES 2012). Om herstel van de aalpopulatie mogelijk te maken heeft De Raad van de Europese Unie in 2007 de “EU Regulation for the Recovery of the Eel Stock (EC 1100/2007)” vastgesteld. Deze verordening verplicht de lidstaten om met een eigen nationaal aalbeheerplan te komen en te implementeren. Het doel van deze aalbeheerplannen is daarbij als volgt omschreven: “...het verminderen van de antropogene sterfte, zodat er een grote kans bestaat dat ten minste 40% van de biomassa van schieraal kan ontsnappen naar zee, gerelateerd aan de beste raming betreffende de ontsnapping die plaats zou hebben gevonden indien de mens geen invloed had uitgeoefend op het bestand.” Deze '40% norm' wordt het streefbeeld genoemd. In het Nederlandse aalbeheerplan (2009) is het streefbeeld voor Nederland vastgesteld op 5200 ton

Population-based study of morbidity risk associated with pathological complete response after chemoradiotherapy for rectal cancer

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer may induce a pathological complete response (pCR) but increase surgical morbidity due to radiation-induced fibrosis. In this study the association between pCR and postoperative surgical morbidity was investigated. METHODS: Patients in the Netherlands with rectal cancer who underwent nCRT followed by total mesorectal excision between 2009 and 2017 were included. Data were stratified into patients who underwent resection with creation of a primary anastomosis and those who had a permanent stoma procedure. The association between pCR and postoperative morbidity was investigated in univariable and multivariable logistic regression analyses. RESULTS: pCR was observed in 976 (12·2 per cent) of 8003 patients. In 3472 patients who had a primary anastomosis, the presence of pCR was significantly associated with surgical complications (122 of 443 (27·5 per cent) versus 598 of 3029 (19·7 per cent) in those without pCR) and anastomotic leak (35 of 443 (7·9 per cent) versus 173 of 3029 (5·7 per cent) respectively). Multivariable analysis also showed associations between pCR and surgical complications (adjusted odds ratio (OR) 1·53, 95 per cent c.i. 1·22 to 1·92) and pCR and anastomotic leak (adjusted OR 1·41, 1·03 to 2·05). Of 4531 patients with a permanent stoma, surgical complications were observed in 120 (22·5 per cent) of 533 patients with a pCR, compared with 798 (20·0 per cent) of 3998 patients with no pCR (adjusted OR 1·17, 0·94 to 1·46). CONCLUSION: Patients with a pCR in whom an anastomosis was created were at increased risk of developing an anastomotic leak

Transparant afwegen; Waarden en risico's beoordelen van voedselkwaliteit

Transparante beleidsafwegingen en bredere risicobeoordelingen lijken cruciaal voor het waarmaken van de maatschappelijke aspiraties die het ministerie van LNV zich op het gebied van voedselkwaliteit heeft gesteld. De implementatie van instrumenten die dergelijke afwegingen ondersteunen blijkt echter problematisch. In dit rapport wordt ingegaan op de toepassing van een TRansparant Afwegingskader (TRAK) en het instrument van een Brede Risicobeoordeling (BRB). Deze instrumenten bieden zeker kansen, maar een succesvolle implementatie zal tijd en energie vergen gezien de knelpunten die er tegenover staan. Transparent policy decisions and broader risk assessments seem to be crucial for fulfilling the social aspirations established by the Ministry of Agriculture, Nature and Food Quality with regard to food quality. However, the use of instruments which support such decision(making seems to be encountering problems. This report discusses the application of a Transparent Consideration Framework (TRansparant AfwegingsKader, TRAK) and a Broad Risk Assessment (Brede Risicobeoordeling, BRB). These instruments certainly offer potential, but successful implementation will take time and energy in view of the problems facing them

Chemical and mechanical influence of root canal irrigation on biofilm removal from lateral morphological features of simulated root canals, dentine discs and dentinal tubules

Aim To investigate the anti-biofilm efficacy of irrigation using a simulated root canal model, the chemical effect of irrigants against biofilms grown on dentine discs and their impact on biofilm viscoelasticity, the efficacy of the irrigants in decontaminating infected dentinal tubules and the capacity of bacteria to regrow. Methodology Biofilm removal, viscoelastic analysis of remaining biofilms and bacterial viability were evaluated using a simulated root canal model with lateral morphological features, dentine discs and a dentinal tubule model, respectively. Experiments were conducted using a two-phase irrigation protocol. Phase 1: a modified salt solution (RISA) and sodium hypochlorite (NaOCl) were used at a low flow rate to evaluate the chemical action of the irrigants. Ultrasonic activation (US) of a chemically inert solution (buffer) was used to evaluate the mechanical efficacy of irrigation. Phase 2: a final irrigation with buffer at a high flow rate was performed for all groups. Optical coherence tomography (OCT), low load compression testing (LLCT) and confocal scanning laser microscopy analysis were used in the different models. One-way analysis of variance (anova) was performed for the OCT and LLCT analysis, whilst Kruskal-Wallis and Wilcoxon ranked tests for the dentinal tubule model. Results US and high flow rate removed significantly more biofilm from the artificial lateral canal. For biofilm removal from the artificial isthmus, no significant differences were found between the groups. Within-group analysis revealed significant differences between the steps of the experiment, with the exception of NaOCl. For the dentine discs, no significant differences regarding biofilm removal and viscoelasticity were detected. In the dentinal tubule model, NaOCl exhibited the greatest anti-biofilm efficacy. Conclusions The mechanical effect of irrigation is important for biofilm removal. An extra high flow irrigation rate resulted in greater biofilm removal than US in the artificial isthmus. The mechanical effect of US seemed to be more effective when the surface contact biofilm-irrigant was small. After the irrigation procedures, the remaining biofilm could survive after a 5-day period. RISA and NaOCl seemed to alter post-treatment remaining biofilms

Association of homozygous variants of STING1 with outcome in human cervical cancer

DNA-sensing receptor Cyclic GMP-AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS-STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING-encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8(+) T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS-STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer

The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression

Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P1B-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process

Accelerating Cosmic Microwave Background map-making procedure through preconditioning

Estimation of the sky signal from sequences of time ordered data is one of the key steps in Cosmic Microwave Background (CMB) data analysis, commonly referred to as the map-making problem. Some of the most popular and general methods proposed for this problem involve solving generalised least squares (GLS) equations with non-diagonal noise weights given by a block-diagonal matrix with Toeplitz blocks. In this work we study new map-making solvers potentially suitable for applications to the largest anticipated data sets. They are based on iterative conjugate gradient (CG) approaches enhanced with novel, parallel, two-level preconditioners. We apply the proposed solvers to examples of simulated non-polarised and polarised CMB observations, and a set of idealised scanning strategies with sky coverage ranging from nearly a full sky down to small sky patches. We discuss in detail their implementation for massively parallel computational platforms and their performance for a broad range of parameters characterising the simulated data sets. We find that our best new solver can outperform carefully-optimised standard solvers used today by a factor of as much as 5 in terms of the convergence rate and a factor of up to $4$ in terms of the time to solution, and to do so without significantly increasing the memory consumption and the volume of inter-processor communication. The performance of the new algorithms is also found to be more stable and robust, and less dependent on specific characteristics of the analysed data set. We therefore conclude that the proposed approaches are well suited to address successfully challenges posed by new and forthcoming CMB data sets.Comment: 19 pages // Final version submitted to A&