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Cell-derived extracellular vesicles (EVs) are evolutionary-conserved secretory organelles that, based on their molecular composition, are important intercellular signaling regulators. At least three classes of circulating EVs are known based on mechanism of biogenesis: exosomes (sEVs/Exos), microparticles (lEVs/MPs) and shed midbody remnants (sMB-Rs). sEVs/Exos are of endosomal pathway origin, microparticles (lEVs/MPs) from plasma membrane blebbing, and shed midbody remnants (sMB-Rs) arise from symmetric cytokinetic abscission. Here, we isolate sEVs/Exos, lEVs/MPs and sMB-Rs secreted from human isogenic primary (SW480) and metastatic (SW620) colorectal cancer (CRC) cell lines in milligram quantities for label-free MS/MS-based proteomic profiling. Purified EVs revealed selective composition packaging of exosomal protein markers in SW480/SW620-sEVs/Exos, metabolic enzymes in SW480/SW620-lEVs/MPs, while centralspindlin complex proteins, nucleoproteins, splicing factors, RNA granule proteins, translation-initiation factors, and mitochondrial proteins selectively traffic to SW480/SW620-sMB-Rs. Collectively, we identify 39 human cancer-associated genes in EVs; 17 associated with SW480-EVs, 22 with SW620-EVs. We highlight oncogenic receptors/transporters selectively enriched in sEVs/Exos (EGFR/ FAS in SW480-Exos and MET, TGFBR2, ABCB1 in SW620-sEVs/Exos). Interestingly, MDK, STAT1, and TGM2 are selectively enriched in SW480-sMB-Rs, and ADAM15 to SW620-sMB-Rs. Our study reveals sEVs/Exos, lEVs/MPs and sMB-Rs have distinct protein signatures that open potential diagnostic avenues of distinct types of EVs for clinical utility.

Statistically and clinically significant cognitive declines are observed in a small subset of individuals with Parkinson's Disease (PD) following treatment with Deep Brain Stimulation (DBS).We examine the association between multi-domain cognitive decline (MCD) and demographic and baseline clinical variables and the incidence of serious adverse events (SAE) arising within a six-month interval following DBS for PD.Study participants with PD who displayed MCD at 6-month follow-up evaluation after DBS (n = 18) were contrasted with individuals with PD from the same study who did not show cognitive decline after DBS (n = 146). Logistic regression analyses were employed to assess relationship between predictors, including age (70 years old), pre-DBS cognitive screening test performance, SAE, and MCD. MCD+ and MCD-groups were also compared on other baseline clinical and demographic variables.MCD showed modest association with older age and lower baseline neurocognitive screening performance, whereas the groups did not differ on most other baseline clinical and demographic variables. SAEs during the study interval were the most robust predictor of MCD in the DBS group. A variety of SAEs were documented in study participants experiencing MCD after DBS surgery, including, but not limited to, infections and small intracranial hemorrhages.Older age and lower baseline cognition measured prior to treatment are associated with MCD measured at six-months after DBS. SAE occurring following DBS surgery are also predictive of MCD. These predictors may reflect aspects of "frailty" in advanced PD. Risk factors for SAE warrant careful consideration in clinical trials.

This article explores what is essential to analytic work by drawing not only on Freud, but also on two additional sources: Friedman's (2019) notion of the psychoanalytic phenomenon as described in Freud's book on technique; and Weber's (1991, 2000) understanding of Freud's metapsychology as a creation of terms that are necessary in order to work with a non-observable object, the unconscious. Using Freud's emphasis on the importance of dreams as a form of thinking, the author links the work of Friedman and Weber and extends it in doing a close reading of a specific passage by Freud, showing that the precarious nature of metapsychology is understandable as a form of paradigmatic logic. A dream of the author's gives a certain counterpoint to the paper.

Das Europäische Klimaschutzgesetz 2021 setzt sich das Ziel, die Netto- Treibhausgasemissionen bis zum Jahr 2030 um mindestens 55 % im Vergleich zum Jahr 1990 zu senken. Bis 2050 soll die Klimaneutralität erreicht werden. Hierzu bedarf es einer geschlossenen Kreislaufwirtschaft, die nur durch gemeinsame Anstrengungen aller Beteiligten zu erreichen ist. Die europäische Kreislaufwirtschaft leistet hier bereits einen bedeutenden Beitrag - und das auf allen Wertschöpfungsstufen.

Haematospermia is the presence of blood in the ejaculate. Noticing blood within the ejaculate can cause men great anxiety. In the majority of cases, the aetiology is benign with a self-limiting course. For a small proportion of men, haematospermia can indicate malignancy, so a thorough work up of certain cohorts is necessary. This article will discuss the initial investigation in primary care, when and which men to refer, and provide further evidence for GPs to counsel and reassure patients.

Background: Since its emergence in November, 2021, in southern Africa, the SARS-CoV-2 omicron variant of concern (VOC) has rapidly spread across the world. We aimed to investigate the severity of omicron and the extent to which booster vaccines are effective in preventing symptomatic infection. Methods: In this study, using the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) platform, we did a cohort analysis with a nested test-negative design incident case-control study covering the period Nov 1–Dec 19, 2021, to provide initial estimates of omicron severity and the effectiveness of vaccine boosters against symptomatic disease relative to 25 weeks or more after the second vaccine dose. Primary care data derived from 940 general practices across Scotland were linked to laboratory data and hospital admission data. We compared outcomes between infection with the delta VOC (defined as S-gene positive) and the omicron VOC (defined as S-gene negative). We assessed effectiveness against symptomatic SARS-CoV-2 infection, with infection confirmed through a positive RT-PCR. Findings: By Dec 19, 2021, there were 23 840 S-gene-negative cases in Scotland, which were predominantly among those aged 20–39 years (11 732 [49·2%]). The proportion of S-gene-negative cases that were possible reinfections was more than ten times that of S-gene-positive cases (7·6% vs 0·7%; p

Introduction As humans’ advance towards a Mars mission, ensuring astronaut safety, well-being, and performance becomes increasingly critical. Long-duration space exploration presents several challenges for human sleep, including altered photoperiods, prolonged confinement, and monotony. Antarctica provides an ideal analog for understanding how these and other stressors impact sleep over time. Prior studies among Antarctic cohorts have found reduced total sleep, increased sleep onset, and circadian phase delay. However, day-to-day regularity of sleep-wake patterns in the Antarctic over prolonged periods has not been studied. Methods Crew members (N= 110) at a coastal (McMurdo: MM, n = 88) and an inland Antarctic station (South Pole: SP, n = 22) were studied longitudinally for up to 9-months. Sleep was monitored continuously with actigraphy (Actiwatch Spectrum, Philips Respironics) and examined in relation to cumulative time on station and calendar month (photoperiod). Self-reported mental health symptoms were also examined monthly using The Mental Health Checklist (MHCL). The Sleep Regularity Index (SRI; Phillips et al., 2017) which calculates the percentage probability of an individual being in the same state (sleep vs. wake) at any two time-points 24 hours apart was calculated to examine sleep regularity over time. Results Controlling for time on station prior to participation, we observed no significant changes in monthly SRI over a 6-month period at MM where photoperiod alterations are less extreme. At SP, SRI remained very stable during months of total daylight but declined during winter months in the absence of sunlight. SRI scores were significantly different between month-8 and month-9 and with large effect sizes across month-7, month-8, and month-9. Participants with lower month-7 SRI scores had significantly higher MHCL poor self-regulation scores at the end of the mission. Conclusion Day-to-day variability in sleep–wake patterns is an important predictor of health and safety. Our findings show reductions in sleep regularity during prolonged Antarctic residence particularly at the SP station, where sunlight is absent for 6 months of the year. Less sleep regularity predicted worse mental health functioning. These findings suggest that mitigation the impact of altered light-dark cycles on sleep is critical for a Mars mission. Support (if any) NASA award #NNX15AC13G S014 to the last author.

Objective In view of changing landscape of surgical treatment for LUTS secondary to BPE, this audit was undertaken to assess key aspects of the processes and outcomes of the current interventional treatments for BPE, across different units in the UK. Materials and method A multi-institutional snapshot audit was conducted for patients undergoing interventions for LUTS/BPE over 8-week period. Using Delphi process two-part proforma was designed to capture data. Results 529 patients were included across 20 NHS trusts in England and Wales. Median age was 73 years. Indications for surgery were acute retention (47%) and LUTS (45%). 80% of patients had prior medical therapy. TURP formed the commonest procedure. 27% patients had Conclusion Monopolar TURP still remains the commonest intervention for BPE. Most departments are adopting newer technologies. The audit identified opportunities for development of consistent, effective and patient centric practices as well as need for large-scale focused studies.

AimsThe principal aim of this multicentre, international cohort study is to explore the safety concerns of clinicians when performing urodynamic studies (UDS) during the COVID-19 pandemic. This study will also assess provider preference on personal protective equipment (PPE) during UDS and awareness of relevant international guidelines. The outcome is to offer a practical means of reducing the risk of aerosol transmis-sion during UDS, to include a protocol for screening patients, and to consider safer methods of inducing urethral leak-point pressure. MethodsA 14-point, multiple-response, online questionnaire was designed through Survey Monkey. This was distributed to healthcare workers involved in UDS via email, WhatsApp, and Twitter. This included, of varying experience; urologists, urogynaecologists, clinical nurse specialists, and clinical scientists across the United Kingdom (UK), United States of America (USA), Australia, Europe, and Middle-East.ResultsThe study was conducted over two weeks and there were 104 responses to the survey. The majority of respondents were consultants (60%) and 73% of respondents performed UDS regularly. There were 56.7% of respondents who felt that UDS was safe to be re-instated and there were 52.8% who did not feel coughing was safe during the procedure. At the time of the survey, 83.5% were unaware of any national or international urological guidelines on the best practice for urodynamics during this era and 52.8% of clinicians stated they would wear PPE during UDS if it were reinstated. ConclusionThe majority of respondents felt safe to reinstate UDS; however, they felt more official guidance and recommendation is needed. Our proposed protocol can provide a safe and practical approach that keeps healthcare workers and patients safe.

The aim of emergency nephrectomy in cases of blunt renal trauma is to control bleeding and so should not be delayed. We present a case of grade V blunt renal trauma where renal artery emoblisation (RAE) was used in the operating theatre immediately prior to trauma nephrectomy in order to control arterial haemorrhage. In this case, prior utilisation of RAE allowed the urologist to perform a standard approach to the renal pedicle by opening the retroperitoneal space. This is more routinely practiced and carries less risk of vascular mesenteric injury compared with the standard approach in trauma. Intra-operatively, there was minimal bleeding and the intra-vascular coils were easily ligated. Post operatively the patient avoids the sequelae of an ischaemic kidney associated with delayed interval nephrectomy.

An energy-efficient (1.02 pJ/b) and high-speed (20.83 Gb/s/wire, 417 Gb/s/mm) link for ultra-short reach (USR) applications (up to 6-dB channel loss at the Nyquist frequency of 12.5 GHz) is presented. Correlated non-return to zero (CNRZ) signaling with low sensitivity to inter-symbol interference (ISI) has been developed to improve the link budget. In addition to high pin efficiency (5b6w: 5 bits over 6 wires), the proposed signaling method provides very good resistance against common-mode and crosstalk noise sources, allowing for dense routing. A very wide-band (1.3 GHz) jitter tracking mechanism has been employed to reduce the sensitivity of the system to random and deterministic jitter and relax design constraints on transmitter. A slicer with low kick-back noise and a circuit topology well matched to the continuous-time linear equalizer (CTLE) has been designed to provide both high input sensitivity and Process, supply Voltage, and Temperature (PVT) variations tolerance. The link operates with more than 22-ps (42.5% UI) eye opening at BER = 1E-15. Calibration loops are running in background for quadrature mismatch error correction, clock and data alignment (CDA), and offset removal.

Purpose Organic anions commonly released from plant roots are widely reported to mobilize soil phosphorus (P). We characterized soil organic P that was mobilized by organic anions and assessed its amenability to hydrolysis by phosphatase enzymes. Methods Six soils differing in organic P content were extracted with citrate, malate or oxalate solutions and incubated with preparations of phosphomonoesterase, phosphodiesterase, or phytase. Organic P compounds present in these extracts were putatively identified and quantified with solution 31P NMR spectroscopy and the enzyme-labile P fractions were assessed by changes in molybdate reactive P (MRP) concentration. Results Organic P mobilization varied markedly among the organic anions. Extraction with 10 mM citrate was most effective and extracted 7.8-fold more total P than the water controls across all soils. Approximately 95% of the extracted P was non-MRP. The organic anions increased both the amount of P extracted and the proportion of the total extracted P that was phosphatase labile. Phytase was generally the most effective enzyme with up to 60% of the total non-MRP being amenable to hydrolysis by phytase across all extracts. The presence of inositol hexakisphosphates in the extracts, as well as other forms of organic P including nucleic acids and phospholipids, was verified by 31P NMR with concentrations dependent on both organic anion and soil type. Conclusion The combination of organic anions and phosphatases represents a key mechanism by which plants and microorganisms can enhance the bioavailability of soil P. This has important implications for understanding P dynamics in natural and managed ecosystems and for ongoing efforts to improve the P-use efficiency of agricultural plants.

For women, being underrepresented in high-performance sport coaching is endemic. They also often report a sense of minoritisation, and incidents of discrimination. The purpose of the present study was to understand, using a gender-microaggressions perspective, how sexism manifests for women in elite coaching who report to be the “only” woman in their context, how they respond to such experiences, and how such discrimination is enabled. Through interviews with nine high-performance female head coaches globally, the prevalent type of microaggressions experienced were gendered microinvalidations. But findings also demonstrate that these women attempted to resist sexism. Nevertheless, being the “only” women restricted their resistance because they could not form collective power that led to transformations in the coaching culture. More action is required to build critical, evenly distributed masses of women across the coaching pathway. Future research must also address the features of organisational contexts that provide fertile grounds for exclusionary cultures.

Correlated Non-Return-to-Zero (CNRZ) signaling exhibits better pin-efficiency compared to the conventional binary differential NRZ signaling, while it does not compromise the sensitivity to Inter-Symbol Interference (ISI). This article analyzes performance of CNRZ transceivers, and provides experimental data for an Ultra-Short Reach (USR) link at 20.83 Gb/s/wire, implemented in FinFET 16 nm technology, consuming 1.02 pJ/b, As CNRZ is based on an orthogonal transformation, both encoding and decoding can be performed in analog, without any cost in terms of latency.

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent,Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anti-cancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an anti-reovirus neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin, However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic anti-tumour efficacy of reovirus and rapamycin combination.

A 1.02pJ/b USR link carrying 416.67 Gb/s/mm die edge (500Gb/s aggregated data rate) in 16nm FinFET, while occupying 2.4mm2, is presented. To enable dense routing over conventional package material, a modified correlated NRZ signaling with low sensitivity to ISI, Xtalk, and common-mod noise has been developed. A matched CTLE/slicer topology has been employed to enhance robustness of the receiver over PVT. A very wideband Rx PLL tracks the majority of Tx jitter, resulting in significant power saving by relaxing Tx design constraints.

Ageing has profound impact on the immune system, mainly on T-cells. However, it has been suggested that chronic exercise may delay immunosenescence. Master athletes represent an interesting sub-demographic group to test this theory since they maintain a high training frequency and load throughout life. The purpose of this study was to evaluate the effects of lifelong training on the senescence and mobilization of T lymphocytes in response to acute exercise.Nineteen athletes who regularly participated in training and competitions for more than 20 years throughout their lives and a control group of 10 healthy individuals participated in this study. All subjects performed a progressive test to exhaustion on a cycle ergometer. Blood samples were obtained before (Pre), 10 min after the test (Post) and 1 h after the test (1h). Phenotypic study of peripheral blood T-cells was performed by flow cytometry. Genes of interest expression was done on T-cells purified by cell sorting.Master athletes had a lower percentage of senescent naïve, central memory and effector memory CD8+ T-cells and senescent naïve and effector memory CD4+ T-cells. Age had a positive effect on SLEC CD8+ T-cells and a negative effect on naïve CD8+ T-cells. VO2max positively correlated with the proportion of naïve CD4+ T-cells and negatively correlated with the percentage of total lymphocytes. No differences were founded for CD4+ and CD8+ T-cells and their subsets between master athletes and the control group at all times of measurement. No differences were observed in the CD45RA expressing effector memory cells (EMRA) for the various study conditions. The mRNA expression of the CCR7 gene for naïve CD8+ T-cells and the Fas-L gene for effector-terminal CD8+ T-cells was not different between masters and controls and did not change in response to the maximal protocol test.In conclusion, maintaining high levels of aerobic fitness during the natural course of aging may help prevent the accumulation of senescent T-cells.

This study develops the argument that academic discourse may be seen as a feature of the discourse community within which it takes place. ‘Multiliteracies’, ‘Academic Literacies’, and ‘Digital Literacies’ with particular reference to EAP and Academic Discourse are considered. We argue for the inclusion of digital literacies within the EAP curriculum and specify the key components of the pedagogy of multiliteracies and attempt to locate them within the general field of EAP with relation to new technologies.

Local governments must continuously innovate to respond to dynamic pressures from changing social, environmental and economic conditions in their localities. Local governments therefore need to have access to the latest technology and techniques developed through research, and in turn, researchers need to respond to the requirements of local governments. In the last decades, many tools and instruments with a focus on urban sustainability have been produced. Nevertheless, the potential of this wealth of knowledge is not fully used, as many tools are hardly known by policy-makers at the local level and thus not employed. This paper acknowledges that scientific research approaches and findings on urban sustainability are not independent from political and institutional contexts. By exploring three different cases through which knowledge is exchanged and shared between researchers and policy-makers, this paper analyses the mechanisms to improve such “connectivity” and outlines the related benefits.

What is the central question of the study? Are CD31

Summary Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

As readers of the BSHM Bulletin will be aware, Leonardo of Pisa wrote his seminal work on Arithmetic, the Liber Abbaci, in 1202. This enormous work, comprising some 600 pages written in Latin, is c...