Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is ...associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially.
Love is one of our most powerful emotions, inspiring some of the greatest art, literature and conquests of human history. Although aspects of love are surely unique to our species, human romantic ...relationships are displays of a mating system characterized by pair bonding, likely built on ancient foundational neural mechanisms governing individual recognition, social reward, territorial behaviour and maternal nurturing. Studies in monogamous prairie voles and mice have revealed precise neural mechanisms regulating processes essential for the pair bond. Here, we discuss current viewpoints on the biology underlying pair bond formation, its maintenance and associated behaviours from neural and evolutionary perspectives.
Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving ...increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead.
Research on robotic exoskeletons has rapidly expanded over the previous decade. Advances in robotic hardware and energy supplies have enabled viable prototypes for human testing. This review paper ...describes current lower limb robotic exoskeletons, with specific regard to common trends in the field. The preponderance of published literature lacks rigorous quantitative evaluations of exoskeleton performance, making it difficult to determine the disadvantages and drawbacks of many of the devices. We analyzed common approaches in exoskeleton design and the convergence, or lack thereof, with certain technologies. We focused on actuators, sensors, energy sources, materials, and control strategies. One of the largest hurdles to be overcome in exoskeleton research is the user interface and control. More intuitive and flexible user interfaces are needed to increase the success of robotic exoskeletons. In the last section, we discuss promising future solutions to the major hurdles in exoskeleton control. A number of emerging technologies could deliver substantial advantages to existing and future exoskeleton designs. We conclude with a listing of the advantages and disadvantages of the emerging technologies and discuss possible futures for the field.
Frailty is a state of vulnerability to poor resolution of homeostasis following a stressor event, such as chemotherapy or cancer surgery. Better knowledge of the epidemiology of frailty could help ...drive a global cancer care strategy for older people. The aim of this review was to establish the prevalence and outcomes of frailty and pre-frailty in older cancer patients.
Observational studies that reported data on the prevalence and/or outcomes of frailty in older cancer patients with any stage of solid or haematological malignancy were considered. We searched Medline, CINAHL, Cochrane Library, EMBASE, Web of Science, Allied and Complementary medicine, Psychinfo and ProQuest (1 January 1996 to 30 June 2013). The primary outcomes were prevalence of frailty, treatment-related side-effects, unplanned hospitalization and mortality. Risk of bias was assessed using the Newcastle–Ottawa checklist.
Data from 20 studies evaluating 2916 participants are included. The median reported prevalence of frailty and pre-frailty was 42% (range 6%–86%) and 43% (range 13%–79%), respectively. A median of 32% (range 11%–78%) of patients were classified as fit. Frailty was independently associated with increased all-cause mortality adjusted 5-year hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.36–2.57. There was evidence of increased risk of postoperative mortality for both frailty (adjusted 30-day HR 2.67, 95% CI 1.08–6.62) and pre-frailty (adjusted HR 2.33, 95% CI 1.20–4.52). Treatment complications were more frequent in those with frailty, including intolerance to cancer treatment (adjusted odds ratio 4.86, 95% CI 2.19–10.78) and postoperative complications (adjusted 30-day HR 3.19, 95% CI 1.68–6.04).
More than half of older cancer patients have pre-frailty or frailty and these patients are at increased risk of chemotherapy intolerance, postoperative complications and mortality. The findings of this review support routine assessment of frailty in older cancer patients to guide treatment decisions, and the development of multidisciplinary geriatric oncology services.
In this present review, the current status of the intrinsic mechanical properties of the graphene-family of materials along with the preparation and properties of bulk graphene-based nanocomposites ...is thoroughly examined. The usefulness of Raman spectroscopy for the characterization and study of the mechanical properties of graphene flakes and their composites is clearly exhibited. Furthermore, the preparation strategies of bulk graphene-based nanocomposites are discussed and the mechanical properties of nanocomposites reported in the literature are analysed. In particular, through the analyse of several hundred literature papers on graphene composites, we have found a unique correlation between the filler modulus, derived from the rule of mixtures, and the composite matrix. This correlation is found to hold true across a wide range of polymer matrices and thus suggests that the common assumption that the filler modulus is independent of the matric is incorrect, explaining the apparent under performance of graphene in some systems. The presence of graphene even at very low loadings can provide significant reinforcement to the final material, while the parameters that affect the nanocomposite strongly are thoroughly reviewed. Finally, the potential applications and future perspectives are discussed with regard to scale up capabilities and possible developments of graphene-based nanocomposite materials.
Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in ...a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.
Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these ...men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.
At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes).
Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.
After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).
Translation is the fundamental biological process converting mRNA information into proteins. Single-molecule imaging in live cells has illuminated the dynamics of RNA transcription; however, it is ...not yet applicable to translation. Here, we report single-molecule imaging of nascent peptides (SINAPS) to assess translation in live cells. The approach provides direct readout of initiation, elongation, and location of translation. We show that mRNAs coding for endoplasmic reticulum (ER) proteins are translated when they encounter the ER membrane. Single-molecule fluorescence recovery after photobleaching provides direct measurement of elongation speed (5 amino acids per second). In primary neurons, mRNAs are translated in proximal dendrites but repressed in distal dendrites and display "bursting" translation. This technology provides a tool with which to address the spatiotemporal translation mechanism of single mRNAs in living cells.
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