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Proteins provide essential functional regulation of many bioprocesses across all scales of life; however, new techniques to specifically modulate protein activity within living systems and in engineered biomaterials are needed to better interrogate fundamental cell signalling and guide advanced decisions of biological fate. Here we establish a generalizable strategy to rapidly and irreversibly activate protein function with full spatiotemporal control. Through the development of a genetically encoded and light-activated SpyLigation (LASL), bioactive proteins can be stably reassembled from non-functional split fragment pairs following brief exposure (typically minutes) to cytocompatible light. Employing readily accessible photolithographic processing techniques to specify when, where and how much photoligation occurs, we demonstrate precise protein activation of UnaG, NanoLuc and Cre recombinase using LASL in solution, biomaterials and living mammalian cells, as well as optical control over protein subcellular localization. Looking forward, we expect that these photoclick-based optogenetic approaches will find tremendous utility in probing and directing complex cellular fates in both time and three-dimensional space.Techniques to specifically modulate protein activity are needed to interrogate spatial effects in cellular processes. A genetically encoded method for site-specific protein–protein conjugation based on a photoclick chemical reaction has now been developed. This method permits rapid and irreversible reassembly of bioactive proteins from non-functional split fragment pairs with full spatiotemporal control in solution, biomaterials and living mammalian cells.

Five cases of STEC O157 phage type (PT) 21/28 reported consumption of raw cows' drinking milk (RDM) produced at a dairy farm in the South West of England. STEC O157 PT21/28 was isolated from faecal specimens from milking cows on the implicated farm. Whole genome sequencing (WGS) showed that human and cattle isolates were the same strain. Further analysis of WGS data confirmed that sequences of isolates from an additional four cases (who did not report consumption of RDM when first questioned) fell within the same five single nucleotide polymorphism cluster as the initial five cases epidemiologically linked to the consumption of RDM. These four additional cases identified by WGS were investigated further and were, ultimately, associated with the implicated farm. The RDM outbreak strain encoded stx2a, which is associated with increased pathogenicity and severity of symptoms. Further epidemiological analysis showed that 70% of isolates within a wider cluster containing the outbreak strain were from cases residing in, or linked to, the same geographical region of England. During this RDM outbreak, use of WGS improved case ascertainment and provided insights into the evolution of a highly pathogenic clade of STEC O157 PT21/28 stx2a associated with the South West of England.

Top-end cosmic rays The origin of ultrahigh-energy cosmic rays is one of the most profound mysteries in high-energy astrophysics. No standard supernovae, pulsars or black holes can accelerate particles to such enormous energies, so various exotic sources have been proposed. An obstacle to identifying the source is the difficulty of finding out what particles are actually present in the rays: once they enter the Earth's atmosphere they lose their original identity, producing a shower of elementary particles travelling close to the speed of light. A collaboration between radio astronomers and particle physicists may offer a new way of learning more about the nature and structure of ultrahigh-energy cosmic rays. Using low-cost radio receivers it is possible to detect radio flashes coincident with cosmic-ray air showers. The radiation can be explained by the geosynchrotron effect. With radio telescopes and particle detectors trained on the incoming rays, their structure may soon be revealed. The nature of ultrahigh-energy cosmic rays (UHECRs) at energies >10 20  eV remains a mystery 1 . They are likely to be of extragalactic origin, but should be absorbed within ∼50 Mpc through interactions with the cosmic microwave background. As there are no sufficiently powerful accelerators within this distance from the Galaxy, explanations for UHECRs range from unusual astrophysical sources to exotic string physics 2 . Also unclear is whether UHECRs consist of protons, heavy nuclei, neutrinos or γ-rays. To resolve these questions, larger detectors with higher duty cycles and which combine multiple detection techniques 3 are needed. Radio emission from UHECRs, on the other hand, is unaffected by attenuation, has a high duty cycle, gives calorimetric measurements and provides high directional accuracy. Here we report the detection of radio flashes from cosmic-ray air showers using low-cost digital radio receivers. We show that the radiation can be understood in terms of the geosynchrotron effect 4 , 5 , 6 , 7 , 8 . Our results show that it should be possible to determine the nature and composition of UHECRs with combined radio and particle detectors, and to detect the ultrahigh-energy neutrinos expected from flavour mixing 9 , 10 .

Anxiety and depression are highly prevalent in patients with COPD and their informal carers, and associated with numerous risk factors. However, few studies have investigated these in primary care or the link between patient and carer anxiety and depression. We aimed to determine this association and factors associated with anxiety and depression in patients, carers, and both (dyads), in a population-based sample. This was a prospective, cross-sectional study of 119 advanced COPD patients and their carers. Patient and carer scores ≥8 on the Hospital Anxiety and Depression Scale defined symptoms of anxiety and depression, tests determined associations between patient and carer symptoms of anxiety/depression, and and independent -tests for normally distributed variables (otherwise Mann-Whitney tests) were used to identify other variables significantly associated with these symptoms in the patient or carer. Patient-carer dyads were categorized into four groups relating to the presence of anxious/depressive symptoms in: both patient and carer, patient only, carer only, and neither. Factors associated with dyad symptoms of anxiety/depression were determined with tests and one-way analysis of variance for normally distributed variables (otherwise Kruskal-Wallis tests). Prevalence of symptoms of anxiety and depression was 46.4% (n=52) and 42.9% (n=48) in patients, and 46% (n=52) and 23% (n=26) in carers, respectively. Patient and carer symptoms of anxiety/depression were significantly associated. Anxious and depressive symptoms in the patient were also significantly associated with more physical comorbidities, more exacerbations, greater dyspnea, greater fatigue, poor mastery, and depressive symptoms with younger age. Symptoms of carer anxiety were significantly associated with being female and separated/divorced/widowed, and depressive symptoms with younger age, higher educational level, and more physical comorbidities, and symptoms of carer anxiety and depression with more unmet support needs, greater subjective caring burden, and poor patient mastery. Dyad symptoms of anxiety/depression were significantly associated with greater patient fatigue. Symptoms of anxiety and depression in COPD patients and carers are significantly associated. Given their high prevalence, considerable impact on mortality, impact on quality of life and health care use, and associations with each other, screening for and addressing patient and carer anxiety and depression in advanced COPD is recommended.

Lightning is a dangerous yet poorly understood natural phenomenon. Lightning forms a network of plasma channels propagating away from the initiation point with both positively and negatively charged ends—called positive and negative leaders 1 . Negative leaders propagate in discrete steps, emitting copious radio pulses in the 30–300-megahertz frequency band 2 – 8 that can be remotely sensed and imaged with high spatial and temporal resolution 9 – 11 . Positive leaders propagate more continuously and thus emit very little high-frequency radiation 12 . Radio emission from positive leaders has nevertheless been mapped 13 – 15 , and exhibits a pattern that is different from that of negative leaders 11 – 13 , 16 , 17 . Furthermore, it has been inferred that positive leaders can become transiently disconnected from negative leaders 9 , 12 , 16 , 18 – 20 , which may lead to current pulses that both reconnect positive leaders to negative leaders 11 , 16 , 17 , 20 – 22 and cause multiple cloud-to-ground lightning events 1 . The disconnection process is thought to be due to negative differential resistance 18 , but this does not explain why the disconnections form primarily on positive leaders 22 , or why the current in cloud-to-ground lightning never goes to zero 23 . Indeed, it is still not understood how positive leaders emit radio-frequency radiation or why they behave differently from negative leaders. Here we report three-dimensional radio interferometric observations of lightning over the Netherlands with unprecedented spatiotemporal resolution. We find small plasma structures—which we call ‘needles’—that are the dominant source of radio emission from the positive leaders. These structures appear to drain charge from the leader, and are probably the reason why positive leaders disconnect from negative ones, and why cloud-to-ground lightning connects to the ground multiple times. Radio interferometric observations of lightning over the Netherlands reveal small needle-shaped plasma structures associated with the positive leader channels, explaining why cloud-to-ground lightning connects to the ground multiple times.

DISCUSSION The term \"ischaemic colitis\" was used by Marston et al in 1966 with three typical patterns of injury described: transient reversible ischaemia, ischaemic ulcers with stricturing, and gangrenous ischaemic colitis. 12 The latter two patterns of ischaemic colitis occur predominantly in elderly and debilitated patients with significant comorbidity. 13 However, the literature describes 50 cases of ischaemic colitis in otherwise \"healthy\" patients aged less than 50 years of age. 2- 9 In these individuals the condition is usually associated with complete recovery of the colon, in both structure and function, within one to two weeks. A raised white cell count is often the only abnormality on blood tests. 2 Barium enema may reveal characteristic \"thumbprinting\" with the condition most commonly affecting the splenic flexure and descending colon. 2 Colonoscopy is the investigation of choice. 13 Matsumoto et al described red oedematous mucosa in association with scarred longitudinal ulcers in all of their patients. 5 Characteristic histological features include epithelial sloughing, oedematous and necrotic superficial mucosal layers with vascular congestion, mucin depletion, degeneration of normal crypt architecture, and a polymorphonuclear leucocyte mucosal infiltrate. 2 In all 50 cases described the condition appeared to be self limiting with complete recovery within a few weeks. Recorded predisposing factors include: previous abdominal surgery, 5 history of thromboembolic disease, 2 activated protein C resistance, 10 protein S deficiency, 6 hypovolaemic shock, 8 vasculitis, 13 drugs (for example, cocaine), 13 diabetes, 2 sickle cell disease, 13 and long distance running. 13 The most common association in young women is the use of the oral contraceptive pill which is reported to increase the relative risk of ischaemic colitis sixfold. 4 Both patients in this report presented with typical symptoms of sudden onset colicky abdominal pain and bloody diarrhoea.

Suicide is a tragic, traumatic loss, and one of the most emotionally devastating events families, friends, and communities experience. Suicide claims more than 800,000 lives every year, and some of the highest rates of suicide in the United States and globally are among older adults. The purpose of this evidence-based guideline is to help health care providers recognize those at risk for suicide and recommend appropriate and effective secondary suicide prevention interventions. The information in this guideline is intended for health care providers who work in a variety of settings, including hospitals, nursing homes, rehabilitation centers, out-patient clinics, mental health clinics, home health care, and other long-term care facilities. Assessment and preventive treatment strategies were derived by exhaustive literature review and synthesis of the current evidence on secondary prevention of late-life suicide across practice settings. [ Journal of Gerontological Nursing, 44 (11), 20–32.]

Signs and symptoms include rash, fever, tender lymphadenopathy, hepatitis, eosinophilia and other hematological abnormalities and facial edema. [1],[3],[4],[5] There is one previous case report of gabapentin-induced hypersensitivity syndrome; [6] this was reported in a 72-year-old gentleman who developed confusion, fever, diffuse macular rash and splenomegaly nine days after gabapentin was introduced. In retrospect this is unlikely in view of multiple negative blood and urine cultures, the presence of cervical lymphadenopathy and the lack of response to treatment.

BackgroundMen with localised prostate cancer have a number of treatment options. Treatments carry associated benefits and side- and late-effects. The Life After Prostate Cancer Diagnosis study is a UK-wide survey of men 18–42 months post-diagnosis of prostate cancer. The survey included treatment questions, the Decision Regret Scale (DRS) and a single item on decision-making participation. The aim of this sub-study is to explore the association of decision regret with prostate cancer treatment and patient perception of participation in decision making.MethodsThe English arm of the survey achieved a 60.3% response rate (30 465 respondents). Men diagnosed with stage 1–3 disease were included in this sub-study (n=16,808). Descriptive statistics were used to explore associations between DRS scores (0–100), self-reported treatments and perceived participation in decision-making.Results12 600 (75.0%) men completed the DRS. Due to the skewed nature of the data, decision regret was categorised as ‘None’ (score=0; 36.5%), ‘Low’ (score=5–20; 31.6%) and ‘High’ (score=≥25; 31.8%). Levels of regret were lowest in men who underwent brachytherapy alone and surgery alone (25.8% and 27.5% respectively reporting ‘High’ regret). Men who received combination therapy (e.g. radiotherapy and hormones) reported higher levels of regret compared to men having a single therapy (34.8% vs. 28.3% reporting ‘High’ regret). 28.6% of men on active surveillance reported a high level of regret. 74.2% of men said their views were definitely taken into account in treatment decisions: 22.6% of these reported high regret. 2.8% of men said their views were not taken into account; 62.8% reported high regret.ConclusionThese preliminary analyses show a strong association between perceived involvement in treatment decision making and subsequent decision regret in men with prostate cancer. Levels of regret also vary according to the type of treatment received. Interestingly, men on active surveillance who receive no treatment report similar levels of regret to those who undergo surgery. Further analysis will investigate the impact of patient characteristics and functional outcomes (urinary, bowel and sexual) on levels of regret.