Riviste scientifiche

Topological pumping of a 1D dipolar gas into strongly correlated prethermal states

Science - Gio, 14/01/2021 - 19:37

Long-lived excited states of interacting quantum systems that retain quantum correlations and evade thermalization are of great fundamental interest. We create nonthermal states in a bosonic one-dimensional (1D) quantum gas of dysprosium by stabilizing a super-Tonks-Girardeau gas against collapse and thermalization with repulsive long-range dipolar interactions. Stiffness and energy-per-particle measurements show that the system is dynamically stable regardless of contact interaction strength. This enables us to cycle contact interactions from weakly to strongly repulsive, then strongly attractive, and finally weakly attractive. We show that this cycle is an energy-space topological pump (caused by a quantum holonomy). Iterating this cycle offers an unexplored topological pumping method to create a hierarchy of increasingly excited prethermal states.

Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81

Science - Gio, 14/01/2021 - 19:37

Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo–electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.

Structure of a transcribing RNA polymerase II-U1 snRNP complex

Science - Gio, 14/01/2021 - 19:37

To initiate cotranscriptional splicing, RNA polymerase II (Pol II) recruits the U1 small nuclear ribonucleoprotein particle (U1 snRNP) to nascent precursor messenger RNA (pre-mRNA). Here, we report the cryo–electron microscopy structure of a mammalian transcribing Pol II–U1 snRNP complex. The structure reveals that Pol II and U1 snRNP interact directly. This interaction positions the pre-mRNA 5' splice site near the RNA exit site of Pol II. Extension of pre-mRNA retains the 5' splice site, leading to the formation of a "growing intron loop." Loop formation may facilitate scanning of nascent pre-mRNA for the 3' splice site, functional pairing of distant intron ends, and prespliceosome assembly. Our results provide a starting point for a mechanistic analysis of cotranscriptional spliceosome assembly and the biogenesis of mRNA isoforms by alternative splicing.

New Products

Science - Gio, 14/01/2021 - 19:37

No use in shouting

Science - Gio, 14/01/2021 - 19:37

Noncanonical transnitrosylation network contributes to synapse loss in Alzheimers disease

Science - Gio, 14/01/2021 - 19:37

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function—transnitrosylation—that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer’s disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.

Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2

Science - Gio, 14/01/2021 - 19:37

A long-standing question in infectious disease dynamics concerns the role of transmission heterogeneities, which are driven by demography, behavior, and interventions. On the basis of detailed patient and contact-tracing data in Hunan, China, we find that 80% of secondary infections traced back to 15% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primary infections, which indicates substantial transmission heterogeneities. Transmission risk scales positively with the duration of exposure and the closeness of social interactions and is modulated by demographic and clinical factors. The lockdown period increases transmission risk in the family and households, whereas isolation and quarantine reduce risks across all types of contacts. The reconstructed infectiousness profile of a typical SARS-CoV-2 patient peaks just before symptom presentation. Modeling indicates that SARS-CoV-2 control requires the synergistic efforts of case isolation, contact quarantine, and population-level interventions because of the specific transmission kinetics of this virus.

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

Science - Gio, 14/01/2021 - 19:37

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon- (IFN-)– and signal transducer and activator of transcription 1 (STAT1)–dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN- or Janus kinase (JAK)–STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell–dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.

Phylodynamics for cell biologists

Science - Gio, 14/01/2021 - 19:37

Multicellular organisms are composed of cells connected by ancestry and descent from progenitor cells. The dynamics of cell birth, death, and inheritance within an organism give rise to the fundamental processes of development, differentiation, and cancer. Technical advances in molecular biology now allow us to study cellular composition, ancestry, and evolution at the resolution of individual cells within an organism or tissue. Here, we take a phylogenetic and phylodynamic approach to single-cell biology. We explain how "tree thinking" is important to the interpretation of the growing body of cell-level data and how ecological null models can benefit statistical hypothesis testing. Experimental progress in cell biology should be accompanied by theoretical developments if we are to exploit fully the dynamical information in single-cell data.

Comment on "Boosted molecular mobility during common chemical reactions"

Science - Gio, 14/01/2021 - 19:37

The apparent "boosted mobility" observed by Wang et al. (Reports, 31 July 2020, p. 537) is the result of a known artifact. When signal intensities are changing during a nuclear magnetic resonance (NMR) diffusion measurement for reasons other than diffusion, the use of monotonically increasing gradient amplitudes produces erroneous diffusion coefficients. We show that no boosted molecular mobility is observed when shuffled gradient amplitudes are applied.

Response to Comment on "Boosted molecular mobility during common chemical reactions"

Science - Gio, 14/01/2021 - 19:37

Günther et al. report that their control experiment using randomized magnetic field gradient sequences disagreed with findings we had reported using linear gradients. However, we show that measurements in our laboratory are consistent using both methods.

Covid-19 news: Pandemic has 'calamitous impact' on England's hospitals

New Scientist - Gio, 14/01/2021 - 18:26
The latest coronavirus news updated every day including coronavirus cases, the latest news, features and interviews from New Scientist and essential information about the covid-19 pandemic

Embryos set to be implanted in the last two northern white rhinos

New Scientist - Gio, 14/01/2021 - 17:40
Fertilised eggs are set to be implanted in the two remaining northern white rhinos this year, with the hope of producing offspring

A Perfect Planet review: Attenborough's new show is one of his best

New Scientist - Gio, 14/01/2021 - 17:36
David Attenborough documentary A Perfect Planet blends earth science with dazzling images of flamingos, finches and frogs to reveal how natural forces have nurtured life

Lush meadows of underwater seagrass are removing plastic from the sea

New Scientist - Gio, 14/01/2021 - 17:00
A seagrass that forms lush underwater meadows can naturally trap plastic items in ball-shaped tangles and remove them from the seawater

Seabirds raise fewer chicks as the pandemic keeps tourists away

New Scientist - Gio, 14/01/2021 - 17:00
With fewer tourists flocking to see guillemot breeding sites in Sweden, white-tailed eagles have taken up residence nearby – spooking the seabirds so they raise fewer chicks

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses

PLoS Medicine - Gio, 14/01/2021 - 15:00

by Luanluan Sun, Lisa Pennells, Stephen Kaptoge, Christopher P. Nelson, Scott C. Ritchie, Gad Abraham, Matthew Arnold, Steven Bell, Thomas Bolton, Stephen Burgess, Frank Dudbridge, Qi Guo, Eleni Sofianopoulou, David Stevens, John R. Thompson, Adam S. Butterworth, Angela Wood, John Danesh, Nilesh J. Samani, Michael Inouye, Emanuele Di Angelantonio

Background

Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD.

Methods and findings

Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.

Conclusions

Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.

Recognition and management of community-acquired acute kidney injury in low-resource settings in the ISN 0by25 trial: A multi-country feasibility study

PLoS Medicine - Gio, 14/01/2021 - 15:00

by Etienne Macedo, Ulla Hemmila, Sanjib Kumar Sharma, Rolando Claure-Del Granado, Henry Mzinganjira, Emmanuel A. Burdmann, Jorge Cerdá, John Feehally, Fredric Finkelstein, Guillermo García-García, Vivekanand Jha, Norbert H. Lameire, Euyhyun Lee, Nathan W. Levin, Andrew Lewington, Raúl Lombardi, Michael V. Rocco, Eliah Aronoff-Spencer, Marcello Tonelli, Karen Yeates, Giuseppe Remuzzi, Ravindra L. Mehta, for the ISN 0by25 Trial Study Group

Background

Acute kidney injury (AKI) is increasingly encountered in community settings and contributes to morbidity, mortality, and increased resource utilization worldwide. In low-resource settings, lack of awareness of and limited access to diagnostic and therapeutic interventions likely influence patient management. We evaluated the feasibility of the use of point-of-care (POC) serum creatinine and urine dipstick testing with an education and training program to optimize the identification and management of AKI in the community in 3 low-resource countries.

Methods and findings

Patients presenting to healthcare centers (HCCs) from 1 October 2016 to 29 September 2017 in the cities Cochabamba, Bolivia; Dharan, Nepal; and Blantyre, Malawi, were assessed utilizing a symptom-based risk score to identify patients at moderate to high AKI risk. POC testing for serum creatinine and urine dipstick at enrollment were utilized to classify these patients as having chronic kidney disease (CKD), acute kidney disease (AKD), or no kidney disease (NKD). Patients were followed for a maximum of 6 months with repeat POC testing. AKI development was assessed at 7 days, kidney recovery at 1 month, and progression to CKD and mortality at 3 and 6 months. Following an observation phase to establish baseline data, care providers and physicians in the HCCs were trained with a standardized protocol utilizing POC tests to evaluate and manage patients, guided by physicians in referral hospitals connected via mobile digital technology. We evaluated 3,577 patients, and 2,101 were enrolled: 978 in the observation phase and 1,123 in the intervention phase. Due to the high number of patients attending the centers daily, it was not feasible to screen all patients to assess the actual incidence of AKI. Of enrolled patients, 1,825/2,101 (87%) were adults, 1,117/2,101 (53%) were females, 399/2,101 (19%) were from Bolivia, 813/2,101 (39%) were from Malawi, and 889/2,101 (42%) were from Nepal. The age of enrolled patients ranged from 1 month to 96 years, with a mean of 43 years (SD 21) and a median of 43 years (IQR 27–62). Hypertension was the most common comorbidity (418/2,101; 20%). At enrollment, 197/2,101 (9.4%) had CKD, and 1,199/2,101 (57%) had AKD. AKI developed in 30% within 7 days. By 1 month, 268/978 (27%) patients in the observation phase and 203/1,123 (18%) in the intervention phase were lost to follow-up. In the intervention phase, more patients received fluids (observation 714/978 [73%] versus intervention 874/1,123 [78%]; 95% CI 0.63, 0.94; p = 0.012), hospitalization was reduced (observation 578/978 [59%] versus intervention 548/1,123 [49%]; 95% CI 0.55, 0.79; p < 0.001), and admitted patients with severe AKI did not show a significantly lower mortality during follow-up (observation 27/135 [20%] versus intervention 21/178 [11.8%]; 95% CI 0.98, 3.52; p = 0.057). Of 504 patients with kidney function assessed during the 6-month follow-up, de novo CKD arose in 79/484 (16.3%), with no difference between the observation and intervention phase (95% CI 0.91, 2.47; p = 0.101). Overall mortality was 273/2,101 (13%) and was highest in those who had CKD (24/106; 23%), followed by those with AKD (128/760; 17%), AKI (85/628; 14%), and NKD (36/607; 6%). The main limitation of our study was the inability to determine the actual incidence of kidney dysfunction in the health centers as it was not feasible to screen all the patients due to the high numbers seen daily.

Conclusions

This multicenter, non-randomized feasibility study in low-resource settings demonstrates that it is feasible to implement a comprehensive program utilizing POC testing and protocol-based management to improve the recognition and management of AKI and AKD in high-risk patients in primary care.

Wind farm construction creates noise that may harm squid fisheries

New Scientist - Gio, 14/01/2021 - 12:07
The noisy construction of offshore wind turbines can discourage squid from hunting, which could lead to decreased squid populations and potentially decrease profits at fisheries