pH-dependent water permeability switching and its memory in MoS2 membranes.

Intelligent transport of molecular species across different barriers is critical for various biological functions and is achieved through the unique properties of biological membranes1-4. Two essential features of intelligent transport are the ability to (1) adapt to different external and internal conditions and (2) memorize the previous state5. In biological systems, the most common form of such intelligence is expressed as hysteresis6. Despite numerous advances made over previous decades on smart membranes, it remains a challenge to create a synthetic membrane with stable hysteretic behaviour for molecular transport7-11. Here we demonstrate the memory effects and stimuli-regulated transport of molecules through an intelligent, phase-changing MoS2 membrane in response to external pH. We show that water and ion permeation through 1T' MoS2 membranes follows a pH-dependent hysteresis with a permeation rate that switches by a few orders of magnitude. We establish that this phenomenon is unique to the 1T' phase of MoS2, due to the presence of surface charge and exchangeable ions on the surface. We further demonstrate the potential application of this phenomenon in autonomous wound infection monitoring and pH-dependent nanofiltration. Our work deepens understanding of the mechanism of water transport at the nanoscale and opens an avenue for the development of intelligent membranes.

Error rates in SARS-CoV-2 testing examined with Bayes' theorem.

The SARS-CoV-2 pandemic has created a demand for large scale testing, as part of the effort to understand and control transmission. It is important to quantify the error rates of test equipment under field conditions, which might differ significantly from those obtained in the laboratory. A literature review on SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) is used to construct a clinical test confusion matrix. A simple correction method for bulk test results is then demonstrated with examples. The required sensitivity and specificity of a test are explored for societal needs and use cases, before a sequential analysis of common example scenarios is explored. The analysis suggests that many of the people with mild symptoms and positive test results are unlikely to be infected with SARS-CoV-2 in some regions. It is concluded that current and foreseen alternative tests can not be used to "clear" people as being non-infected. Recommendations are given that regional authorities must establish a programme to monitor operational test characteristics before launching large scale testing; and that large scale testing for tracing infection networks in some regions is not viable, but may be possible in a focused way that does not exceed the working capacity of the laboratories staffed by competent experts. RT-PCR tests can not be solely relied upon as the gold standard for SARS-CoV-2 diagnosis at scale, instead clinical assessment supported by a range of expert diagnostic tests should be used.

Early initiation of direct anticoagulation after stroke in patients with atrial fibrillation.

BACKGROUND AND PURPOSE: The safety of early initiation of anticoagulant therapy in patients with ischaemic stroke related to atrial fibrillation (AF) is unknown. We investigated the safety of early initiation of direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs) or no anticoagulation. METHODS: This observational, retrospective, single-centre study included consecutive patients with recent (<4 weeks) ischaemic stroke and AF. The primary outcome was the rate of major (intracranial and extracranial) bleeding in patients on different treatment schemes, i.e. DOACs, VKAs and not anticoagulated. We also investigated the rate of ischaemic cerebrovascular events and mortality. RESULTS: We included 959 consecutive patients with AF and ischaemic stroke followed up for an average of 16.1 days after the index event. A total of 559 out of 959 patients (58.3%) were anticoagulated with either VKAs (n = 259) or DOACs (n = 300). Anticoagulation was started after a mean of 7 ± 9.4 days in the DOAC group and 11.9 ± 19.7 days in the VKA group. Early initiation of any anticoagulant was not associated with an increased risk of any major bleeding [odds ratio (OR), 0.49; 95% confidence intervals (CI), 0.21-1.16] and in particular of intracranial bleeding (OR, 0.47; 95% CI, 0.17-1.29; P = 0.143) compared with no anticoagulation. In contrast to VKAs (OR, 0.78; 95% CI, 0.28-2.13), treatment with DOACs (OR, 0.32; 95% CI, 0.10-0.96) reduced the rate of major bleeding compared with no anticoagulation. Early recurrences of ischaemic stroke did not differ significantly among the three groups. CONCLUSIONS: Starting DOACs within a mean of 7 days after stroke appeared to be safe. Randomized controlled studies are needed to establish the added efficacy of starting anticoagulation early after stroke.

Responses of the mammary transcriptome of dairy cows to altered photoperiod during late gestation.

Cows exposed to short day photoperiod (SD, 8L:16D) during the 60-day nonlactating period prior to parturition produce more milk in their subsequent lactation compared with cows exposed to long day photoperiod (LD, 16L:8D). Although this response is well established in dairy cows, the underlying mechanisms are not understood. We hypothesized that differential gene expression in cows exposed to SD or LD photoperiods during the dry period could be used to identify the functional basis for the subsequent increase in milk production during lactation. Pregnant, multiparous cows were maintained on an SD or LD photoperiod for 60 days prior to parturition. Mammary biopsies were obtained on days -24 and -9 relative to parturition and Affymetrix GeneChip Bovine Genome Arrays were used to quantify gene expression. Sixty-four genes were differentially expressed (P ≤ 0.05 and fold-change ≥ |1.5|) between SD and LD treatments. Many of these genes were associated with cell growth and proliferation, or immune function. Ingenuity Pathway Analysis predicted upstream regulators to include TNF, TGF-ß1, interferon-γ, and several interleukins. In addition, expression of 125 genes was significantly different between day -24 and day -9; those genes were associated with milk component metabolism and immune function. The interaction of photoperiod and time affected 32 genes associated with insulin-like growth factor I signaling. Genes differentially expressed in response to photoperiod were associated with mammary development and immune function consistent with the enhancement of milk yield in the ensuing lactation. Our results provide insight into the mechanisms by which photoperiod affects the mammary gland and subsequently lactation.

Lesion locations influencing baseline severity and early recovery in ischaemic stroke.

BACKGROUND AND PURPOSE: Strokes caused by lesions to certain brain areas are associated with poor outcome, which is important both prognostically and to understand the neural basis for recovery. However, lesion anatomy associations with outcome may occur because of effects on baseline severity rather than because of effects on recovery per se. Here, all common stroke locations were surveyed to determine the strongest lesion anatomy associations separately for baseline functional severity and proportional recovery. Since most recovery occurs early, the focus here is on functional changes over the first week. METHOD: Global functional scores (National Institutes of Health Stroke Scale) at baseline and proportional recovery over 1 week were derived from the records of 550 ischaemic stroke patients and related to magnetic resonance imaging lesion location using voxel-lesion mapping. The effects of lesions extending over more than one location were also considered. Cross-validation estimated the percentage of recovery rate variance (r(2) ) accountable by lesion location information. RESULTS: High baseline severity was associated with lesions to the left capsule, striatum and thalamocortical white matter, whereas high recovery rate was associated with lesions to more superficial left fronto-temporal areas. Low recovery rates were associated with lesions to bilateral parietal, right insula, medial frontal, capsule and brainstem. Inclusion of these regions into a multivariate model of proportional recovery rate increased r(2) from 8% to 45%. CONCLUSION: The strongest stroke lesion location associations with 1-week recovery were identified, and it was shown that anatomical information accounts for a sizeable proportion of early recovery variability.

Knowledge of blood pressure in a U.K. general public population.

Little is known about the general public's understanding of the role of blood pressure (BP) in contributing to heart disease and stroke. This study aimed to gain a wider understanding of the knowledge and awareness of BP in a selected London population. As part of a stroke awareness campaign, members of the public were offered BP testing and were asked about their knowledge and awareness of BP. Descriptive statistics were employed to explore knowledge and awareness of BP. χ2-test was run to explore the difference between knowledge and awareness of BP, and whether there was a difference in BP readings in normotensive and hypertensive participants. A total of 1019 participants (males 295; mean age 54 years, range 16-92) were recruited with a mean BP of 130/77 mm Hg. Over half (52%) of the total population was unable to correctly estimate an acceptable range of BP, and of that group 28% had a systolic BP (SBP) >140 mm Hg. Of the 31% self-reporting hypertension and on medication, over a quarter (27%) did not know the range for acceptable BP. A third were poorly controlled with a SBP >140 mm Hg. Mean SBP in the hypertensive participants who correctly estimated 'acceptable BP' was 3 mm Hg lower (147 mm Hg) than those who guessed incorrectly (150 mm Hg) (P<0.04). There remains a lack of understanding of BP in the general public population with individuals having little knowledge of an acceptable BP range. Hypertensive patients demonstrate a particularly poor understanding of BP. This study suggests that good knowledge of BP influences BP control in a hypertensive population and has important public health implications.

A time dependent kinetic small angle neutron scattering study of a novel YFe phase.

Crystallization of amorphous Y67Fe33 into the YFe2 C15 Laves phase via a novel 'YFe' intermediate phase has been observed through to completion using time-resolved small angle neutron scattering (SANS). The nucleation and growth kinetics of the phase transformations have been studied at annealing temperatures below the crystallization temperatures for both the 'YFe' phase and the YFe2 phase. The SANS results agree with previously reported neutron diffraction and SANS data. At the annealing temperatures of 360, 370 and 380 °C, changes in the scattering intensity I(Q) occur as a result of the contrast between the amorphous matrix and the nucleating and growing Y and 'YFe' phases. Critical scattering occurs during each of the isotherms, relating to the full crystallization of Y67Fe33, and extrapolation gives a crystallization temperature of 382 °C. Beyond critical scattering, isotherms at 435, 450, and 465 °C reveal the details of the continuing transformation of the 'YFe' intermediate phase into the YFe2 C15 Laves phase.

Evaluation of the clinical utility of a carotid bruit.

BACKGROUND: Uncertainty exists over whether listening for carotid bruits as part of the clinical examination is informative in terms of predicting the presence or severity of carotid stenosis. AIM: We sought to undertake a comprehensive meta-analysis and meta-regression of all studies to date that have assessed the relationship between a carotid bruit and severity of degree of stenosis. METHODS: Electronic databases were used to identify all published studies in humans evaluating the association between bruit and stenosis published until and including October 2011. Pooled sensitivity, specificity and diagnostic odds ratio (DOR) were calculated for each stenosis group. Summary receiver operating characteristic (SROC) curve analysis was performed in studies assessing clinically relevant (i.e. >70%) stenosis. Meta-regression was performed in all studies, using random effects. RESULTS: We identified 26 studies evaluating the association between carotid bruit and stenosis, in 15 117 arteries. For clinically relevant stenosis (i.e. >70%), we found pooled sensitivity 0.53 [95% confidence interval (CI): 0.5-0.55], specificity 0.83 (95% CI: 0.82-0.84) and DOR 4.32 (95% CI: 2.78-6.66). SROC curve analysis gave an area under the curve of 0.73. Meta-regression analysis showed a (non-significant) (P = 0.067) inverse relationship between carotid bruit and stenosis. CONCLUSION: The carotid bruit is of moderate value for detecting clinically relevant carotid stenosis. It gives high specificity but low sensitivity. The likelihood of a carotid bruit does not increase at increasing degrees of stenosis.

Characterization of bovine glucose transporter 1 kinetics and substrate specificities in Xenopus oocytes.

Glucose is an essential substrate for lactose synthesis and an important energy source in milk production. Glucose uptake in the mammary gland, therefore, plays a critical role in milk synthesis. Facilitative glucose transporters (GLUT) mediate glucose uptake in the mammary gland. Glucose transporter 1 (GLUT1) is the major facilitative glucose transporter expressed in the bovine mammary gland and has been shown to localize to the basolateral membrane of mammary epithelial cells. Glucose transporter 1 is, therefore, thought to play a major role in glucose uptake during lactation. The objective of this study was to determine the transport kinetic properties and substrate specificity of bovine GLUT1 using the Xenopus oocyte model. Bovine GLUT1 (bGLUT1) was expressed in Xenopus oocytes by microinjection of in vitro transcribed cRNA and was found to be localized to the plasma membrane, which resulted in increased glucose uptake. This bGLUT1-mediated glucose uptake was dramatically inhibited by specific facilitative glucose transport inhibitors, cytochalasin B, and phloretin. Kinetic analysis of bovine and human GLUT1 was conducted under zero-trans conditions using radio-labeled 2-deoxy-D-glucose and the principles of Michaelis-Menten kinetics. Bovine GLUT1 exhibited a Michaelis constant (K(m)) of 9.8 ± 3.0mM for 2-deoxy-d-glucose, similar to 11.7 ± 3.7 mM for human GLUT1. Transport by bGLUT1 was inhibited by mannose and galactose, but not fructose, indicating that bGLUT1 may also be able to transport mannose and galactose. Our data provides functional insight into the transport properties of bGLUT1 in taking up glucose across mammary epithelial cells for milk synthesis.

Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure.

WHAT IS KNOWN AND OBJECTIVE: Intravenous immunoglobulin (IVIg) is a commonly used therapy for autoimmune disease, but may cause chronic hypertension and thrombosis. We determined whether: (i) IVIg systematically affects blood pressure in the short term; (ii) acute changes in plasma viscosity because of IVIg correlate with blood pressure effects; (iii) effects of IVIg on acute blood pressure are related to baseline blood pressure or hypertension status and (iv) IVIg influences plasma markers of inflammation, anticardiolipin antibodies and homocysteine as additional putative prothrombotic risk factors. METHODS: Twenty adults with autoimmune neurological disease who received a course of IVIg were evaluated immediately before and after each infusion, on every day of the course. Blood pressure, pulse and the following haematological parameters were determined: plasma viscosity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), haematocrit, fibrinogen, interleukin-6 (IL-6), homocysteine and anticardiolipin positivity. RESULTS: Intravenous immunoglobulin caused both acute and cumulative rises in plasma viscosity across a treatment course, but no concordant changes in blood pressure. There was also no correlation between individual blood pressure changes and viscosity, baseline blood pressure or hypertension status. Levels of IL-6 rose across the course of therapy, but the acute-phase reactants CRP and fibrinogen did not. One patient developed anticardiolipin antibodies during therapy. WHAT IS NEW AND CONCLUSION: Individual courses of IVIg do not systematically raise blood pressure. Where IVIg is found to cause hypertension, this does not appear to be due to a direct effect of IVIg on plasma viscosity.

Modulation of fusiform cortex activity by cholinesterase inhibition predicts effects on subsequent memory.

Cholinergic influences on memory are likely to be expressed at several processing stages, including via well-recognized effects of acetylcholine on stimulus processing during encoding. Since previous studies have shown that cholinesterase inhibition enhances visual extrastriate cortex activity during stimulus encoding, especially under attention-demanding tasks, we tested whether this effect correlates with improved subsequent memory. In a within-subject physostigmine versus placebo design, we measured brain activity with functional magnetic resonance imaging while healthy and mild Alzheimer's disease subjects performed superficial and deep encoding tasks on face (and building) visual stimuli. We explored regions in which physostigmine modulation of face-selective neural responses correlated with physostigmine effects on subsequent recognition performance. In healthy subjects physostigmine led to enhanced later recognition for deep- versus superficially-encoded faces, which correlated across subjects with a physostigmine-induced enhancement of face-selective responses in right fusiform cortex during deep- versus superficial-encoding tasks. In contrast, the Alzheimer's disease group showed neither a depth of processing effect nor restoration of this with physostigmine. Instead, patients showed a task-independent improvement in confident memory with physostigmine, an effect that correlated with enhancements in face-selective (but task-independent) responses in bilateral fusiform cortices. Our results indicate that one mechanism by which cholinesterase inhibitors can improve memory is by enhancing extrastriate cortex stimulus selectivity at encoding, in a manner that for healthy people but not in Alzheimer's disease is dependent upon depth of processing.

Chiral paramagnetic skyrmion-like phase in MnSi.

We present a comprehensive study of chiral fluctuations in the reference helimagnet MnSi by polarized neutron scattering and neutron spin echo spectroscopy, which reveals the existence of a completely left-handed and dynamically disordered phase. This phase may be identified as a spontaneous Skyrmion phase: it appears in a limited temperature range just above the helical transition T_{C} and coexists with the helical phase at T_{C}.

Evidence for a spin emulsion.

Magnetic small-angle neutron scattering from the itinerant electron magnet, Y(Mn1-xFex)2, in which ferromagnetic and antiferromagnetic spin correlations compete, is found to follow an anomalous Q(-6) dependence (Q = 4pisintheta/lambda). It is suggested that this scattering is the magnetic analogue of that predicted for a structural microemulsion by Teubner's extension of conventional Kirste-Porod scattering to well-defined interfaces with extreme differences between mean and Gaussian curvatures. The "spin-emulsion-like" morphology of magnetic interfaces in Y(Mn1-xFex)2 is confirmed both qualitatively and quantitatively by a simple model based upon reported near neighbor Mn and Fe spin correlations.

Highly purified CD38+ and CD38- sub-clones derived from the same chronic lymphocytic leukemia patient have distinct gene expression signatures despite their monoclonal origin.

CD38 expression is an important prognostic marker in chronic lymphocytic leukemia (CLL) with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38(+) and CD38(-) chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38(+) and CD38(-) CLL cells derived from the same patient were shown to be monoclonal by V(H) gene sequencing but despite this, CD38(+) CLL cells possessed a distinct gene expression profile when compared with their CD38(-) sub-clones. Importantly, CD38(+) CLL cells relatively over expressed vascular endothelial growth factor (VEGF) and appeared to preferentially utilize an internal autocrine VEGF survival loop. Elevated VEGF expression was associated with increased expression of the anti-apoptotic protein Mcl-1. Inhibition of VEGF receptor signaling also resulted in a reduction in cell viability. In contrast, exogenous VEGF caused a significant increase in CD38(-) CLL cell viability and a marked induction of Mcl-1; both effects were less obvious in CD38(+) CLL cells. Taken together, our data provide a biological rationale for the poor prognosis of CD38(+) CLL and indicate that both VEGF and Mcl-1 may prove to be useful therapeutic targets.

Kinetic neutron diffraction and SANS studies of phase formation in bioactive machinable glass ceramics.

Bioactive fluormica-fluorapatite glass-ceramic materials offer a very encouraging solution to the problem of efficient restoration and reconstruction of hard tissues. To produce material with the desired crystalline phases, a five-stage heat treatment must be performed. This thermal processing has a large impact on the microstructure and ultimately the final mechanical properties of the materials. We have examined the thermal processing of one of our most promising machinable biomaterials, using time-resolved small angle neutron scattering and neutron diffraction to study the nucleation and growth of crystallites. The processing route had already been optimized by studying the properties of quenched samples using x-ray diffraction, mechanical measurements and differential thermal analysis. However these results show that the heat treatment can be further optimized in terms of crystal nucleation, and we show that these techniques are the only methods by which a truly optimized thermal processing route may be obtained.

Consequences of mitochondrial injury induced by pharmaceutical fatty acid oxidation inhibitors is characterized in human and rat liver slices.

Inhibition of liver mitochondrial beta-oxidation by pharmaceuticals may lead to safety concerns including mitochondrial dysfunction, lipid accumulation, inflammation and necrosis. In this study, the consequences of mitochondrial beta-oxidation inhibition by pharmaceuticals is investigated in human and rat liver slices. The fatty acid oxidation inhibitors Etomoxir and CPI975, inhibit the rate limiting mitochondrial beta-oxidation enzyme carnitine palmitoyltransferase I, while FOX988 and SDZ51-641, sequester mitochondrial coenzyme A to inhibit carnitine palmitoyltransferase II. Mitochondrial dysfunction was evident by a significant decrease of liver slice ATP levels and mitochondrial injury was verified by ultrastructural changes in morphology, manifested as enlarged mitochondria, C- or O-shaped mitochondria, and granular or crystalline inclusions. Gene expression changes were evident prior to changes in mitochondrial morphology. Time- and concentration dependent changes in mitochondrial genes linked with respiration and mitochondrial fatty acid beta-oxidation were associated with an up-regulation of peroxisome fatty acid oxidation genes, likely as a compensatory mechanism for the inhibition of the mitochondrial pathways. Gene expression changes preceding the decline of liver slice ATP and GSH levels included an up-regulation of stress response and oxidative stress gene expression, as well as genes linked with transcription, transporters, proliferation, cell matrix and signaling. In association with the decline of liver slice ATP and GSH was increased apoptosis and inflammation. Caspase activity, a functional indicator of apoptosis, was significantly increased as well as an up-regulation of genes linked with apoptosis. The increased gene and protein expression of the pro-inflammatory cytokine IL-8, produced by endothelial cells, is likely in response to the manifestation of oxidative stress and GSH depletion; further amplifying the oxidative stress response induced by the fatty acid oxidation inhibitors and triggering an inflammatory response. In summary, human and rat liver slices exhibited similar effects to the inhibitors of mitochondrial beta-oxidation, and the mitochondrial injury is associated with apoptosis and inflammation in the liver slices.

Synthesis of a potentially bioactive, hydroxyapatite-nucleating molecule.

A human phosphophoryn (PP) cDNA was previously cloned from immature root apex total RNA in our laboratory. This cDNA comprises 2,364 bp, encoding 788 amino acids. More than 80% of the sequences are arranged as (DSS)(n) (n = 1-16), DS, and NSS motifs. We hypothesize that the capability of PP to bind Ca(2+) and nucleate hydroxyapatite may depend on these repeated sequences. Two polypeptides were synthesized based on the human PP cDNA sequence to test the hypothesis. One polypeptide has the amino acid sequence DDPNSSDESNGNDD (synthetic polypeptide 1, SP1), which is from the N-terminal end of PP; the other polypeptide, DSKSDSSKSESDSS (synthetic polypeptide 2, SP2), is the PP repeated sequence motif. Phosphorylation of the polypeptides was accomplished by reacting them with adenosine triphosphate and casein kinases I and II. The ability of these molecules to cause mineralization was tested in a steady-state agarose gel system. The results show that phosphorylated SP2 (P-SP2) precipitated approximately 60% of the total Ca + PO(4) precipitated by PP. P-SP1 precipitated about 23% of that precipitated by PP and was similar to the amount precipitated in the control gel, that is, without added peptides. Transmission electron microscopy and X-ray diffraction analysis showed that the precipitate formed in the P-SP2-containing gel was hydroxyapatite. The capability of P-SP2 to nucleate Ca + PO(4) and precipitate hydroxyapatite is a result of the repeated sequence motif, which contains a high percentage of phosphorylated serine. This molecule could be used in the repair and regeneration of dental tissue.

Determination of hyperfine field distributions in amorphous magnets.

We present an overview of two leading methods of determining probability distributions from Mössbauer spectra, using the model amorphous magnet Fe(80)B(20). A comparison is made between the maximum-entropy method, which permits analysis using truly arbitrary parameter probability distributions, and a Voigtian-based analysis, which uses a sum of Gaussian components to create parameter distributions of pseudo-arbitrary shape. Our results indicate that, in Fe(80)B(20), a Gaussian distribution of magnetic hyperfine fields is a very good approximation, although small deviations from a Gaussian shape are evident. We find that the apparent existence of correlations between the isomer shift and magnetic hyperfine field parameters, as found using Voigt-based analyses, may be an artefact of imposing a Gaussian shape on the parameter distributions. We conclude that maximum entropy and Voigtian analyses together provide a very powerful means of characterizing magnetic materials with Mössbauer spectroscopy.