41 research outputs found
Simulation of Drosophila Circadian Oscillations, Mutations, and Light Responses by a Model with VRI, PDP-1, and CLK
A model of Drosophila circadian rhythm generation was developed to represent
feedback loops based on transcriptional regulation of per, Clk (dclock), Pdp-1,
and vri (vrille). The model postulates that histone acetylation kinetics make
transcriptional activation a nonlinear function of [CLK]. Such a nonlinearity
is essential to simulate robust circadian oscillations of transcription in our
model and in previous models. Simulations suggest two positive feedback loops
involving Clk are not essential for oscillations, because oscillations of [PER]
were preserved when Clk, vri, or Pdp-1 expression was fixed. Eliminating the
negative feedback loop in which PER represses per expression abolished
oscillations. Simulations of per or Clk null mutations and of vri, Clk, or
Pdp-1 heterozygous null mutations altered model behavior in ways similar to
experimental data. The model simulated a photic phase-response curve resembling
experimental curves, and oscillations entrained to simulated light-dark cycles.
The model makes experimental predictions, some of which could be tested in
transgenic Drosophila.Comment: Accepted to Biophysical Journal, 1/16/04. Single PDF file, 7 figures
at en
D\u27Amico Risk Stratification Correlates with Degree of Suspicion of Prostate Cancer on Multiparametric Magnetic Resonance Imaging.
PURPOSE: We determined whether there is a correlation between D\u27Amico risk stratification and the degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging based on targeted biopsies done with our electromagnetically tracked magnetic resonance imaging/ultrasound fusion platform.
MATERIALS AND METHODS: A total of 101 patients underwent 3 Tesla multiparametric magnetic resonance imaging of the prostate, consisting of T2, dynamic contrast enhanced, diffusion weighted and spectroscopy images in cases suspicious for or with a diagnosis of prostate cancer. All prostate magnetic resonance imaging lesions were then identified and graded by the number of positive modalities, including low-2 or fewer, moderate-3 and high-4 showing suspicion on multiparametric magnetic resonance imaging. The biopsy protocol included standard 12-core biopsy, followed by real-time magnetic resonance imaging/ultrasound fusion targeted biopsies of the suspicious magnetic resonance lesions. Cases and lesions were stratified by the D\u27Amico risk stratification.
RESULTS: In this screening population 90.1% of men had a negative digital rectal examination. Mean±SD age was 62.7±8.3 years and median prostate specific antigen was 5.8 ng/ml. Of the cases 54.5% were positive for cancer on protocol biopsy. Chi-square analysis revealed a statistically significant correlation between magnetic resonance suspicion and D\u27Amico risk stratification (p
CONCLUSIONS: Our data support the notion that using multiparametric magnetic resonance prostate imaging one may assess the degree of risk associated with magnetic resonance visible lesions in the prostate
vrille, Pdp1, and dClock Form a Second Feedback Loop in the Drosophila Circadian Clock
AbstractThe Drosophila circadian clock consists of two interlocked transcriptional feedback loops. In one loop, dCLOCK/CYCLE activates period expression, and PERIOD protein then inhibits dCLOCK/CYCLE activity. dClock is also rhythmically transcribed, but its regulators are unknown. vrille (vri) and Par Domain Protein 1 (Pdp1) encode related transcription factors whose expression is directly activated by dCLOCK/CYCLE. We show here that VRI and PDP1 proteins feed back and directly regulate dClock expression. Repression of dClock by VRI is separated from activation by PDP1 since VRI levels peak 3-6 hours before PDP1. Rhythmic vri transcription is required for molecular rhythms, and here we show that the clock stops in a Pdp1 null mutant, identifying Pdp1 as an essential clock gene. Thus, VRI and PDP1, together with dClock itself, comprise a second feedback loop in the Drosophila clock that gives rhythmic expression of dClock, and probably of other genes, to generate accurate circadian rhythms
DNDI-6148:A novel benzoxaborole preclinical candidate for the treatment of visceral leishmaniasis
Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL
Orbital-selective Mott transitions: Heavy fermions and beyond
Quantum phase transitions in metals are often accompanied by violations of
Fermi liquid behavior in the quantum critical regime. Particularly fascinating
are transitions beyond the Landau-Ginzburg-Wilson concept of a local order
parameter. The breakdown of the Kondo effect in heavy-fermion metals
constitutes a prime example of such a transition. Here, the strongly correlated
f electrons become localized and disappear from the Fermi surface, implying
that the transition is equivalent to an orbital-selective Mott transition, as
has been discussed for multi-band transition-metal oxides. In this article,
available theoretical descriptions for orbital-selective Mott transitions will
be reviewed, with an emphasis on conceptual aspects like the distinction
between different low-temperature phases and the structure of the global phase
diagram. Selected results for quantum critical properties will be listed as
well. Finally, a brief overview is given on experiments which have been
interpreted in terms of orbital-selective Mott physics.Comment: 29 pages, 4 figs, mini-review prepared for a special issue of JLT
Quantum Criticality in Heavy Fermion Metals
Quantum criticality describes the collective fluctuations of matter
undergoing a second-order phase transition at zero temperature. Heavy fermion
metals have in recent years emerged as prototypical systems to study quantum
critical points. There have been considerable efforts, both experimental and
theoretical, which use these magnetic systems to address problems that are
central to the broad understanding of strongly correlated quantum matter. Here,
we summarize some of the basic issues, including i) the extent to which the
quantum criticality in heavy fermion metals goes beyond the standard theory of
order-parameter fluctuations, ii) the nature of the Kondo effect in the quantum
critical regime, iii) the non-Fermi liquid phenomena that accompany quantum
criticality, and iv) the interplay between quantum criticality and
unconventional superconductivity.Comment: (v2) 39 pages, 8 figures; shortened per the editorial mandate; to
appear in Nature Physics. (v1) 43 pages, 8 figures; Non-technical review
article, intended for general readers; the discussion part contains more
specialized topic
Global Phase Diagram of the Kondo Lattice: From Heavy Fermion Metals to Kondo Insulators
We discuss the general theoretical arguments advanced earlier for the T=0
global phase diagram of antiferromagnetic Kondo lattice systems, distinguishing
between the established and the conjectured. In addition to the well-known
phase of a paramagnetic metal with a "large" Fermi surface (P_L), there is also
an antiferromagnetic phase with a "small" Fermi surface (AF_S). We provide the
details of the derivation of a quantum non-linear sigma-model (QNLsM)
representation of the Kondo lattice Hamiltonian, which leads to an effective
field theory containing both low-energy fermions in the vicinity of a Fermi
surface and low-energy bosons near zero momentum. An asymptotically exact
analysis of this effective field theory is made possible through the
development of a renormalization group procedure for mixed fermion-boson
systems. Considerations on how to connect the AF_S and P_L phases lead to a
global phase diagram, which not only puts into perspective the theory of local
quantum criticality for antiferromagnetic heavy fermion metals, but also
provides the basis to understand the surprising recent experiments in
chemically-doped as well as pressurized YbRh2Si2. We point out that the AF_S
phase still occurs for the case of an equal number of spin-1/2 local moments
and conduction electrons. This observation raises the prospect for a global
phase diagram of heavy fermion systems in the Kondo-insulator regime. Finally,
we discuss the connection between the Kondo breakdown physics discussed here
for the Kondo lattice systems and the non-Fermi liquid behavior recently
studied from a holographic perspective.Comment: (v3) leftover typos corrected. (v2) Published version. 32 pages, 4
figures. Section 7, on the connection between the Kondo lattice systems and
the holographic models of non-Fermi liquid, is expanded. (v1) special issue
of JLTP on quantum criticalit
A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial
Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation
Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study
Introduction:
The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.
Methods:
In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.
Findings:
Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.
Interpretation:
After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification
Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): a UK multicentre, prospective cohort study
Background
The impact of COVID-19 on physical and mental health and employment after hospitalisation with acute disease is not well understood. The aim of this study was to determine the effects of COVID-19-related hospitalisation on health and employment, to identify factors associated with recovery, and to describe recovery phenotypes.
Methods
The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a multicentre, long-term follow-up study of adults (aged ≥18 years) discharged from hospital in the UK with a clinical diagnosis of COVID-19, involving an assessment between 2 and 7 months after discharge, including detailed recording of symptoms, and physiological and biochemical testing. Multivariable logistic regression was done for the primary outcome of patient-perceived recovery, with age, sex, ethnicity, body-mass index, comorbidities, and severity of acute illness as covariates. A post-hoc cluster analysis of outcomes for breathlessness, fatigue, mental health, cognitive impairment, and physical performance was done using the clustering large applications k-medoids approach. The study is registered on the ISRCTN Registry (ISRCTN10980107).
Findings
We report findings for 1077 patients discharged from hospital between March 5 and Nov 30, 2020, who underwent assessment at a median of 5·9 months (IQR 4·9–6·5) after discharge. Participants had a mean age of 58 years (SD 13); 384 (36%) were female, 710 (69%) were of white ethnicity, 288 (27%) had received mechanical ventilation, and 540 (50%) had at least two comorbidities. At follow-up, only 239 (29%) of 830 participants felt fully recovered, 158 (20%) of 806 had a new disability (assessed by the Washington Group Short Set on Functioning), and 124 (19%) of 641 experienced a health-related change in occupation. Factors associated with not recovering were female sex, middle age (40–59 years), two or more comorbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial but only weakly associated with the severity of acute illness. Four clusters were identified with different severities of mental and physical health impairment (n=767): very severe (131 patients, 17%), severe (159, 21%), moderate along with cognitive impairment (127, 17%), and mild (350, 46%). Of the outcomes used in the cluster analysis, all were closely related except for cognitive impairment. Three (3%) of 113 patients in the very severe cluster, nine (7%) of 129 in the severe cluster, 36 (36%) of 99 in the moderate cluster, and 114 (43%) of 267 in the mild cluster reported feeling fully recovered. Persistently elevated serum C-reactive protein was positively associated with cluster severity.
Interpretation
We identified factors related to not recovering after hospital admission with COVID-19 at 6 months after discharge (eg, female sex, middle age, two or more comorbidities, and more acute severe illness), and four different recovery phenotypes. The severity of physical and mental health impairments were closely related, whereas cognitive health impairments were independent. In clinical care, a proactive approach is needed across the acute severity spectrum, with interdisciplinary working, wide access to COVID-19 holistic clinical services, and the potential to stratify care.
Funding
UK Research and Innovation and National Institute for Health Research