Introducing genomics into cancer care Hill, S.
British journal of surgery,
January 2018, 2018-01-00, 20180101, Letnik:
105, Številka:
2
Journal Article
Familial neuropsychological deficits are well established in schizophrenia but remain less well characterized in other psychotic disorders. This study from the Bipolar-Schizophrenia Network on ...Intermediate Phenotypes (B-SNIP) consortium 1) compares cognitive impairment in schizophrenia and bipolar disorder with psychosis, 2) tests a continuum model of cognitive dysfunction in psychotic disorders, 3) reports familiality of cognitive impairments across psychotic disorders, and 4) evaluates cognitive impairment among nonpsychotic relatives with and without cluster A personality traits.
Participants included probands with schizophrenia (N=293), psychotic bipolar disorder (N=227), schizoaffective disorder (manic, N=110; depressed, N=55), their first-degree relatives (N=316, N=259, N=133, and N=64, respectively), and healthy comparison subjects (N=295). All participants completed the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery.
Cognitive impairments among psychotic probands, compared to healthy comparison subjects, were progressively greater from bipolar disorder (z=-0.77) to schizoaffective disorder (manic z=-1.08; depressed z=-1.25) to schizophrenia (z=-1.42). Profiles across subtests of the BACS were similar across disorders. Familiality of deficits was significant and comparable in schizophrenia and bipolar disorder. Of particular interest were similar levels of neuropsychological deficits in relatives with elevated cluster A personality traits across proband diagnoses. Nonpsychotic relatives of schizophrenia probands without these personality traits exhibited significant cognitive impairments, while relatives of bipolar probands did not.
Robust cognitive deficits are present and familial in schizophrenia and psychotic bipolar disorder. Severity of cognitive impairments across psychotic disorders was consistent with a continuum model, in which more prominent affective features and less enduring psychosis were associated with less cognitive impairment. Cognitive dysfunction in first-degree relatives is more closely related to psychosis-spectrum personality disorder traits in psychotic bipolar disorder than in schizophrenia.
Spins in solids or in molecules possess discrete energy levels, and the associated quantum states can be tuned and coherently manipulated by means of external electromagnetic fields. Spins therefore ...provide one of the simplest platforms to encode a quantum bit (qubit), the elementary unit of future quantum computers. Performing any useful computation demands much more than realizing a robust qubit-one also needs a large number of qubits and a reliable manner with which to integrate them into a complex circuitry that can store and process information and implement quantum algorithms. This 'scalability' is arguably one of the challenges for which a chemistry-based bottom-up approach is best-suited. Molecules, being much more versatile than atoms, and yet microscopic, are the quantum objects with the highest capacity to form non-trivial ordered states at the nanoscale and to be replicated in large numbers using chemical tools.
How cells control their size and maintain size homeostasis is a fundamental open question. Cell-size homeostasis has been discussed in the context of two major paradigms: “sizer,” in which the cell ...actively monitors its size and triggers the cell cycle once it reaches a critical size, and “timer,” in which the cell attempts to grow for a specific amount of time before division. These paradigms, in conjunction with the “growth law” 1 and the quantitative bacterial cell-cycle model 2, inspired numerous theoretical models 3–9 and experimental investigations, from growth 10, 11 to cell cycle and size control 12–15. However, experimental evidence involved difficult-to-verify assumptions or population-averaged data, which allowed different interpretations 1–5, 16–20 or limited conclusions 4–9. In particular, population-averaged data and correlations are inconclusive as the averaging process masks causal effects at the cellular level. In this work, we extended a microfluidic “mother machine” 21 and monitored hundreds of thousands of Gram-negative Escherichia coli and Gram-positive Bacillus subtilis cells under a wide range of steady-state growth conditions. Our combined experimental results and quantitative analysis demonstrate that cells add a constant volume each generation, irrespective of their newborn sizes, conclusively supporting the so-called constant Δ model. This model was introduced for E. coli 6, 7 and recently revisited 9, but experimental evidence was limited to correlations. This “adder” principle quantitatively explains experimental data at both the population and single-cell levels, including the origin and the hierarchy of variability in the size-control mechanisms and how cells maintain size homeostasis.
Display omitted
•Individual cells show systematic deviations from the population-level growth law•Cells sense neither space nor time but add constant mass, irrespective of birth size•The adder principle automatically ensures size homeostasis•All measured distributions collapse when rescaled by their respective means
Taheri-Araghi et al. present extensive single-cell data from Gram-negative E. coli and Gram-positive B. subtilis showing that in both cases, cells add a constant volume, irrespective of birth size, and this automatically ensures size homeostasis.
Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided ...insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets.
Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor beta (TGF-beta)-superfamily signals from transmembrane receptors into the nucleus. It is now ...clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-beta-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-beta-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-beta superfamily members is discussed.
Vaccines against malaria Hill, Adrian V. S.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2011, Letnik:
366, Številka:
1579
Journal Article
Recenzirano
Odprti dostop
There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has ...led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.
This book offers an account of perceptual experience—its intrinsic nature, its engagement with the world, its relations to mental states of other kinds, and its role in epistemic norms. One of the ...book’s main claims is that perceptual experience constitutively involves representations of worldly items. A second claim is that the relevant form of representation can be explained in broadly biological terms. After defending these foundational doctrines, the book proceeds to give an account of perceptual appearances and how they are related to the objective world. Appearances turn out to be relational, viewpoint dependent properties of external objects. There is also a complementary account of how the objects that possess these properties are represented. Another major concern is the phenomenological dimension of perception. The book maintains that perceptual phenomenology can be explained reductively in terms of the representational contents of experiences, and it uses this doctrine to undercut the traditional arguments for dualism. This treatment of perceptual phenomenology is then expanded to encompass cognitive phenomenology, the phenomenology of moods and emotions, and the phenomenology of pain. The next topic is the various forms of consciousness that perceptual experience can possess. A principal aim is to show that phenomenology is metaphysically independent of these forms of consciousness, and another is to de-mystify the form known as phenomenal consciousness. The book concludes by discussing the relations of various kinds that perceptual experiences bear to higher level cognitive states, including relations of format, content, and justification or support.
Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. ...Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.
Cell Size Control in Bacteria Chien, An-Chun; Hill, Norbert S.; Levin, Petra Anne
Current biology,
05/2012, Letnik:
22, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Like eukaryotes, bacteria must coordinate division with growth to ensure cells are the appropriate size for a given environmental condition or developmental fate. As single-celled organisms, nutrient ...availability is one of the strongest influences on bacterial cell size. Classic physiological experiments conducted over four decades ago first demonstrated that cell size is directly correlated with nutrient source and growth rate in the Gram-negative bacterium Salmonella typhimurium. This observation subsequently served as the basis for studies revealing a role for cell size in cell cycle progression in a closely related organism, Escherichia coli. More recently, the development of powerful genetic, molecular, and imaging tools has allowed us to identify and characterize the nutrient-dependent pathway responsible for coordinating cell division and cell size with growth rate in the Gram-positive model organism Bacillus subtilis. Here, we discuss the role of cell size in bacterial growth and development and propose a broadly applicable model for cell size control in this important and highly divergent domain of life.
PDF
