The most widely used approach for defining gene function is to reduce or completely disrupt its normal expression. For over a decade, RNAi has ruled the lab, offering a magic bullet to disrupt gene ...expression in many organisms. However, new biotechnological tools—specifically CRISPR-based technologies—have become available and are squeezing out RNAi dominance in mammalian cell studies. These seemingly competing technologies leave research investigators with the question: “Which technology should I use in my experiment?” This review offers a practical resource to compare and contrast these technologies, guiding the investigator when and where to use this fantastic array of powerful tools.
Boettcher and McManus provide a practical guide to choosing the right tool for your gene silencing experiment—RNAi, TALEN, or CRISPR.
Parkinson's Disease and Parkinsonism Hayes, Michael T.
The American journal of medicine,
July 2019, 2019-07-00, 20190701, Letnik:
132, Številka:
7
Journal Article
Recenzirano
Parkinson's disease is a progressive neurodegenerative disease characterized by tremor and bradykinesia and is a common neurologic ailment. Male sex and advancing age are independent risk factors ...and, as the population ages, is taking an increasing toll on productivity and medical resources. There are a number of other extrapyramidal conditions that can make the diagnosis challenging. Unlike other neurodegenerative diseases, idiopathic Parkinson's disease has effective treatments that mitigate symptoms. Medications can improve day-to-day function and, in cases where medication does not give a sustained benefit or has significant side effects, treatments like deep brain stimulation result in improved quality of life.
Conventionally, engineers have employed rigid materials to fabricate precise, predictable robotic systems, which are easily modelled as rigid members connected at discrete joints. Natural systems, ...however, often match or exceed the performance of robotic systems with deformable bodies. Cephalopods, for example, achieve amazing feats of manipulation and locomotion without a skeleton; even vertebrates such as humans achieve dynamic gaits by storing elastic energy in their compliant bones and soft tissues. Inspired by nature, engineers have begun to explore the design and control of soft-bodied robots composed of compliant materials. This Review discusses recent developments in the emerging field of soft robotics.
Reciprocal feedback processes between experience and development are central to contemporary developmental theory. Autoregressive cross-lagged panel (ARCL) models represent a common analytic approach ...intended to test such dynamics. The authors demonstrate that—despite the ARCL model's intuitive appeal—it typically (a) fails to align with the theoretical processes that it is intended to test and (b) yields estimates that are difficult to interpret meaningfully. Specifically, using a Monte Carlo simulation and two empirical examples concerning the reciprocal relation between spanking and child aggression, it is shown that the cross-lagged estimates derived from the ARCL model reflect a weighted—and typically uninterpretable—amalgam of between- and within-person associations. The authors highlight one readily implemented respecification that better addresses these multiple levels of inference.
Microglia in Alzheimer's disease Sarlus, Heela; Heneka, Michael T
The Journal of clinical investigation,
2017-Sep-01, 2017-9-1, 20170901, Letnik:
127, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or ...endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an "activated state"). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed.
To validate an interpretation or use of test scores is to evaluate the plausibility of the claims based on the scores. An argument-based approach to validation suggests that the claims based on the ...test scores be outlined as an argument that specifies the inferences and supporting assumptions needed to get from test responses to score-based interpretations and uses. Validation then can be thought of as an evaluation of the coherence and completeness of this interpretation/use argument and of the plausibility of its inferences and assumptions. In outlining the argument-based approach to validation, this paper makes eight general points. First, it is the proposed score interpretations and uses that are validated and not the test or the test scores. Second, the validity of a proposed interpretation or use depends on how well the evidence supports the claims being made. Third, more-ambitious claims require more support than less-ambitious claims. Fourth, more-ambitious claims (e.g., construct interpretations) tend to be more useful than less-ambitious claims, but they are also harder to validate. Fifth, interpretations and uses can change over time in response to new needs and new understandings leading to changes in the evidence needed for validation. Sixth, the evaluation of score uses requires an evaluation of the consequences of the proposed uses; negative consequences can render a score use unacceptable. Seventh, the rejection of a score use does not necessarily invalidate a prior, underlying score interpretation. Eighth, the validation of the score interpretation on which a score use is based does not validate the score use.
To compare neurocognitive, language, executive function, academic achievement, neurologic and behavioral outcomes, and quality of life at age 10 years in children born extremely preterm who developed ...bronchopulmonary dysplasia (BPD) to children who did not develop BPD.
The Extremely Low Gestational Age Newborns study population included 863 children born extremely preterm whose BPD status before discharge was known had an IQ (Differential Ability Scales II DAS II) assessment at 10 years. We evaluated the association of BPD with any cognitive (DAS II), executive function (NEuroPSYchological Assessment II), academic achievement (Wechsler Individual Achievement Test-III and Oral and Written Language Scales OWLS) as well as social dysfunctions (Social Responsiveness Scale). We used logistic regression models, adjusting for potential confounding factors, to assess the strength of association between the severity of BPD and each outcomes.
Three hundred and seventy-two (43%) children were oxygen-dependent at 36 weeks postconception age, whereas an additional 78 (9%) were also oxygen- and ventilator-dependent. IQ scores 2 or more SDs below the expected mean (ie,
scores ≤-2) occurred twice as commonly among children who had BPD as among those who did not. Children with severe BPD consistently had the lowest scores on DAS II, OWLS, Wechsler Individual Achievement Test-III, NEuroPSYchological Assessment II, and Social Responsiveness Scale assessments.
Among 10-year-old children born extremely preterm, those who had BPD were at increased risk of cognitive, language, and executive dysfunctions; academic achievement limitations; social skill deficits; and low scores on assessments of health-related quality of life.
How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem ...cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.
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•Bone, cartilage, and stroma are derived from clonal, lineage-restricted progenitors•We defined a postnatal skeletal stem cell (mSSC) and seven downstream progenitors•Skeletal progenitor fate can be directed from bone to cartilage and vice versa•Manipulation of mSSC niche signaling can induce de novo bone or cartilage formation
Bone, cartilage, and stroma development in mice is mapped from a population of postnatal skeletal stem cells to their downstream progenitors of bone, cartilage, and stromal tissue.
Activation of innate immunity and the assembly of microglial cells at sites of Alzheimer disease pathology has long been regarded as bystander phenomenon, which does not actively contribute to ...disease pathogenesis and progression. Recent data emerging from genetics, clinical imaging and animal experimentation point to an intimate and mutual interaction of innate immune mechanisms and neurodegenerative processes. NOD‐like receptor (NLR) family, pyrin domain containing 3 and 1 inflammasomes, present in myeloid cells and neurons, respectively, represent key components of the innate immune reaction observed in Alzheimer patient brains. Inhibition of inflammasome activation just begins to prove beneficial and protective from cognitive deficits and neuronal death in cell culture and animal models of Alzheimer's disease, thereby opening a new avenue for therapeutic intervention.
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