The human side of microglia Smith, Amy M; Dragunow, Mike
Trends in neurosciences (Regular ed.),
03/2014, Letnik:
37, Številka:
3
Journal Article
Recenzirano
Highlights • There are key differences between human and rodent microglia. • Established protocols are available for primary human microglial cell culture. • Human cell models of brain disease and ...neuroinflammation are expanding. • New technologies bridge the gap between in vitro human cell and in vivo animal research. • These can be used to gain insight into human brain microglial cell physiology.
Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the ...striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma‐aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain‐derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.
Early Huntington disease is characterized by involuntary motor symptoms, especially chorea, due to dominance of direct pathway Striatal Projection Neurons (SPN) which facilitate movement. Initially, deficits in endocannabinoid and BDNF signaling, increased dopamine and GABA contribute to impair some forms of synaptic plasticity in indirect pathway SPNs, as well as their vulnerability to degeneration before other cell types. In this paper we summarize mutant huntington (mHtt)‐induced changes in neurotransmission in the striatum and cortex. DA, dopamine; dSPN, direct pathway SPN; eCB, endocannabinoid; iSPN, indirect pathway SPN.
Among older adults, decreased handgrip strength is associated with greater risk of frailty, and loss of physical function, mobility, lean mass, and overall muscular strength and power. Frailty is ...also associated with sarcopenia, for which handgrip strength measurement has been recommended for diagnostic purposes. Specific cutoff points for diagnosis have been identified, but use of different devices may affect measurement. Therefore to assess validity and reliability, we compared the two most frequently used devices, the Jamar hydraulic and Smedley spring handgrip dynamometers. Sixty-seven older (76.2 ± 0.9 years) men (n = 34) and women (n = 33) completed two trials of handgrip strength measurement on sequential days (T1, T2) using both devices in random order. Intraclass correlations were used to assess test-retest reliability, and Bland-Altman analysis was used to assess validity as the level of agreement between devices. There were significant (p < 0.001) relationships between devices at T1 (r = 0.94) and T2 (r = 0.94) and strong (p < 0.001) intraclass correlations were observed for both devices (Jamar = 0.98; Smedley = 0.96), indicating excellent reliability. However, there were significant differences between devices. Strength measured with Jamar was greater than Smedley at both T1 (27.4 ± 1.4 vs. 23.4 ± 1.1 kg, p < 0.001) and T2 (25.3 ± 1.4 vs. 21.8 ± 1.2 kg, p 75 years) participants, differences between devices were closer to zero for both measurements compared to men and young-old (65-75 years) participants. Our results demonstrate that despite excellent reliability, there is poor agreement between devices, indicating a lack of validity. For use as a diagnostic tool, standardization and device-specific cutoff points for handgrip dynamometry are needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The U.S. government has recently spent several hundred million dollars to promote healthy relationships in new parents. The influx of money implies that relationships of new parents are at elevated ...risk for declining satisfaction and dissolution. This meta-analysis aggregates data from 37 studies that track couples from pregnancy to after the birth of the first child and 4 studies that track childless newlywed couples over time and compare couples who do and do not become parents. Results indicate significant, small declines in relationship satisfaction for both men and women from pregnancy to 11 months postbirth; 5 studies that followed couples for 12-14 months found moderate-sized declines. Seven variables moderated the decrease in relationship satisfaction from pregnancy to early parenthood. However, the decrease in satisfaction may not indicate anything unique about the transition to parenthood; the 4 studies following newlyweds indicated that those who do not become parents experience a decrease in relationship satisfaction similar to that of parents across a comparable span of time. Implications for prevention and future directions are discussed.
Retrieval practice protects memory against acute stress Smith, Amy M.; Floerke, Victoria A.; Thomas, Ayanna K.
Science (American Association for the Advancement of Science),
11/2016, Letnik:
354, Številka:
6315
Journal Article
Recenzirano
More than a decade of research has supported a robust consensus: Acute stress impairs memory retrieval. We aimed to determine whether a highly effective learning technique could strengthen memory ...against the negative effects of stress. To bolster memory, we used retrieval practice, or the act of taking practice tests. Participants first learned stimuli by either restudying or engaging in retrieval practice. Twenty-four hours later, we induced stress in half of the participants and assessed subsequent memory performance. Participants who learned by restudying demonstrated the typical stress-related memory impairment, whereas those who learned by retrieval practice were immune to the deleterious effects of stress. These results suggest that the effects of stress on memory retrieval may be contingent on the strength of the memory representations themselves.
Countries have reached universal health coverage by different paths and with varying health systems. Nonetheless, the trajectory toward universal health coverage regularly has three common features. ...The first is a political process driven by a variety of social forces to create public programmes or regulations that expand access to care, improve equity, and pool financial risks. The second is a growth in incomes and a concomitant rise in health spending, which buys more health services for more people. The third is an increase in the share of health spending that is pooled rather than paid out-of-pocket by households. This pooled share is sometimes mobilised as taxes and channelled through governments that provide or subsidise care—in other cases it is mobilised in the form of contributions to mandatory insurance schemes. The predominance of pooled spending is a necessary condition (but not sufficient) for achieving universal health coverage. This paper describes common patterns in countries that have successfully provided universal access to health care and considers how economic growth, demographics, technology, politics, and health spending have intersected to bring about this major development in public health.
Abstract
Objectives
In two studies, we examined the effects of age-related stereotype threat on eyewitness memory using the misinformation paradigm to (a) examine stereotype threat in the context of ...a more ecologically valid memory task and (b) to determine the relationship between task difficulty and susceptibility to stereotype threat.
Methods
After watching a video that depicted a crime, older and younger adult participants were presented with a written synopsis in which information consistent or inconsistent with the original event was presented. Half of the participants were then presented with information designed to activate negative stereotypes about aging. Finally, participants completed a memory test.
Results
In Study 1, when participants were instructed to report information from either the video or the synopsis to complete the final memory test, older adults under high stereotype threat were less accurate than those under low threat. In Study 2, when participants were required to engage in more controlled processes at retrieval and respond with only video information, older adults under stereotype threat performed as well or better than those under low threat.
Discussion
The results are consistent with the Regulatory Focus Model of Stereotype Threat.
The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase ...inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the
kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these
SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated
Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the
p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT
tauopathy mice ...revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
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