Karen Hansen's richly anecdotal narrative explores the textured community lives of New England's working women and men—both white and black—n the half century before the Civil War. Her use of ...diaries, letters, and autobiographies brings their voices to life, making this study an extraordinary combination of historical research and sociological interpretation.
Hansen challenges conventional notions that women were largely relegated to a private realm and men to a public one. A third dimension—the social sphere—also existed and was a critical meeting ground for both genders. In the social worlds of love, livelihood, gossip, friendship, and mutual assistance, working people crossed ideological gender boundaries.
The book's rare collection of original writings reinforces Hansen's arguments and also provides an intimate glimpse into antebellum New England life.
A cornerstone of epidemiologic research is to understand the causal pathways from an exposure to an outcome. Mediation analysis based on counterfactuals is an important tool when addressing such ...questions. However, none of the existing techniques for formal mediation analysis can be applied to survival data. This is a severe shortcoming, as many epidemiologic questions can be addressed only with censored survival data. A solution has been to use a number of Cox models (with and without the potential mediator), but this approach does not allow a causal interpretation and is not mathematically consistent. In this paper, we propose a simple measure of mediation in a survival setting. The measure is based on counterfactuals, and measures the natural direct and indirect effects. The method allows a causal interpretation of the mediated effect (in terms of additional cases per unit of time) and is mathematically consistent. The technique is illustrated by analyzing socioeconomic status, work environment, and long-term sickness absence. A detailed implementation guide is included in an online eAppendix (http://links.lww.com/EDE/A476).
Microglia in Alzheimer's disease Hansen, David V; Hanson, Jesse E; Sheng, Morgan
The Journal of cell biology,
02/2018, Letnik:
217, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer's disease (AD). Human genetics data point to a key role for microglia ...in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.
Alzheimer’s disease (AD) is the most common form of dementia and the 6th leading cause of death in the US. The neuropathological hallmarks of the disease are extracellular amyloid-β (Aβ) plaques and ...intraneuronal hyperphosphorylated tau aggregates. Genetic variants of TREM2 (triggering receptor expressed on myeloid cells 2), a cell-surface receptor expressed selectively in myeloid cells, greatly increase the risk of AD, implicating microglia and the innate immune system as pivotal factors in AD pathogenesis. Recent studies have advanced our understanding of TREM2 biology and microglial activities in aging and neurodegenerative brains, providing new insights into TREM2 functions in amyloid plaque maintenance, microglial envelopment of plaque, microglia viability, and the identification of novel TREM2 ligands. Our increased understanding of TREM2 and microglia has opened new avenues for therapeutic intervention to delay or prevent the progression of AD.
The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a ...lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution.
The aim of this longitudinal study was to assess with positron emission tomography (PET) the relationship between levels of inflammation and the loads of aggregated β-amyloid and tau at baseline and ...again after 2 years in prodromal Alzheimer's disease.
Forty-three subjects with mild cognitive impairment (MCI) had serial
C-PK11195 PET over 2 years to measure inflammation changes, and
C-PiB PET to determine β-amyloid fibril load; 22 also had serial
F-Flortaucipir PET to determine tau tangle load. Cortical surface statistical mapping was used to localise areas showing significant changes in tracer binding over time and to interrogate correlations between tracer binding of the tracers at baseline and after 2 years.
Those MCI subjects with high
C-PiB uptake at baseline (classified as prodromal Alzheimer's disease) had raised inflammation levels which significantly declined across cortical regions over 2 years although their β-amyloid levels continued to rise. Those MCI cases who had low/normal
C-PiB uptake at baseline but their levels then rose over 2 years were classified as prodromal AD with low Thal phase 1-2 amyloid deposition at baseline. They showed levels of cortical inflammation which correlated with their rising β-amyloid load. Those MCI cases with baseline low
C-PiB uptake that remained stable were classified as non-AD, and they showed no correlated inflammation levels. Finally, MCI cases which showed both high
C-PiB and
F-Flortaucipir uptake at baseline (MCI due to AD) showed a further rise in their tau tangle load over 2 years with a correlated rise in levels of inflammation.
Our baseline and 2-year imaging findings are compatible with a biphasic trajectory of inflammation in Alzheimer's disease: MCI cases with low baseline but subsequently rising β-amyloid load show correlated levels of microglial activation which then later decline when the β-amyloid load approaches AD levels. Later, as tau tangles form in β-amyloid positive MCI cases with prodromal AD, the rising tau load is associated with higher levels of inflammation.
is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of
in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking
(PS2APP;Trem2
) ...at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2
mice, with
-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2
females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2
mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2
brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2
hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2
mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2
mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of
deficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity.
Genetic studies indicate that
gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of
deletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of
-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in
-deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species.
Damage-associated microglia (DAM) profiles observed in Alzheimer’s disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD ...microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
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•Transcriptomic data from FACS-sorted microglia from frozen AD and control samples•APOE and other differentially expressed genes define the human Alzheimer’s microglia state•Scant overlap with mouse models but strong enrichment of age-related changes•Web resource to browse data: http://research-pub.gene.com/BrainMyeloidLandscape
Gene expression analysis of human AD microglia has been limited by technical challenges. Srinivasan et al. use RNA-seq to profile FACS-purified microglia from frozen AD and control brains, revealing that human AD microglia exhibit accelerated aging, as well as age-independent changes, like upregulation of APOE.
Previous research has reported that sexual harassment can lead to reduced mental health. Few studies have focused on sexual harassment conducted by clients or customers, which might occur in ...person-related occupations such as eldercare work, social work or customer service work. This study examined the cross-sectional association between sexual harassment by clients or customers and depressive symptoms. We also examined if this association was different compared to sexual harassment conducted by a colleague, supervisor or subordinate. Further, we investigated if psychosocial workplace initiatives modified the association between sexual harassment by clients or customers and level of depressive symptoms.
We used data from the Work Environment and Health in Denmark cohort study (WEHD) and the Work Environment Activities in Danish Workplaces Study (WEADW) collected in 2012. WEHD is based on a random sample of employed individuals aged 18-64. In WEADW, organizational supervisors or employee representatives provided information on workplace characteristics. By combining WEHD and WEADW we included self-reported information on working conditions and health from 7603 employees and supervisors in 1041 organizations within 5 occupations. Data were analyzed using multilevel regression and analyses adjusted for gender, age, occupation and socioeconomic position.
Exposure to workplace sexual harassment from clients or customers was statistically significantly associated with a higher level of depressive symptoms (2.05; 95% CI: 0.98-3.12) compared to no exposure. Employees harassed by colleagues, supervisors or subordinates had a higher mean level of depressive symptoms (2.45; 95% CI: 0.57-4.34) than employees harassed by clients or customers. We observed no statistically significant interactions between harassment from clients and customers and any of the examined psychosocial workplace initiatives (all p > 0.05).
The association between sexual harassment and depressive symptoms differed for employees harassed by clients or customers and those harassed by colleagues, supervisors or subordinates. The results underline the importance of investigating sexual harassment from clients or customers and sexual harassment by colleagues, supervisors or subordinates as distinct types of harassment. We found no modification of the association between sexual harassment by clients or customers and depressive symptoms by any of the examined psychosocial workplace initiatives.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer’s disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work ...examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.
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•Increased glial classical complement expression in amyloidosis and tauopathy models•C3 deficiency rescues plaque-proximal synapse loss in PS2APP mice•C3 deficiency mitigates neurodegeneration and neuronal loss in TauP301S mice•C3 protein is increased in brains and cerebrospinal fluid from AD patients
Wu et al. show that loss of the central complement component C3, which is elevated and activated in brains and cerebrospinal fluid from AD patients, ameliorates synapse loss and neurodegeneration in amyloidosis and tauopathy AD mouse models despite ongoing glial activation.
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