Systematic review techniques are about to become the “new normal” in reviews of management research. However, there is not yet much advice on how to organize the sample selection process as part of ...such reviews. This article addresses this void and analyzes this vital part of systematic reviews in more detail. In particular, it offers a critical review of systematic literature reviews published in the Academy of Management Annals and the International Journal of Management Reviews between 2004 and 2018. Based on this methodological literature review, the article presents issues to consider in the most critical choices during the sample selection process. Furthermore, this review identifies several descriptive features such as the mean number of research items included in systematic reviews, the mean number of databases used, and the mean coverage period of such reviews. These numbers may be used as benchmark figures in future reviews.
Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A ...distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.
Vimentin is an epithelial-to-mesenchymal transition (EMT) biomarker and intermediate filament protein that functions during cell migration to maintain structure and motility. Despite the abundance of ...clinical data linking vimentin to poor patient outcome, it is unclear if vimentin is required for metastasis or is a correlative biomarker. We developed a novel genetically engineered mouse model (GEMM) to probe vimentin in lung adenocarcinoma metastasis.
We used the
model (
), which incorporates a whole-body knockout of vimentin and is derived from the Cre-dependent
model (
). We compared the metastatic phenotypes of the GEMMs and analyzed primary tumors from the
models and lung adenocarcinoma patients to assess vimentin expression and function.
Characterization of
and
mice shows that although vimentin is not required for primary lung tumor growth, vimentin is required for metastasis, and vimentin loss generates lower grade primary tumors. Interestingly, in the
mice, vimentin was not expressed in tumor cells but in cancer-associated fibroblasts (CAFs) surrounding collective invasion packs (CIPs) of epithelial tumor cells, with significantly less CIPs in
mice. CIPs correlate with tumor grade and are vimentin-negative and E-cadherin-positive, indicating a lack of cancer cell EMT. A similar heterotypic staining pattern was observed in human lung adenocarcinoma samples.
studies show that vimentin is required for CAF motility to lead tumor cell invasion, supporting a vimentin-dependent model of collective invasion.
These data show that vimentin is required for lung adenocarcinoma metastasis by maintaining heterotypic tumor cell-CAF interactions during collective invasion.
.
Liquid-liquid phase separation seems to play critical roles in the compartmentalization of cells through the formation of biomolecular condensates. Many proteins with low-complexity regions are found ...in these condensates, and they can undergo phase separation in vitro in response to changes in temperature, pH, and ion concentration. Low-complexity regions are thus likely important players in mediating compartmentalization in response to stress. However, how the phase behavior is encoded in their amino acid composition and patterning is only poorly understood. We discuss here that polymer physics provides a powerful framework for our understanding of the thermodynamics of mixing and demixing and for how the phase behavior is encoded in the primary sequence. We propose to classify low-complexity regions further into subcategories based on their sequence properties and phase behavior. Ongoing research promises to improve our ability to link the primary sequence of low-complexity regions to their phase behavior as well as the emerging miscibility and material properties of the resulting biomolecular condensates, providing mechanistic insight into this fundamental biological process across length scales.
A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).
To describe the ...epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.
Retrospective multicenter study.
The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.
Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are ...in patients who are lost to programmes.
We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness.
In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes.
Calmodulin (CaM) is a ubiquitous Ca2+ receptor protein mediating a large number of signaling processes in all eukaryotic cells. CaM plays a central role in regulating a myriad of cellular functions ...via interaction with multiple target proteins. This review focuses on the action of CaM and CaM-dependent signaling systems in the control of vertebrate cell proliferation, programmed cell death and autophagy. The significance of CaM and interconnected CaM-regulated systems for the physiology of cancer cells including tumor stem cells, and processes required for tumor progression such as growth, tumor-associated angiogenesis and metastasis are highlighted. Furthermore, the potential targeting of CaM-dependent signaling processes for therapeutic use is discussed.
•Calmodulin is the major intracellular calcium receptor regulating a multitude of physiological processes.•Calmodulin regulates cell proliferation, programmed cell death and autophagy in higher eukaryotes.•Calmodulin has a major impact on the regulation of several specific cell cycle phases.•Most of these functions are mediated through calmodulin-dependent kinases and phosphatases.•The significance of calmodulin-dependent mechanisms in the physiology of tumor cells is highlighted.
Pyramidal cells in cortical Layers 5 and 6 are the only cells in the cerebral cortex with axons that leave the cortex to influence the thalamus. Layer 6 cells provide modulatory feedback input to all ...thalamic nuclei. Layer 5 cells provide driving input to higher‐order thalamic nuclei and do not innervate first‐order nuclei, which get their driving inputs from subcortical sources. Higher‐order nuclei innervated by Layer 5 cells thus seem to be involved with cortico‐thalamo‐cortical communication. The Layer 5 axons branch to also target additional subcortical structures that mediate interactions with the external environment. These corticofugal pathways represent the only means by which the cortex influences the rest of the neuraxis and thus are essential for proper cortical function and species survival. Here we review current understanding of the corticofugal pathways from Layers 5 and 6 and speculate on their functional contributions to neural processing and behavior.
Pyramidal cells in cortical Layers 5 and 6 are the only cells in the cerebral cortex with axons that leave the cortex to influence the thalamus. Layer 6 cells provide modulatory feedback input to all thalamic nuclei, whereas Layer 5 cells provide driving input to higher‐order thalamic nuclei. Here, we review current understanding of the corticofugal pathways and speculate on their functional contributions to neural processing and behavior.
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