The emetic syndrome of
is a food intoxication caused by cereulide (CER) and manifested by emesis, nausea and in most severe cases with liver failure. While acute effects have been studied in the ...aftermath of food intoxication, an exposure to low doses of cereulide might cause unnoticed damages to the intestines and liver. The toxicity which relies on the mitochondrial dysfunction was assessed on Caco-2 and HepG2 cells after exposure of one, three and ten days to a range of low doses of cereulide. Oxygen consumption rate analyses were used to study the impact of low doses of CER on the bioenergetics functions of undifferentiated Caco-2 and HepG2 cells using Seahorse XF extracellular flux analyzer. Both Caco-2 and HepG2 cells experienced measurable mitochondrial impairment after prolonged exposure of 10 days to 0.25 nM of cereulide. Observed mitochondrial dysfunction was greatly reflected in reduction of maximal cell respiration. At 0.50 nM CER, mitochondrial respiration was almost completely shut down, especially in HepG2 cells. These results corresponded with a severe reduction in the amount of cells and an altered morphology, observed by microscopic examination of the cells. Accurate and robust quantification of basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration allowed better understanding of the effects of cereulide in underlying respiratory malfunctions in low-dose exposure.
Breast cancer is the most common nonskin cancer among women in the United States and the second leading cause of cancer death. The median age at diagnosis is 62 years, and an estimated 1 in 8 women ...will develop breast cancer at some point in their lifetime. African American women are more likely to die of breast cancer compared with women of other races.
To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on medications for risk reduction of primary breast cancer.
The USPSTF reviewed evidence on the accuracy of risk assessment methods to identify women who could benefit from risk-reducing medications for breast cancer, as well as evidence on the effectiveness, adverse effects, and subgroup variations of these medications. The USPSTF reviewed evidence from randomized trials, observational studies, and diagnostic accuracy studies of risk stratification models in women without preexisting breast cancer or ductal carcinoma in situ.
The USPSTF found convincing evidence that risk assessment tools can predict the number of cases of breast cancer expected to develop in a population. However, these risk assessment tools perform modestly at best in discriminating between individual women who will or will not develop breast cancer. The USPSTF found convincing evidence that risk-reducing medications (tamoxifen, raloxifene, or aromatase inhibitors) provide at least a moderate benefit in reducing risk for invasive estrogen receptor-positive breast cancer in postmenopausal women at increased risk for breast cancer. The USPSTF found that the benefits of taking tamoxifen, raloxifene, and aromatase inhibitors to reduce risk for breast cancer are no greater than small in women not at increased risk for the disease. The USPSTF found convincing evidence that tamoxifen and raloxifene and adequate evidence that aromatase inhibitors are associated with small to moderate harms. Overall, the USPSTF determined that the net benefit of taking medications to reduce risk of breast cancer is larger in women who have a greater risk for developing breast cancer.
The USPSTF recommends that clinicians offer to prescribe risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, to women who are at increased risk for breast cancer and at low risk for adverse medication effects. (B recommendation) The USPSTF recommends against the routine use of risk-reducing medications, such as tamoxifen, raloxifene, or aromatase inhibitors, in women who are not at increased risk for breast cancer. (D recommendation) This recommendation applies to asymptomatic women 35 years and older, including women with previous benign breast lesions on biopsy (such as atypical ductal or lobular hyperplasia and lobular carcinoma in situ). This recommendation does not apply to women who have a current or previous diagnosis of breast cancer or ductal carcinoma in situ.
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•Unsteady MHD nanofluid flow past stretching sheet with velocity slip is analyzed.•Suitable similarity variables are devised.•Similarity solutions are obtained numerically using ...finite element technique.•Unsteadiness tends to enhance values of all quantities of practical interests.•Velocity slip reduces Shear stress and enhances Nusselt and Sherwood numbers.
Induced boundary layer flow in the nanofluid caused by impulsively started nonlinear stretching sheet is analyzed in the presence of thermal radiation and magnetic field considering Navier’s velocity sip boundary condition. The similarity solution is achieved numerically using Galerkin finite element technique. The variation of flow characteristics viz. nanofluid velocity, temperature and nanoparticle concentration is examined corresponding to different flow parameters considered in the problem. The findings of the investigation reveal that nonlinearity in the stretching sheet leads to a deceleration in the nanofluid velocity, temperature and nanoparticle concentration while the unsteadiness in the stretching tends to decelerate the velocity whereas temperature and nanoparticle concentration are found to be increasing with increase in unsteadiness. The problem investigated in this article is basically an extension for unsteady case of the previously done works on nanofluid flow over a sheet stretching with a power-law velocity.
Exogenous administration of various neurotrophic factors has been shown to protect neurons in animal model of Parkinson's disease (PD). Several attempts are being made to search a tissue source ...simultaneously expressing many of these neurotrophic factors. Carotid body (CB) contains oxygen‐sensitive glomus cells rich in dopamine (DA) and expresses glial cell line‐derived neurotrophic factor, brain‐derived neurotrophic factor and neurotrophin‐3. We have attempted to study the functional restoration following co‐transplantation of CB cells and ventral mesencephalic cells (VMC) in a 6‐hydroxydopamine‐lesioned rat model of PD. A significant recovery (p < 0.001) in d‐amphetamine‐induced circling behavior (80%) and spontaneous locomotor activity (85%) was evident in co‐transplanted animals at 12 weeks post‐transplantation as compared to lesioned animals. Similarly, a significant (p < 0.001) restoration was observed in DA‐D2 receptor binding (77%), striatal DA (87%) and 3,4‐dihydroxyphenylacetic acid (DOPAC) (85%) levels and nigral DA (75%) and DOPAC (74%) levels. Functional recovery was accompanied by tyrosine hydroxylase (TH) expression and quantification of TH‐positive cells by image analysis revealed a significant restoration in TH‐immunoreactive (IR) fiber density in striatum, as well as TH‐IR neurons in substantia nigra pars compacta in co‐transplanted animals over VMC‐transplanted animals. The result suggests that co‐transplantation of CB cells along with VMC provides better and long‐term functional restoration in the rat model of PD, possibly by supporting the survival of newly grafted cells as well as remaining host DA neurons.
Directed cell migration plays a crucial role in physiological and pathological conditions. One important mechanical cue, known to influence cell migration, is the gradient of substrate elastic ...modulus (E). However, the cellular microenvironment is viscoelastic and hence the elastic property alone is not sufficient to define its material characteristics. To bridge this gap, in this study, we investigated the influence of the gradient of viscous property of the substrate, as defined by loss modulus (G″) on cell migration. We cultured human mesenchymal stem cells (hMSCs) on a collagen-coated polyacrylamide gel with constant storage modulus (G′) but with a gradient in the loss modulus (G″). We found hMSCs to migrate from high to low loss modulus. We have termed this form of directional cellular migration as “Viscotaxis”. We hypothesize that the high loss modulus regime deforms more due to creep in the long timescale when subjected to cellular traction. Such differential deformation drives the observed Viscotaxis. To verify our hypothesis, we disrupted the actomyosin contractility with myosin inhibitor blebbistatin and ROCK inhibitor Y27632, and found the directional migration to disappear. Further, such time-dependent creep of the high loss material should lead to lower traction, shorter lifetime of the focal adhesions, and dynamic cell morphology, which was indeed found to be the case. Together, findings in this paper highlight the importance of considering the viscous modulus while preparing stiffness-based substrates for the field of tissue engineering.
While the effect of substrate elastic modulus has been investigated extensively in the context of cell biology, the role of substrate viscoelasticity is poorly understood. This omission is surprising as our body is not elastic, but viscoelastic. Hence, the role of viscoelasticity needs to be investigated at depth in various cellular contexts. One such important context is cell migration. Cell migration is important in morphogenesis, immune response, wound healing, and cancer, to name a few. While it is known that cells migrate when presented with a substrate with a rigidity gradient, cellular behavior in response to viscoelastic gradient has never been investigated. The findings of this paper not only reveal a completely novel cellular taxis or directed migration, it also improves our understanding of cell mechanics significantly.
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The palladium-nickel binary nanocluster is reported as a new catalyst system for Suzuki-Miyaura cross-coupling of ortho-heterocycle-tethered sterically hindered aryl bromides. The inferior results ...obtained with the reported Pd/Ni salts/complexes or individual Pd/Ni nanoparticles as catalyst reveal the cooperative catalytic effect of the Pd and Ni nanoparticles in the Pd-Ni nanocluster. The broad substrate scope with respect to variation of the 2-arylbenzoxazole moiety and boronic acids, which offers a means for diversity generation and catalyst recyclability, marks a distinct advantage.
Research on the importance of race in the 2008 presidential campaign has focused almost exclusively on how white racial prejudice influenced vote choice. Instead, I test a theory about how mass ...public exposure to Obama influenced white racial prejudice. This is the first study to assess the impact of exposure to Obama on individuallevel changes in prejudice using nationally representative panel data collected during the campaign. Throughout the campaign, innumerable images of Obama and his family contradicted negative racial stereotypes and changed the balance of black exemplars in mass media in a positive direction, thus causing reductions in prejudice among political television viewers. Exposure to Obama caused the largest reductions in prejudice among McCain supporters, Republicans, and conservatives. Although these individuals surely resisted Obama's political message, consistent with previous research, racial exemplars influence judgments without deliberative processing, thus minimizing resistance to counter-stereotypical portrayals. Because conservatives have more negative preexisting images of blacks, exposure to Obama countered their expectations far more than those with more positive expectations. Moreover, consistent with the psychological basis for mediated intergroup contact, even exposure to conservative programs that criticized Obama's politics reduced prejudice because these programs nonetheless portrayed him as countering negative racial stereotypes. Using three waves of panel data and fixed effects analyses of within-person change, I am able to make the strongest causal argument possible outside of experiments.
In the Global South, the COVID-19 crisis has compelled varied efforts to quickly address the pandemic's impact on urban livelihoods. Families, friends as well as public, private, and civil society ...organizations have mobilized various resources to avert the pandemic's onslaught on the survival of the urban vulnerable. Indeed, there is a burgeoning ‘pandemic urban scholarship’ that shed insights on COVID-19 risks, local responses, and impacts on everyday urban life. Yet, it is unclear how many of these responses are affecting urban livelihoods. This paper thus investigates the impact of COVID-19 on urban livelihood capitals (financial, human, social, and physical) and analyses the moderating role of COVID-19-related support (from families, friends, government agencies, faith-based and non-governmental organizations) to address the pandemic's impact on these capitals. Drawing on a quantitative study in Adenta Municipality of the Greater Accra Region, Ghana, the study finds a negative association between COVID-19 impacts and all urban livelihood capitals. Crucially, COVID-19-related support only reduced the negative impact of the pandemic on financial capital, and not on the other forms of capital. The study suggests that building post-pandemic community resilience warrants the need to transition from the usual reactive, fragmented support to integrated, holistic, and contextually embedded long-term strategies that consider the multi-dimensionality of everyday urban life.
Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell ...exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma.
EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1).
CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice.
These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.
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