Comprehensive Characterization of Ifnγ Signaling in Acute Myeloid Leukemia Reveals Prognostic and Therapeutic Strategies

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states

ATLAS pixel detector electronics and sensors

The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed

Patent foramen ovale: Unanswered questions

The foramen ovale is a remnant of the fetal circulation that remains patent in 20-25% of the adult population. Although long overlooked as a potential pathway that could produce pathologic conditions, the presence of a patent foramen ovale (PFO) has been associated with a higher than expected frequency in a variety of clinical syndromes including cryptogenic stroke, migraines, sleep apnea, platypnea-orthodeoxia, deep sea diving associated decompression illness, and high altitude pulmonary edema. A unifying hypothesis is that a chemical or particulate matter from the venous circulation crosses the PFO conduit between the right and left atria to produce a variety of clinical syndromes. Although observational studies suggest a therapeutic benefit of PFO closure compared to medical therapy alone in patients with cryptogenic stroke, 3 randomized controlled trials (RCTs) did not confirm the superiority of PFO closure for the secondary prevention of stroke. However, meta-analyses of these RCTs demonstrate a significant benefit of PFO closure over medical therapy alone. Similarly, observational studies provide support for PFO closure for symptomatic relief of migraines. But one controversial randomized study failed to replicate the results of the observational studies while another two demonstrated a partial benefit. The goal of this review is to discuss the clinical conditions associated with PFO and provide internists and primary care physicians with current data on PFO trials, and clinical insight to help guide their patients who are found to have a PFO on echocardiographic testing

Rare presentation of BK encephalitis in a child: imaging and pathological findings

Clinically apparent BK virus infections mostly involve the genitourinary system of immunocompromised patients, particularly those who have undergone renal or bone marrow transplantations. Central nervous system involvement is extremely rare. In this report, we describe the pathologic and MR findings of BK encephalitis in a child. Initial involvement of the brainstem and the cervicomedullary junction was noted that later rapidly progressed to involve other regions of the supratentorial brain parenchyma including the basal ganglia and the thalami as well as the cerebellum

Effect of Heparin on Protein Aggregation: Inhibition versus Promotion

The effect of heparin on both native and denatured protein aggregation was investigated by turbidimetry and dynamic light scattering (DLS). Turbidimetric data show that heparin is capable of inhibiting and reversing the native aggregation of bovine serum albumin (BSA), β-lactoglobulin (BLG), and Zn–insulin at a pH near pI and at low ionic strength <i>I</i>; however, the results vary with regard to the range of pH, <i>I</i>, and protein–heparin stoichiometry required to achieve these effects. The kinetics of this process were studied to determine the mechanism by which interaction with heparin could result in inhibition or reversal of native protein aggregates. For each protein, the binding of heparin to distinctive intermediate aggregates formed at different times in the aggregation process dictates the outcome of complexation. This differential binding was explained by changes in the affinity of a given protein for heparin, partly due to the effects of protein charge anisotropy as visualized by electrostatic modeling. The heparin effect can be further extended to include inhibition of denaturing protein aggregation, as seen from the kinetics of BLG aggregation under conditions of thermally induced unfolding with and without heparin

Associations Between HIV Serostatus and Cardiac Structure and Function Evaluated by 2-Dimensional Echocardiography in the Multicenter AIDS Cohort Study.

Background We aimed to investigate whether there are differences in cardiac structure and systolic and diastolic function evaluated by 2-dimensional echocardiography among men living with versus without HIV in the era of combination antiretroviral therapy. Methods and Results We performed a cross-sectional analysis of 1195 men from MACS (Multicenter AIDS Cohort Study) who completed a transthoracic echocardiogram examination between 2017 and 2019. Associations between HIV serostatus and echocardiographic indices were assessed by multivariable regression analyses, adjusting for demographics and cardiovascular risk factors. Among men who are HIV+, associations between HIV disease severity markers and echocardiographic parameters were also investigated. Average age was 57.1±11.9&nbsp;years; 29% of the participants were Black, and 55% were HIV+. Most men who were HIV+ (77%) were virally suppressed; 92% received combination antiretroviral therapy. Prevalent left ventricular (LV) systolic dysfunction (ejection fraction &lt;50%) was low and HIV serostatus was not associated with left ventricular ejection fraction. Multivariable adjustment models showed that men who were HIV+ versus those who were HIV- had greater LV mass index and larger left atrial diameter and right ventricular (RV) end-diastolic area; lower RV function; and higher prevalence of diastolic dysfunction. Higher current CD4+ T cell count ≥400&nbsp;cell/mm3 versus &lt;400 was associated with smaller LV diastolic volume and RV area. Virally suppressed men who were HIV+ versus those who were HIV- had higher indexed LV mass and left atrial areas and greater diastolic dysfunction. Conclusions HIV seropositivity was independently associated with greater LV mass index, left atrial and RV sizes, lower RV function and diastolic abnormalities, but not left ventricular ejection fraction, which may herald a future predisposition to heart failure with preserved ejection fraction among men living with HIV

Association of HIV Serostatus and Inflammation With Ascending Aortic Size.

Background The prevalence and extent of subclinical large vessel vasculopathy is not well defined among people living with HIV. We aimed to evaluate associations between aortic root and ascending aortic sizes measured by 2-dimensional transthoracic echocardiography and HIV serostatus, and to identify risk factors for larger aortic sizes among men with HIV, including levels of circulating inflammatory markers. Methods and Results Using clinical and echocardiographic data from the MACS (Multicenter AIDS Cohort Study), adjusted multivariable linear and logistic regression was performed. Four segments of the proximal aorta were measured: aortic annulus, aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta. HIV infection was associated with significantly larger aortic root (0.03&nbsp;cm [95% CI, 0.002-0.06&nbsp;cm]) and ascending aorta (0.04&nbsp;cm [95% CI, 0.01-0.06&nbsp;cm]) diameters. Higher standardized nadir CD4 (cluster of differentiation 4) T-cell count was significantly associated with smaller aortic root (-0.03&nbsp;cm [95% CI, -0.05 to -0.01&nbsp;cm]), sinotubular junction (-0.03&nbsp;cm [95% CI, -0.05 to -0.01&nbsp;cm]), and ascending aorta (-0.03&nbsp;cm [95% CI, -0.05 to -0.004&nbsp;cm]) diameters. Higher levels of standardized TNF-α (tumor necrosis factor-α) were associated with larger diameters of the aortic annulus (0.02&nbsp;cm [95% CI, 0.003-0.04&nbsp;cm]) and sinotubular junction (0.02&nbsp;cm [95% CI, 0.002-0.04&nbsp;cm]). There were no other cardiovascular or HIV disease severity-related risk factors associated with the aortic dimensions. Conclusions HIV infection is an independent risk factor for greater ascending aortic sizes. Lower nadir CD4 T-cell count and higher TNF-α levels are associated with larger aortic sizes in men with HIV. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00046280