Photoactivatable genetically encoded calcium indicators for targeted neuronal imaging.

Circuit mapping requires knowledge of both structural and functional connectivity between cells. Although optical tools have been made to assess either the morphology and projections of neurons or their activity and functional connections, few probes integrate this information. We have generated a family of photoactivatable genetically encoded Ca(2+) indicators that combines attributes of high-contrast photolabeling with high-sensitivity Ca(2+) detection in a single-color protein sensor. We demonstrated in cultured neurons and in fruit fly and zebrafish larvae how single cells could be selected out of dense populations for visualization of morphology and high signal-to-noise measurements of activity, synaptic transmission and connectivity. Our design strategy is transferrable to other sensors based on circularly permutated GFP (cpGFP)

Doppler ultrasound color flow imaging in the study of breast cancer: Preliminary findings

A prospective study of the Doppler color flow features of 55 proved breast cancers was performed. On a three-level scale of low to marked vascularity, visual assessment of the color flow images classified 82% of the cancers as moderately or markedly vascular (minimal: 14%, moderate: 29%, marked: 53%). Four percent of the cancers had no detectable flow. In 29 women, a volume of tissue comparable to the cancer was scanned in the contralateral normal breast. Sixty-nine percent of the normal breasts had moderate or marked vascularity (minimal: 28%, moderate: 41%, marked: 28%), and 3% were avascular. There was poor distinction between normal tissues and cancer which suggests that more sensitive Doppler methods than were employed in this study may be needed in order to detect the small vessel flow reported to be rather specific for malignancy. The high, 82%, detection rate of tumor vessels in this study suggests the potential use of color flow Doppler for directing more specific but lengthy Doppler procedures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28897/1/0000734.pd

Limits to Quantum Gravity Effects from Observations of TeV Flares in Active Galaxies

We have used data from the TeV gamma-ray flare associated with the active galaxy Markarian 421 observed on 15 May 1996 to place bounds on the possible energy-dependence of the speed of light in the context of an effective quantum gravitational energy scale. The possibility of an observable time dispersion in high energy radiation has recently received attention in the literature, with some suggestions that the relevant energy scale could be less than the Planck mass and perhaps as low as 10^16 GeV. The limits derived here indicate this energy scale to be in excess of 4x10^16 GeV at the 95% confidence level. To the best of our knowledge, this constitutes the first convincing limit on such phenomena in this energy regime.Comment: 6 pages, including 2 figure

Tuberculosis IRIS: Pathogenesis, Presentation, and Management across the Spectrum of Disease.

Antiretroviral therapy (ART), while essential in combatting tuberculosis (TB) and HIV coinfection, is often complicated by the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Depending on the TB disease site and treatment status at ART initiation, this immune-mediated worsening of TB pathology can take the form of paradoxical TB-IRIS, unmasking TB-IRIS, or CNS TB-IRIS. Each form of TB-IRIS has unique implications for diagnosis and treatment. Recently published studies have emphasized the importance of neutrophils and T cell subtypes in TB-IRIS pathogenesis, alongside the recognized role of CD4 T cells and macrophages. Research has also refined our prognostic understanding, revealing how the disease can impact lung function. While corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS, increasing interest has been given to biologic therapies directly targeting the immune pathology. TB-IRIS, especially its unmasking form, remains incompletely described and more data is needed to validate biomarkers for diagnosis. Management strategies remain suboptimal, especially in the highly morbid central nervous system (CNS) form of the disease, and further trials are necessary to refine treatment. In this review we will summarize the current understanding of the immunopathogenesis, the presentation of TB-IRIS and the evidence for management recommendations

Detection of the BL Lac Object H1426+428 at TeV Gamma Ray Energies

A very high energy (VHE) gamma-ray signal has been detected at the 5.4 sigma level from H1426+428, an x-ray selected BL Lacertae object at a redshift of 0.129. The object was monitored from 1995 - 1998 with the Whipple 10m imaging atmospheric Cherenkov telescope as part of a general blazar survey; the results of these observations, although not statistically significant, were consistently positive. X-ray observations of H1426+428 during 1999 with the BeppoSAX instrument revealed that the peak of its synchrotron spectrum occurs at > 100 keV, leading to the prediction of observable TeV emission from this object. H1426+428 was monitored extensively at the Whipple Observatory during the 1999, 2000, and 2001 observing seasons. The strongest TeV signals were detected in 2000 and 2001. During 2001, an integral flux of 2.04 +/- 0.35 x10e-11 cm-2 s-1 above 280 GeV was recorded from H1426+428. The detection of H1426+428 supports the idea that, as also seen in Markarian 501 and 1ES2344+514, BL Lacertae objects with extremely high synchrotron peak frequencies produce gamma rays in the TeV range.Comment: 35 pages, 7 figures, accepted by ApJ Two upper limits in Table 3 (upper limits for 1995 and 1997) are different from the ApJ versio

Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BACKGROUND: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. METHODS: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. RESULTS: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P = .04). CONCLUSIONS: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation

Preembryo Personhood: An Assessment of the President’s Council Arguments

The President’s Council on Bioethics has addressed the moral status of human preembryos in its reports on stem cell research and human therapeutic cloning. Although the Council has been criticized for being hand-picked to favor the right-to-life viewpoint concerning human preembryos, it has embraced the idea that the right-to-life position should be defended in secular terms. This is an important feature of the Council’s work, and it demonstrates a recognition of the need for genuine engagement between opposing sides in the debate over stem cell research. To promote this engagement, the Council has stated in secular terms several arguments for the personhood of human preembryos. This essay presents and critiques those arguments, and it concludes that they are unsuccessful. If the best arguments in support of the personhood of human preembryos have been presented by the Council, then there are no reasonable secular arguments in support of that view

Neurocognitive outcomes of tuberculous meningitis in a primarily HIV-positive Ugandan cohort.

Background: The toll of tuberculous meningitis (TBM) in both mortality and disability is considerable, but advancements in rehabilitation have the potential to improve the functional abilities and the quality of survivors' lives. However, the typical phenotype of neurocognitive impairment in TBM survivors remains unstudied in HIV-predominant populations in sub-Saharan Africa. Methods: We tested 36 survivors of TBM in Uganda with a comprehensive battery of neurocognitive assessments at 8 and 24 weeks after diagnosis, and compared results to a representative cohort of HIV-uninfected Ugandans. Results: While participants had a broad range of impairments at eight weeks, there was marked improvement by 24 weeks, when a phenotype of impairment including deficits in motor functioning, verbal learning and memory, processing speed, and executive function emerged. These deficits were present despite good clinician-rated functional status. The majority (23/27, 85%) had evidence of moderate to severe depression at week 8, and at week 24 (18/24, 75%). Conclusion: These findings highlight the need for more comprehensive neurocognitive assessment in the survivors of TBM, and further investment in and study of rehabilitation, including management of depression, to improve long-term outcomes in this population

VHE γ\gamma-ray observations of Markarian 501

Markarian 501, a nearby (z=0.033) X-ray selected BL Lacertae object, is a well established source of Very High Energy (VHE, E>=300 GeV) gamma rays. Dramatic variability in its gamma-ray emission on time-scales from years to as short as two hours has been detected. Multiwavelength observations have also revealed evidence that the VHE gamma-ray and hard X-ray fluxes may be correlated. Here we present results of observations made with the Whipple Collaboration's 10 m Atmospheric Cerenkov Imaging Telescope during 1999 and discuss them in the context of observations made on Markarian 501 during the period from 1996-1998