Spatial displacement sensitivity of X- and Y-cells in the dorsal lateral geniculate nucleus of the cat

The sensitivity of X- and Y-cells in the dorsal lateral geniculate nucleus of the cat to small, temporally modulated displacements of grating stimuli was measured at 0.175, 0.25, 0.50, 1.00, and 2.00 c/deg. For every cell, two threshold measures were determined: first, a contrast threshold with a counterphase grating and then a displacement threshold with a grating matched in spatial frequency, but whose contrast was 2.5 times the threshold value. The results showed that displacement thresholds of both X- and Y-cells decreased with increasing spatial frequency. At low spatial frequencies, mean displacement thresholds of X- and Y-cells were similar, but at intermediate spatial frequencies, Y-cell thresholds were lower than X. X-cell displacement thresholds were lower than Y only at the highest spatial frequency tested. Consistent with previous reports, contrast thresholds also varied with spatial frequency for both X- and Y-cells. The local luminance differences produced by the contrast threshold and displacement threshold stimuli for the two classes of cells were compared. Across all spatial frequencies, the change in position of the gratings at displacement threshold produced smaller luminance differences than the counterphase gratings at contrast threshold. This enhanced sensitivity of X- and Y-cells to a local luminance changes produced by grating displacement was related to the high spatial contrast of the grating and not to the displacement per se.     

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. VII. Diabetic nonproliferative retinal lesions

The prevalences of hard exudates, soft exudates, intraretinal microvascular abnormalities (IRMAs), and venous beading and their relationships to demographic and other characteristics were examined in a population-based study in southern Wisconsin. For participants whose age at diagnosis was less than 30 years and who were taking insulin (N = 996), hard exudates were found in 24.2%, soft exudates in 15.3%, IRMAs in 16.5%, and venous beading in 7.0% of the population. For participants whose age at diagnosis was 30 years or older and who were taking insulin (N = 674), hard exudates were found in 28.3%, soft exudates in 15.5%, IRMAs in 8.8%, and venous beading in 3.2%. For older-onset persons not taking insulin (N = 696), hard exudates were found in 9.4%, soft exudates in 5.4%, IRMAs in 2.6%, and venous beading in 0.9% of the population. The severities of the lesions were found to be consistently associated with longer duration of diabetes in younger-onset persons and the presence of proteinuria in older-onset persons.     

Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.     

COVID-19 therapeutics: Challenges and directions for the future

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.     

Effects of Peroxide and Catalase on Near Ultraviolet Radiation Sensitivity in Escherichia Coli Strains

Summary

The role of peroxide and catalase on NUV radiation sensitivity was examined in two repair competent E. coli strains, AB1157 and B/r. Exponential phase B/r is considerably more sensitive to NUV radiation than exponential phase AB1157. However, resistance to 5 mmol dm^?3 H₂O₂ was induced in both AB1157 and B/r by pretreating growing cells with 30 μmol dm^?3 H₂O₂. Pretreatment also induced resistance to broad-band NUV radiation in these strains. The addition of catalase to the post-irradiation plating medium increased survival to the same extent as that provided by pretreatment with 30 μmol dm^?3 H₂O₂, in both strains. The NUV radiation sensitivity seen in B/r does not appear to be due to a deficiency in enzymes that scavenge H₂O₂, as a catalase deficient mutant, E. coli UM1, is more resistant to NUV radiation than B/r. Also, assays for H₂O₂ scavenging ability show little difference between AB1157 and B/r in this respect. Two hypotheses are put forward to account for the sensitivity of exponential phase B/r. Whilst it is apparent that peroxides and catalase do have a role in NUV radiation damage, it is clear that other factors also influence survival under certain conditions.     

Ultrasensitive profiling of UV-induced mutations identifies thousands of subclinical facial tumors in tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is a neurogenetic syndrome due to loss-of-function mutations in TSC2 or TSC1, characterized by tumors at multiple body sites, including facial angiofibroma (FAF). Here, an ultrasensitive assessment of the extent and range of UV-induced mutations in TSC facial skin was performed.MethodsA multiplex high-sensitivity PCR assay (MHPA) was developed, enabling mutation detection at extremely low (<0.1%) variant allele frequencies (VAFs).ResultsMHPA assays were developed for both TSC2 and TP53, and applied to 81 samples, including 66 skin biopsies. UV-induced second-hit mutation causing inactivation of TSC2 was pervasive in TSC facial skin with an average of 4.8 mutations per 2-mm biopsy at median VAF 0.08%, generating more than 150,000 incipient facial tumors (subclinical “micro-FAFs”) in the average TSC subject. The MHPA analysis also led to the identification of a refined UV-related indel signature and a recurrent complex mutation pattern, consisting of both a single-nucleotide or dinucleotide variant and a 1- to 9-nucleotide deletion, in cis.ConclusionTSC facial skin can be viewed as harboring a patchwork of clonal fibroblast proliferations (micro-FAFs) with indolent growth, a small proportion of which develop into clinically observable FAF. Our observations also expand the spectrum of UV-related mutation signatures.FundingThis work was supported by the TSC Alliance; the Engles Family Fund for Research in TSC and LAM; and the NIH, National Heart, Lung, and Blood Institute (U01HL131022-04 and Intramural Research Program).