Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.

Effects of N-glycan modifications on spike expression, virus infectivity, and neutralization sensitivity in ancestral compared to Omicron SARS-CoV-2 variants.

The SARS-CoV-2 spike glycoprotein has 22 potential N-linked glycosylation sites per monomer that are highly conserved among diverse variants, but how individual glycans affect virus entry and neutralization of Omicron variants has not been extensively characterized. Here we compared the effects of specific glycan deletions or modifications in the Omicron BA.1 and D614G spikes on spike expression, processing, and incorporation into pseudoviruses, as well as on virus infectivity and neutralization by therapeutic antibodies. We found that loss of potential glycans at spike residues N717 and N801 each conferred a loss of pseudovirus infectivity for Omicron but not for D614G or Delta variants. This decrease in infectivity correlated with decreased spike processing and incorporation into Omicron pseudoviruses. Oligomannose-enriched Omicron pseudoviruses generated in GnTI- cells or in the presence of kifunensine were non-infectious, whereas D614G or Delta pseudoviruses generated under similar conditions remained infectious. Similarly, growth of live (authentic) SARS-CoV-2 in the presence of kifunensine resulted in a greater reduction of titers for the BA.1.1 variant than Delta or D614G variants relative to their respective, untreated controls. Finally, we found that loss of some N-glycans, including N343 and N234, increased the maximum percent neutralization by the class 3 S309 monoclonal antibody against D614G but not BA.1 variants, while these glycan deletions altered the neutralization potency of the class 1 COV2-2196 and Etesevimab monoclonal antibodies without affecting maximum percent neutralization. The maximum neutralization by some antibodies also varied with the glycan composition, with oligomannose-enriched pseudoviruses conferring the highest percent neutralization. These results highlight differences in the interactions between glycans and residues among SARS-CoV-2 variants that can affect spike expression, virus infectivity, and susceptibility of variants to antibody neutralization.

Anthropogenic noise disrupts acoustic cues for recruitment.

Anthropogenic noise is rising and may interfere with natural acoustic cues used by organisms to recruit. Newly developed acoustic technology provides enriched settlement cues to boost recruitment of target organisms navigating to restoration sites, but can it boost recruitment in noise-polluted sites? To address this dilemma, we coupled replicated aquarium experiments with field experiments. Under controlled and replicated laboratory conditions, acoustic enrichment boosted recruitment by 2.57 times in the absence of anthropogenic noise, but yielded comparable recruitment in its presence (i.e. no boosting effect). Using the same technique, we then tested the replicability of these responses in real-world settings where independently replicated 'sites' are unfeasible owing to the inherent differences in soundscapes. Again, acoustic enrichment increased recruitment where anthropogenic noise was low (by 3.33 times), but had no effect at a site of noise pollution. Together, these coupled laboratory-to-field outcomes indicate that anthropogenic noise can mask the signal of acoustic enrichment. While noise pollution may reduce the effectiveness of acoustic enrichment, some of our reported observations suggest that anthropogenic noise per se might also provide an attractive cue for oyster larvae to recruit. These findings underscore the complexity of larval behavioural responses to acoustic stimuli during recruitment processes.

Investigating the association between educational attainment and allostatic load with risk of cancer mortality among African American women.

BACKGROUND: African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. Studies suggest that AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined the joint effect of educational attainment and AL status with long-term risk of cancer mortality, and whether education moderated the association between AL and cancer mortality. METHODS: We performed a retrospective analysis among 4,677 AA women within the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2010 with follow-up data through December 31, 2019. We fit weighted Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, income, and smoking status). RESULTS: AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24-7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, this effect attenuated (age-adjusted HR: 1.11; 95% CI: 0.45-2.74). AA women with high AL had 2.3-fold increased risk of cancer death (fully adjusted HR: 2.26; 95% CI: 1.10-4.57) when compared to AA with low AL, specifically among women with high school diploma or equivalent and without history of cancer. CONCLUSIONS: Our findings suggest that high allostatic load is associated with a higher risk of cancer mortality among AA women with lower educational attainment, while no such association was observed among AA women with higher educational attainment. Thus, educational attainment plays a modifying role in the relationship between allostatic load and the risk of cancer death for AA women. Higher education can bring several benefits, including improved access to medical care and enhanced medical literacy, which in turn may help mitigate the adverse impact of AL and the heightened risk of cancer mortality among AA women.

The effect of visual speech information on linguistic release from masking.

Listeners often experience challenges understanding a person (target) in the presence of competing talkers (maskers). This difficulty reduces with the availability of visual speech information (VSI; lip movements, degree of mouth opening) and during linguistic release from masking (LRM; masking decreases with dissimilar language maskers). We investigate whether and how LRM occurs with VSI. We presented English targets with either Dutch or English maskers in audio-only and audiovisual conditions to 62 American English participants. The signal-to-noise ratio (SNR) was easy at 0 audio-only and -8 dB audiovisual in Experiment 1 and hard at -8 and -16 dB in Experiment 2 to assess the effects of modality on LRM across the same and different SNRs. We found LRM in the audiovisual condition for all SNRs and in audio-only for -8 dB, demonstrating reliable LRM for audiovisual conditions. Results also revealed that LRM is modulated by modality with larger LRM in audio-only indicating that introducing VSI weakens LRM. Furthermore, participants showed higher performance for Dutch maskers compared to English maskers with and without VSI. This establishes that listeners use both VSI and dissimilar language maskers to overcome masking. Our study shows that LRM persists in the audiovisual modality and its strength depends on the modality.

Examining educational attainment and allostatic load in non-Hispanic Black women.

BACKGROUND: Research suggests that non-Hispanic Black (henceforth, Black) women and people with lower educational attainment have higher levels of allostatic load (AL). This study sought to determine the association between educational attainment and AL among a large sample of Black women. METHODS: We analyzed data among 4177 Black women from the National Health and Nutrition Examination Survey years 1999-2018. AL score was defined as the total for abnormal measures of eight biomarkers. We further categorized participants with AL score greater than or equal to 4 as having high AL. We calculated mean estimates of total allostatic load scores using generalized linear models. We performed modified Poisson Regression models with robust variance estimation to estimate prevalence ratios (PRs) of high allostatic load and their associated 95% confidence intervals (CIs) by educational attainment. RESULTS: Black women with a college degree or higher had the lowest prevalence of high allostatic load (31.8% vs. 42.7%, 36.3%, 36.6%), and age adjusted mean allostatic load scores (mean = 1.90 vs. mean = 2.34, mean = 1.99, mean = 2.05) when compared to Black women with less than a high school diploma, high school diploma or GED, and some college or associates degree respectively. Even after accounting for age, poverty-to-income ratio, smoking, congestive heart failure, and heart attack, Black college graduates had an 14.3% lower prevalence of high allostatic load (PR = 0.857, 95% CI 0.839-0.876) when compared to Black women with lower educational attainment. CONCLUSIONS: Black women with a baccalaureate degree or higher educational attainment had lower allostatic load compared to Black women with less than a high school education. This finding further confirms higher education is a social determinant of health. Future research should explore differences in AL by more granular degree types.

A mixed-methods study of the effectiveness and perceptions of a course design institute for health science educators.

BACKGROUND: Most health care professionals get their start in academics without formal teaching training. As such, institutions encourage participation in opportunities to address gaps in faculty's knowledge of pedagogy and learning theory in order to promote both successful student and patient outcomes. This study aimed to examine the reception of a faculty development program focused on teaching participants the basics of course design. METHODS: Applying a mixed-method approach, this retrospective study used pre/post-tests, assignment grades, self-assessment questionnaires, and focus groups to elucidate the impact of the faculty development intervention on course design. The participants (n = 12) were health educators from a private all-graduate level university with campus locations across the United States, including in the Southwest and Midwest. In the Course Design Institute (CDI), the participating faculty learned evidence-based instructional approaches and techniques to implement contemporary teaching practices. RESULTS: The data from the pre/post-tests and focus groups suggest that participants learned about topics including instructional alignment, learning goals and objectives, instructional strategies, assessment planning, feedback approaches, communicating expectations, and adult learning theories by participating in this course. The final deliverable scores indicate that the CDI graduates were able to apply a backward design process to plan their own instruction. Data from both the survey and the focus groups suggest that participants were satisfied with the experience and particularly appreciated that the course was relevant to them as educators in the health sciences. CONCLUSIONS: The results of this study indicate that the CDI was influential in developing the faculty's knowledge of the course design process, promoted the application of course design and pedagogy skills amongst CDI graduates, and positively impacted self-reported attitudes about their teaching abilities. In addition, feedback from participants indicates that they recognized the value of this program in their own development and they believed it should be a required course for all educators at the institution.

Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary ß (ß1-4) and α2δ (α2δ-1-4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, ß2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits ß2X13 and α2δ-4 but not in those with ß2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of ß2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

Repairing recruitment processes with sound technology to accelerate habitat restoration.

Humanity's ambitions to revive ecosystems at large scales require solutions to move restoration efforts beyond the small scale. There are increasing calls for technological solutions to reduce costs and facilitate large-scale restoration through the use of emerging technologies using an adaptive process of research and development. We show how technological enrichment of marine soundscapes may provide a solution that repairs the recruitment process to accelerate the recovery of lost marine habitats. This solution would solve the problems of current practice that largely relies upon natural recruitment processes, which carries considerable risk where recruitment is variable or eroded. By combining the literature with laboratory experiments, we describe evidence for "highways of sound" that convey navigable information for dispersing life stages in search for adult habitat. We show that these navigational cues tend to be silenced as their habitat is lost, creating negative feedbacks that hinders restoration. We suggest that reprovisioning soundscapes using underwater technology offers the potential to reverse this feedback and entice target organisms to recruit in greater densities. Collective evidence indicates that the application of soundscape theory and technology may unlock the recruitment potential needed to trigger the recruitment of target organisms and the natural soundscapes they create at large scales.

The effects of target-masker sex mismatch on linguistic release from masking.

Listeners often experience challenges understanding an interlocutor (target) in the presence of competing talkers (maskers). However, during linguistic release from masking (LRM), this difficulty decreases for native language targets (English) when paired with different language maskers (e.g., Dutch). There is considerable evidence that the linguistic similarity between target-masker pairs determines the size of LRM. This study investigated whether and how LRM is affected when the streams also differed in talker sex. Experiment 1 investigated intelligibility for English targets in sex-matched and mismatched conditions with Dutch or English maskers. While typical LRM effects were obtained when sex was matched, opposite effects were detected when sex was mismatched. In experiment 2, Mandarin maskers were used to increase linguistic dissimilarity and elicit stronger LRM effects. Despite the greater linguistic dissimilarity, the surprising reverse LRM effect in the sex-mismatch condition persisted. In experiment 3, the target stream was held constant and talker sex and language were manipulated in the masker. Here, expected LRM effects were obtained for both the sex-matched and sex-mismatched conditions. This indicated that the locus of the dissimilarities and not just relative properties affect LRM. Broadly, this study suggests that using naturally varying listening situations advances understanding of factors underlying LRM.

Gut immunoglobulin alpha anti-glycan binding profiles as a research tool for local disease detection.

A promising approach capitalizing on the specific and highly sensitive characteristics of the body's own immune system is demonstrated in the context of revealing pancreatic ductal adenocarcinoma cancer (PDAC). IgA from a local biofluid called gastrointestinal lavage fluid (GLF) is used to investigate glycan reactivity to show the potential of this approach. IgA antibody responses, just as with IgG, result in amplification of a small signal which aids in detecting changes from a healthy state. IgA from GLF was screened against glycan arrays containing 609 glycan structures to investigate differential binding patterns associated with the disease. Samples included PDAC (n = 14) and non-PDAC (n = 6). Non-PDAC conditions included samples from healthy patients and the potentially confounding conditions of colon cancer and its precancerous lesion, colon adenoma. Results demonstrated characteristic reactivity in the PDAC sample group to a glycan structure. Also, IgA non-reactive motifs arose showing remarkable consistency within and between sample groups. While sample sizes are too small to identify putative biomarkers, these data show the use of IgA from GLF to be a promising avenue of research for local disease biomarker discovery.

Quality of articles published in predatory nursing journals.

BACKGROUND: Predatory journals exist in nursing and lack the safeguards of traditional publishing practices. PURPOSE: To examine the quality of articles published in predatory nursing journals. METHOD: Randomly selected articles (n = 358) were reviewed for structural content and eight quality indicators. FINDINGS: Two-thirds (67.4%) of the articles were published between 2014 and 2016, demonstrating the acceleration of publications in predatory nursing journals. The majority (75.9%) of the articles were research reports. Most followed the IMRAD presentation of a research report but contained errors, or the study was not pertinent to the nursing discipline. CONCLUSIONS: Nursing research published in predatory journals may appear legitimate by conforming to an expected structure. However, a lack of quality is apparent, representing inadequate peer review and editorial processes. Poor quality research erodes the scholarly nursing literature.

Emergency Providers' Opioid Prescribing Behaviors Among Medicare Part D Beneficiaries in North Carolina, 2013-2014: Medication Utilization and Costs.

BACKGROUND This study sought to quantify utilization and costs associated with opioid prescribing by emergency providers for Medicare Part D beneficiaries in North Carolina and the United States from 2013 to 2014.METHODS This was a retrospective examination of the Medicare Provider Utilization and Payment Data: Part D Prescriber datasets from 2013-2014. The main variables of interest were total number of prescription claims and total Medicare Part D medication costs for opioid analgesic medications. Generalized estimating equations were used to analyze the data.RESULTS Excluding North Carolina, there were 2,030,108 (678.49 per 100,000) opioid claims in the United States in 2013, costing more than $28.3 million. In 2014, also excluding North Carolina, there were 2,061,992 (689.15 per 100,000) claims for opioids, costing almost $35.8 million. In North Carolina, there were 67,570 (708.62 per 100,000) opioid claims from emergency providers in 2013 and 72,881 (764.31 per 100,000) opioid claims in 2014 for Part D beneficiaries. Total Part D drug costs associated with opioids from North Carolina increased from $545,574 to $764,016, more than a 40% increase. In North Carolina, there was a statistically significant increase in costs (P < .001), but not a significant increase in numbers of claims (P = .051).LIMITATIONS This study did not examine patient-level data and could not examine diagnoses leading to opioid prescriptions, or opioid misuse or overdoses.CONCLUSION Almost 1 out of every 4 Part D prescriptions from emergency department providers in North Carolina was for an opioid medication. Given the recent focus on controlling opioid prescribing, future research should examine if the new opioid-prescribing guidelines reduced opioid prescription by these providers.

Characterization of C-terminal Splice Variants of Cav1.4 Ca2+ Channels in Human Retina.

Voltage-gated Ca(2+) channels (Cav) undergo extensive alternative splicing that greatly enhances their functional diversity in excitable cells. Here, we characterized novel splice variants of the cytoplasmic C-terminal domain of Cav1.4 Ca(2+) channels that regulate neurotransmitter release in photoreceptors in the retina. These variants lack a portion of exon 45 and/or the entire exon 47 (Cav1.4Δex p45, Cav1.4Δex 47, Cav1.4Δex p45,47) and are expressed in the retina of primates but not mice. Although the electrophysiological properties of Cav1.4Δex p45 are similar to those of full-length channels (Cav1.4FL), skipping of exon 47 dramatically alters Cav1.4 function. Deletion of exon 47 removes part of a C-terminal automodulatory domain (CTM) previously shown to suppress Ca(2+)-dependent inactivation (CDI) and to cause a positive shift in the voltage dependence of channel activation. Exon 47 is crucial for these effects of the CTM because variants lacking this exon show intense CDI and activate at more hyperpolarized voltages than Cav1.4FL The robust CDI of Cav1.4Δex 47 is suppressed by CaBP4, a regulator of Cav1.4 channels in photoreceptors. Although CaBP4 enhances activation of Cav1.4FL, Cav1.4Δex 47 shows similar voltage-dependent activation in the presence and absence of CaBP4. We conclude that exon 47 encodes structural determinants that regulate CDI and voltage-dependent activation of Cav1.4, and is necessary for modulation of channel activation by CaBP4.

Characterization of Cav1.4 complexes (α11.4, ß2, and α2δ4) in HEK293T cells and in the retina.

In photoreceptor synaptic terminals, voltage-gated Cav1.4 channels mediate Ca(2+) signals required for transmission of visual stimuli. Like other high voltage-activated Cav channels, Cav1.4 channels are composed of a main pore-forming Cav1.4 α1 subunit and auxiliary ß and α2δ subunits. Of the four distinct classes of ß and α2δ, ß2 and α2δ4 are thought to co-assemble with Cav1.4 α1 subunits in photoreceptors. However, an understanding of the functional properties of this combination of Cav subunits is lacking. Here, we provide evidence that Cav1.4 α1, ß2, and α2δ4 contribute to Cav1.4 channel complexes in the retina and describe their properties in electrophysiological recordings. In addition, we identified a variant of ß2, named here ß2X13, which, along with ß2a, is present in photoreceptor terminals. Cav1.4 α1, ß2, and α2δ4 were coimmunoprecipitated from lysates of transfected HEK293 cells and mouse retina and were found to interact in the outer plexiform layer of the retina containing the photoreceptor synaptic terminals, by proximity ligation assays. In whole-cell patch clamp recordings of transfected HEK293T cells, channels (Cav1.4 α1 + ß2X13) containing α2δ4 exhibited weaker voltage-dependent activation than those with α2δ1. Moreover, compared with channels (Cav1.4 α1 + α2δ4) with ß2a, ß2X13-containing channels exhibited greater voltage-dependent inactivation. The latter effect was specific to Cav1.4 because it was not seen for Cav1.2 channels. Our results provide the first detailed functional analysis of the Cav1.4 subunits that form native photoreceptor Cav1.4 channels and indicate potential heterogeneity in these channels conferred by ß2a and ß2X13 variants.

Spatially separating language masker from target results in spatial and linguistic masking release.

Several studies demonstrate that in complex auditory scenes, speech recognition is improved when the competing background and target speech differ linguistically. However, such studies typically utilize spatially co-located speech sources which may not fully capture typical listening conditions. Furthermore, co-located presentation may overestimate the observed benefit of linguistic dissimilarity. The current study examines the effect of spatial separation on linguistic release from masking. Results demonstrate that linguistic release from masking does extend to spatially separated sources. The overall magnitude of the observed effect, however, appears to be diminished relative to the co-located presentation conditions.

The rapid decline in interaural-time-difference sensitivity for pure tones can be explained by peripheral filtering.

Purpose: The interaural time difference (ITD) is a primary horizontal-plane sound localization cue computed in the auditory brainstem. ITDs are accessible in the temporal fine structure of pure tones with a frequency of no higher than about 1400 Hz. Explaining how listeners' ITD sensitivity transitions from very best sensitivity near 700 Hz to impossible to detect within 1 octave currently lacks a fully compelling physiological explanation. Here, it was hypothesized that the rapid decline in ITD sensitivity is dictated not by a central neural limitation but by initial peripheral sound encoding, specifically, the low-frequency (apical) edge of the cochlear excitation pattern produced by a pure tone. Methods: ITD sensitivity was measured in 16 normal-hearing listeners as a joint function of frequency (900-1500 Hz) and level (10-50 dB sensation level). Results: Performance decreased with increasing frequency and decreasing sound level. The slope of performance decline was 90 dB/octave, consistent with the low-frequency slope of the cochlear excitation pattern. Conclusion: Fine-structure ITD sensitivity near 1400 Hz may be conveyed primarily by "off-frequency" activation of neurons tuned to lower frequencies near 700 Hz. Physiologically, this could be realized by having neurons sensitive to fine-structure ITD up to only about 700 Hz. A more extreme model would have only a single narrow channel near 700 Hz that conveys fine-structure ITDs. Such a model is a major simplification and departure from the classic formulation of the binaural display, which consists of a matrix of neurons tuned to a wide range of relevant frequencies and ITDs.

Navigating Pre-exposure Prophylaxis Access: Qualitative Insights From Black Women at a Northeastern Historically Black College and University.

ABSTRACT: Black women are essential to ending the HIV epidemic in the United States; yet prevention, access, testing, and structural racism affect how HIV disproportionately affects them. Limited public health research focuses on Black women attending Historically Black Colleges and Universities (HBCUs) and the ability to address HIV prevention, such as pre-exposure prophylaxis (PrEP) uptake. PrEP is a once-daily oral pill used to prevent HIV transmission and has suboptimal uptake within the Black community. This generic qualitative descriptive analysis identifies the barriers and facilitators of PrEP uptake among Black women attending an HBCU using the health belief model. Overall, 22 Black college women participated in a 60-minute focus group. Emergent categories were as follows: (a) Barriers-stigma, cost, and side effects; (b) Facilitators-PrEP's effectiveness, exposure to HIV, and unprotected sex. Our findings can inform future efforts to increase PrEP uptake among Black women attending an HBCU.

The Rapid Decline in Interaural-Time-Difference Sensitivity for Pure Tones Can Be Explained by Peripheral Filtering.

PURPOSE: The interaural time difference (ITD) is a primary horizontal-plane sound localization cue computed in the auditory brainstem. ITDs are accessible in the temporal fine structure of pure tones with a frequency of no higher than about 1400 Hz. How listeners' ITD sensitivity transitions from very best sensitivity near 700 Hz to impossible to detect within 1 octave currently lacks a fully compelling physiological explanation. Here, it was hypothesized that the rapid decline in ITD sensitivity is dictated not by a central neural limitation but by initial peripheral sound encoding, specifically, the low-frequency (apical) portion of the cochlear excitation pattern produced by a pure tone. METHODS: ITD sensitivity was measured in 16 normal-hearing listeners as a joint function of frequency (900-1500 Hz) and level (10-50 dB sensation level). RESULTS: Performance decreased with increasing frequency and decreasing sound level. The slope of performance decline was 90 dB/octave, consistent with the low-frequency slope of the cochlear excitation pattern. CONCLUSION: Fine-structure ITD sensitivity near 1400 Hz may be conveyed primarily by "off-frequency" activation of neurons tuned to lower frequencies near 700 Hz. Physiologically, this could be realized by having neurons sensitive to fine-structure ITD up to only about 700 Hz. A more extreme model would have only a single narrow channel near 700 Hz that conveys fine-structure ITDs. Such a model is a major simplification and departure from the classic formulation of the binaural display, which consists of a matrix of neurons tuned to a wide range of relevant frequencies and ITDs.

Protective interplay: Mycobacterium tuberculosis diminishes SARS-CoV-2 severity through innate immune priming.

At the beginning of the COVID-19 pandemic those with underlying chronic lung conditions, including tuberculosis (TB), were hypothesized to be at higher risk of severe COVID-19 disease. However, there is inconclusive clinical and preclinical data to confirm the specific risk SARS-CoV-2 poses for the millions of individuals infected with Mycobacterium tuberculosis (M.tb). We and others have found that compared to singly infected mice, mice co-infected with M.tb and SARS-CoV-2 leads to reduced SARS-CoV-2 severity compared to mice infected with SARS-CoV-2 alone. Consequently, there is a large interest in identifying the molecular mechanisms responsible for the reduced SARS-CoV-2 infection severity observed in M.tb and SARS-CoV-2 co-infection. To address this, we conducted a comprehensive characterization of a co-infection model and performed mechanistic in vitro modeling to dynamically assess how the innate immune response induced by M.tb restricts viral replication. Our study has successfully identified several cytokines that induce the upregulation of anti-viral genes in lung epithelial cells, thereby providing protection prior to challenge with SARS-CoV-2. In conclusion, our study offers a comprehensive understanding of the key pathways induced by an existing bacterial infection that effectively restricts SARS-CoV-2 activity and identifies candidate therapeutic targets for SARS-CoV-2 infection.