Accelerating loss and degradation of tropical forests has led to a pressing need to understand the conservation value of remaining forests. Whereas most studies focus on the responses in community ...composition and taxonomic richness, more sensitive responses to habitat degradation are likely to be apparent through changes in the trophic complexity of generalist predators. Food web theory predicts that both trophic position and niche breadth of predators decrease with habitat degradation, with consequences for biotic interactions and ecosystem functioning.
Using a stable isotope approach, we analysed trophic positions and niche breaths of an important guild of top predators: insectivorous bats, in the tropical forests of Sabah, Borneo. We aimed to determine the responses in their trophic ecology across an experimental gradient of forest degradation at different spatial scales.
At the landscape scale, trophic niche breadth contracted substantially (78%) in association with a narrow reduction (26%) in forest cover. However, food chains were longer in ecosystems with lower tree canopies, representative of localised habitat simplification. Marked differences in trophic niche breath of and trophic position between echolocation guilds provided further evidence for inter‐guild niche partitioning within bat assemblages. Overall, the functionally important shifts in trophic pathways discriminated among habitats of varying degrees of degradation more reliably than conventional community descriptors, such as diversity metrics.
Synthesis and applications. This study reveals that habitat quality thresholds—below which we see substantial changes to trophic complexity—are higher than previously considered. Our analysis suggests that patches of forest with cover above 90% should be prioritised for conservation over more highly degraded ecosystems. As these effects were detected after approximately 30 years post‐logging, they likely reflect relatively long‐term responses to forest degradation.
This study reveals that habitat quality thresholds—below which we see substantial changes to trophic ecology—are higher than previously considered for community composition. Our analysis suggests that patches of forest with cover above 90% should be prioritised for conservation over more highly degraded ecosystems. As these effects were detected after approximately 30 years post‐logging, they likely reflect relatively long‐term responses to forest degradation.
Sudden changes in sound and light (e.g., sirens and flashing police beacons) are a common component of working dogs' on-duty environment. Yet, how such stimuli impact dogs' ability to perform ...physical and cognitive tasks has not been explored. To address this shortcoming, we compared the accuracy and time taken for twelve dogs to complete a complex physical and cognitive task, before, during and after exposure to three 'real-world' stimuli: an acoustic distractor (85dB), white strobe lighting (5, 10 & 15 Hz), and exposure to a dazzling white, red, or blue lights. We found that strobe lighting, and to a greater extent, acoustic distraction, significantly reduced dogs' physical performance. Acoustic distraction also tended to impair dogs' cognitive performance. Dazzling lights had no effect on task performance. Most (nine out of twelve) dogs sensitised to the acoustic distraction to the extent of non-participation in the rewarded task. Our results suggest that without effective distractor response training, sudden changes in noise and flickering lights are likely to impede cognitive and physical task performance in working dogs. Repeated uncontrolled exposure may also amplify these effects.
Targeting of general coactivators is an emerging strategy to interfere with oncogenic transcription factors (TFs). However, coactivator perturbations often lead to pleiotropic effects by influencing ...numerous TFs. Here we identify TAF12, a subunit of TFIID and SAGA coactivator complexes, as a selective requirement for acute myeloid leukemia (AML) progression. We trace this dependency to a direct interaction between the TAF12/TAF4 histone-fold heterodimer and the transactivation domain of MYB, a TF with established roles in leukemogenesis. Ectopic expression of the TAF4 histone-fold fragment can efficiently squelch TAF12 in cells, suppress MYB, and regress AML in mice. Our study reveals a strategy for potent MYB inhibition in AML and highlights how an oncogenic TF can be selectively neutralized by targeting a general coactivator complex.
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•AML is hypersensitive to the knockdown of TAF12, a subunit of TFIID and SAGA complexes•Normal tissues can persist in a TAF12-deficient state•A TAF12/TAF4 histone-fold heterodimer binds to the activation domain of MYB•Peptide-based squelching of TAF12/MYB leads to potent anti-leukemia effects
Xu et al. show that TAF12 is a coactivator of MYB and protects MYB from degradation. TAF12, in a heterodimer with TAF4, interacts with the transactivation domain of MYB. Perturbation of this interaction by squelching TAF12 impairs MYB activity and leads to regression of acute myeloid leukemia in mouse models.
Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). ...Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date. However, DPTIP exhibits poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To enhance its PK properties, we conjugated DPTIP to a hydroxyl-PAMAM dendrimer delivery system, creating dendrimer-DPTIP (D-DPTIP). In an acute brain injury model, orally administered D-DPTIP significantly reduced the intra-striatal IL-1β-induced increase in plasma EVs up to 72 h post-dose, while oral DPTIP had a limited effect. In a mouse tau propagation model, where a mutant hTau (P301L/S320F) containing adeno-associated virus was unilaterally seeded into the hippocampus, oral D-DPTIP (dosed 3× weekly) significantly inhibited brain nSMase2 activity and blocked the spread of pTau to the contralateral hippocampus. These data demonstrate that dendrimer conjugation of DPTIP improves its PK properties, resulting in significant inhibition of EV propagation of pTau in mice. Dendrimer-based delivery of DPTIP has the potential to be an exciting new therapeutic for AD.
Background
HIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of ...tuberculosis treatment start, at any CD4 count. We assessed whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis.
Methods
We did a systematic review by searching nine databases for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studies published from database inception to 12 March 2021. We compared ART within four weeks versus ART more than four weeks after TB treatment, and ART within two weeks versus ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS‐defining events. We pooled effect estimates using random effects meta‐analysis.
Results and discussion
We screened 2468 s, and identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤4 week) versus later ART (>4 week) (risk difference RD 0%, 95% confidence interval CI −2% to +1%). Among people with CD4 count ≤50 cells/mm3, earlier ART (≤4 weeks) reduced risk of death (RD −6%, −10% to −1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS‐defining events (RD −2%, 95% CI −4% to 0%). Results were similar when trials were restricted to the four trials which permitted comparison of ART within two weeks to ART between two and eight weeks. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase inhibitors in ART regimens.
Discussion
Earlier ART did not alter risk of death overall among people living with HIV who had TB disease. For logistical and patient preference reasons, earlier ART initiation for everyone with TB and HIV may be preferred to later ART.
The transcription factor FOXP3 is essential for the formation and function of regulatory T cells (Tregs), and Tregs are essential for maintaining immune homeostasis and tolerance. This is ...demonstrated by a lethal autoimmune defect in mice lacking Foxp3 and in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome patients. However, little is known about the molecular basis of human FOXP3 function or the relationship between direct and indirect targets of FOXP3 in human Tregs. To investigate this, we have performed a comprehensive genome-wide analysis for human FOXP3 target genes from cord blood Tregs using chromatin immunoprecipitation array profiling and expression profiling. We have identified 5579 human FOXP3 target genes and derived a core Treg gene signature conserved across species using mouse chromatin immunoprecipitation data sets. A total of 739 of the 5579 FOXP3 target genes were differentially regulated in Tregs compared with Th cells, thus allowing the identification of a number of pathways and biological functions overrepresented in Tregs. We have identified gene families including cell surface molecules and microRNAs that are differentially expressed in FOXP3(+) Tregs. In particular, we have identified a novel role for peptidase inhibitor 16, which is expressed on the cell surface of >80% of resting human CD25(+)FOXP3(+) Tregs, suggesting that in conjunction with CD25 peptidase inhibitor 16 may be a surrogate surface marker for Tregs with potential clinical application.
Introduction
The number of people over the age of 65 attending Emergency Departments (ED) in the United Kingdom (UK) is increasing. Those who attend with a mental health related problem may be ...referred to liaison psychiatry for assessment. Improving responsiveness and integration of liaison psychiatry in general hospital settings is a national priority. To do this psychiatry teams must be adequately resourced and organised. However, it is unknown how trends in the number and type referrals of older people to liaison psychiatry teams by EDs are changing, making this difficult.
Methods
We performed a national multi‐centre retrospective service evaluation, analysing existing psychiatry referral data from EDs of people over 65. We described trends in the number, rate, age, mental health presentation, and time taken to assessment over a 7 years period.
Results
Referral data from 28 EDs across England and Scotland were analysed (n = 18,828 referrals). There was a general trend towards increasing numbers of people referred to liaison psychiatry year on year. Variability in referral numbers between different departments, ranged from 0.1 to 24.3 per 1000 ED attendances. The most common reasons for referral were mood disorders, self‐harm and suicidal ideas. The majority of referrals were assessed within 60 min, however there is variability between departments, some recording waits over 11 h.
Discussion
The data suggests great inter‐departmental variability in referral numbers. Is not possible to establish the cause of variability. However, the data highlights the importance of asking further questions about why the differences exist, and the impact that has on patient care.
Key points
There is a general trend towards increasing numbers of people over the age of 65 referred to liaison psychiatry from Emergency Departments (EDs)
There is variability in the number of people over the age of 65 referred from UK EDs from hospital to hospital
The most common reasons for the referral of people over the age of 65 to liaison psychiatry by the emergency department are mood disorders, self‐harm and suicidal ideas
Distractions that lead to performance deficits in working dogs can be life-threatening to the dog, its handler, and others. To reduce the impact of extraneous stimuli, distractors that are likely to ...occur in the working environment can be incorporated into dogs’ training. Yet, the impact that distraction training has on learning efficacy remains unclear. Here, we investigated how training with an acoustic distractor impacts dogs’ capacity to learn and later perform a task in the presence of novel distractors. We found that dogs trained with an auditory distractor learned the task less efficiently than dogs trained in silence. Further, dogs trained with a distractor did not perform the learned task more efficiently when tested in the presence of novel acoustic or visual distractors. Dogs trained with an auditory distractor did habituate faster to a novel acoustic distractor during testing compared to dogs trained in silence, but this trend was not significant. Our findings suggest that the initial stages of learning should be conducted in a non-distracting environment to avoid negative impacts on learning.
•Dogs trained in distracting environments learn tasks less efficiently than dogs trained in silence.•Dogs do not tend to generalize their ability to ignore learned distractors to novel distractors.•During the initial stages of learning, training should be conducted in a non-distracting environment.
A flow cytometric (FCM) assay has been developed for the determination of cell-mediated cytotoxicity (CMC). In the assay, the target tumour cell population was labelled with a membrane dye, PKH-26, ...prior to incubation with splenocyte effector cells. Cell death within the target population was assessed by the addition of the viability probe TO-PRO-3 iodide (TP3) and analysed by flow cytometry. The extent of cytotoxicity was determined by the relative number of live target cells labelled with PKH-26 only and dead, permeabilised cells labelled with both PKH-26 and TP3. This CMC method allows the analysis to be conducted on a single cell basis and overcomes the need for radiochemicals. This communication indicates that the FCM assay is an accurate and reproducible experimental system capable of analysing natural killer (NK) cell and antibody-dependent cell-mediated cytotoxicity. The procedure is comparable to the chromium release assay. We believe that this is one of the first demonstrations of an FCM-based antibody-dependent cell-mediated cytotoxicity (ADCC) assay.
Purpose Valid, reliable, and efficient patient-reported outcome measures are needed to quantify quality of life (QOL) outcomes after cochlear implantation to supplement information obtained from ...performance-based outcomes. We previously developed the Cochlear Implant Quality of Life (CIQOL) item bank to serve as the source of items for subsequent instruments. This study reports the development and psychometric properties for 2 of these new instruments, the CIQOL-35 Profile and the CIQOL-10 Global. Method Cochlear implant (CI) users referred from the CIQOL Development Consortium (
= 371), consisting of 20 CI centers across the United States, provided responses to the 81-item CIQOL item bank, which are grouped into 6 QOL domains (communication, emotional, entertainment, environment, listening effort, and social). Responses to the 81 CIQOL items were analyzed using item response theory to determine individual item difficulty, discrimination, and model fit to select the set of items for the profile instrument and global measure that would optimize their measurement characteristics. Results The 35-item CIQOL-35 Profile instrument assesses outcomes represented in the 6 domains of the CIQOL final item pool. The 10-item CIQOL-10 Global measure produces a single, overall QOL score. After ensuring the upper and lower ends of the item difficulty continuum were represented (item difficulty range: -2.48 to 2.47), the items with the highest discrimination ability for each domain were selected for the CIQOL-35 Profile instrument (discrimination range: 0.67-1.37). Items were selected for the CIQOL-10 Global measure in a similar manner. Conclusion The CIQOL-35 Profile and CIQOL-10 Global instruments provide psychometrically sound and efficient measures that can be used to assess QOL in adult CI users in both clinical and research settings. Supplemental Material https://doi.org/10.23641/asha.9745010.
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