The ß-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/ß-Catenin/Notch Signaling Axis.

BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on ß-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher ß-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression.

Attention, Musicality, and Familiarity Shape Cortical Speech Tracking at the Musical Cocktail Party.

The "cocktail party problem" challenges our ability to understand speech in noisy environments, which often include background music. Here, we explored the role of background music in speech-in-noise listening. Participants listened to an audiobook in familiar and unfamiliar music while tracking keywords in either speech or song lyrics. We used EEG to measure neural tracking of the audiobook. When speech was masked by music, the modeled peak latency at 50 ms (P1TRF) was prolonged compared to unmasked. Additionally, P1TRF amplitude was larger in unfamiliar background music, suggesting improved speech tracking. We observed prolonged latencies at 100 ms (N1TRF) when speech was not the attended stimulus, though only in less musical listeners. Our results suggest early neural representations of speech are enhanced with both attention and concurrent unfamiliar music, indicating familiar music is more distracting. One's ability to perceptually filter "musical noise" at the cocktail party depends on objective musical abilities.

Sex differences in infant vocalization and the origin of language.

Seeking to discern the earliest sex differences in language-related activities, our focus is vocal activity in the first two years of life, following up on recent research that unexpectedly showed boys produced significantly more speech-like vocalizations (protophones) than girls during the first year of life.We now bring a much larger body of data to bear on the comparison of early sex differences in vocalization, data based on automated analysis of all-day recordings of infants in their homes. The new evidence, like that of the prior study, also suggests boys produce more protophones than girls in the first year and offers additional basis for informed speculation about biological reasons for these differences. More broadly, the work offers a basis for informed speculations about foundations of language that we propose to have evolved in our distant hominin ancestors, foundations also required in early vocal development of modern human infants.

A case series describing the multidisciplinary management of pulmonary arterial hypertension in pregnancy: Time for optimism.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a high-risk condition during pregnancy, with recent literature describing mortality rates of up to 23%. AIM: To describe the course and outcomes of pregnancy for women with PAH in a major Australian metropolitan referral centre over a 15-year period. METHODS: Retrospective review of medical records of all pregnant women with PAH over the period 2005-2020. RESULTS: We report the outcomes of nine pregnancies in six women. In five women, seven pregnancies proceeded to term with birth of a healthy neonate, five vaginal births and two caesareans. Two women opted for a termination of pregnancy in the first trimester following counselling. The planning of care and patient-centred decision-making was individually tailored by a multidisciplinary team. The pulmonary hypertension clinic provided specialist support including the management of pulmonary vasodilators. All women who delivered a live offspring received neuraxial anaesthesia. CONCLUSIONS: Women with this condition are ideally managed in a centre with expertise in PAH; counselling regarding the risks is imperative. Regional anaesthesia, irrespective of the mode of delivery, facilitated safe delivery and improved patient experience. The option of aiming for a term vaginal birth needs to be considered in these complex women.

Song Properties and Familiarity Affect Speech Recognition in Musical Noise.

"Cocktail party" speech perception is largely studied using either linguistic or nonspeech noise maskers. Few studies have addressed how listeners understand speech during concurrent music. We used popular songs to probe the effects of familiarity and different inherent properties of background music (i.e., isolated vocals, isolated instruments, or unprocessed song) on speech recognition. Participants performed an open-set sentence recognition task in the presence of familiar and unfamiliar music maskers (-5 dB signal-to-noise ratio [SNR]) composed of the full unprocessed song, only the instrumentals, or only the vocals. We found that full songs negatively affected recognition performance more so than isolated vocals and instrumentals. Surprisingly, there was also an interaction with music familiarity; well-known music impaired performance in the homologous full song and instrumental conditions. Our results show strong effects of song component and familiarity on speech recognition ability, highlighting interactions between both physical and psychological characteristics of musical noise on task performance. Familiarity impairs speech perception when background music features the instrumentals with or without the vocals. Our findings have implications for understanding the possible facilitation (or interference) of background music during concurrent linguistic tasks including academic study in attempts to promote learning.

Familiarity of Background Music Modulates the Cortical Tracking of Target Speech at the "Cocktail Party".

The "cocktail party" problem-how a listener perceives speech in noisy environments-is typically studied using speech (multi-talker babble) or noise maskers. However, realistic cocktail party scenarios often include background music (e.g., coffee shops, concerts). Studies investigating music's effects on concurrent speech perception have predominantly used highly controlled synthetic music or shaped noise, which do not reflect naturalistic listening environments. Behaviorally, familiar background music and songs with vocals/lyrics inhibit concurrent speech recognition. Here, we investigated the neural bases of these effects. While recording multichannel EEG, participants listened to an audiobook while popular songs (or silence) played in the background at a 0 dB signal-to-noise ratio. Songs were either familiar or unfamiliar to listeners and featured either vocals or isolated instrumentals from the original audio recordings. Comprehension questions probed task engagement. We used temporal response functions (TRFs) to isolate cortical tracking to the target speech envelope and analyzed neural responses around 100 ms (i.e., auditory N1 wave). We found that speech comprehension was, expectedly, impaired during background music compared to silence. Target speech tracking was further hindered by the presence of vocals. When masked by familiar music, response latencies to speech were less susceptible to informational masking, suggesting concurrent neural tracking of speech was easier during music known to the listener. These differential effects of music familiarity were further exacerbated in listeners with less musical ability. Our neuroimaging results and their dependence on listening skills are consistent with early attentional-gain mechanisms where familiar music is easier to tune out (listeners already know the song's expectancies) and thus can allocate fewer attentional resources to the background music to better monitor concurrent speech material.

Are UK pharmacists ready for consultant-level practice? A cross-sectional survey of self-assessed development needs.

OBJECTIVES: The four nations of the United Kingdom (UK) have endorsed a new curriculum and credentialing process for consultant pharmacists. This study aimed to measure the self-reported consultant-level practice development needs of pharmacists across the UK. METHODS: The study was a cross-sectional electronic survey. Inclusion criteria were: pharmacists registered to practice with the General Pharmaceutical Council; working in any professional sector across the UK; and self-identifying as already working at an advanced level of practice or in an advanced pharmacist role. Participants were asked to rate their confidence that their current practice aligns to the level described in the Royal Pharmaceutical Society Consultant Pharmacist curriculum on a 5-point Likert scale. Predictors of overall confidence with the whole curriculum were analysed using binomial regression. KEY FINDINGS: Nine hundred and forty-four pharmacists participated. Median age was 42 years; 72.6% were female. Research skills and strategic leadership skills had low self-reported confidence. Patient-Centred Care and Collaboration was the domain with the highest reported confidence. 10.2% (96/944) of participants self-reported confidence across the whole curriculum. The strongest predictors of overall confidence across the curriculum were advanced clinical practitioner qualification, research qualifications and self-identifying as a specialist. Increasing age and male gender also predicted confidence. White ethnicity and having an independent prescribing qualification negatively predicted confidence. CONCLUSION: A small minority of pharmacists self-reported confidence across the whole curriculum. A planned approach to develop research skills across the career spectrum, coupled with better identification of workplace-based experiential strategic leadership opportunities, may help deliver a larger cohort of 'consultant-ready' pharmacists.

PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer's Disease: A Data Mining and Bioinformatics Study.

The ß-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer's disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aß) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aß concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD.

Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

[Figure: see text].

The current and potential role of community pharmacy in asset-based approaches to health and wellbeing: a qualitative study.

Background Asset-based approaches seek to positively mobilise the strengths, capabilities, and resources of individuals and communities. To date, limited consideration has been given to the potential value of this approach in relation to community pharmacy practice, yet this is important and timely given community pharmacy's expanding role and contribution to public health initiatives. Objectives This qualitative study aimed to explore the current and potential role of community pharmacy in asset-based approaches. Methods Fifteen semi-structured telephone interviews were undertaken with community pharmacists and project leads, and public health policy and strategic leads in the UK. Transcripts were analysed using simultaneous inductive open and deductive coding using an applied Theory of Change as an illustrative lens. Results The shift towards patient-facing roles in community pharmacy was felt to offer expanded relational opportunities to engage and collaborate with individuals, communities, and other stakeholders. However, only a small number of respondents described examples of systemic asset-based working within the pharmacy sector. The adoption of asset-based approaches was challenged or enabled by several factors including the availability of protected time/resources, workplace and organisational culture/values, strategic leadership, commissioning, and funding arrangements. Conclusions The study provides valuable insights into the potential for community pharmacy, a previously unconsidered sector, to further adopt and contribute to asset-based approaches and play a more central role in the improvement of public health and reduction of health inequalities.

Discrimination of natural acoustic variation in vocal signals.

Studies of acoustic communication often focus on the categories and units of vocalizations, but subtle variation also occurs in how these signals are uttered. In human speech, it is not only phonemes and words that carry information but also the timbre, intonation, and stress of how speech sounds are delivered (often referred to as "paralinguistic content"). In non-human animals, variation across utterances of vocal signals also carries behaviorally relevant information across taxa. However, the discriminability of these cues has been rarely tested in a psychophysical paradigm. Here, we focus on acoustic communication in the zebra finch (Taeniopygia guttata), a songbird species in which the male produces a single stereotyped motif repeatedly in song bouts. These motif renditions, like the song repetitions of many birds, sound very similar to the casual human listener. In this study, we show that zebra finches can easily discriminate between the renditions, even at the level of single song syllables, much as humans can discriminate renditions of speech sounds. These results support the notion that sensitivity to fine acoustic details may be a primary channel of information in zebra finch song, as well as a shared, foundational property of vocal communication systems across species.

Auditory cortex supports verbal working memory capacity.

Working memory (WM) is a fundamental construct of human cognition. The neural basis of auditory WM is thought to reflect a distributed brain network consisting of canonical memory and central executive brain regions including frontal lobe and hippocampus. Yet, the role of auditory (sensory) cortex in supporting active memory representations remains controversial. Here, we recorded neuroelectric activity via electroencephalogram as listeners actively performed an auditory version of the Sternberg memory task. Memory load was taxed by parametrically manipulating the number of auditory tokens (letter sounds) held in memory. Source analysis of scalp potentials showed that sustained neural activity maintained in auditory cortex (AC) prior to memory retrieval closely scaled with behavioral performance. Brain-behavior correlations revealed that lateralized modulations in left (but not right) AC were predictive of individual differences in auditory WM capacity. Our findings confirm a prominent role of AC, traditionally viewed as a sensory-perceptual processor, in actively maintaining memory traces and dictating individual differences in behavioral WM limits.

Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction.

Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased ß-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and ß-amyloid (Aß) are linked with vascular disease development and increased BACE1 and Aß accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Aß, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular Aß42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and Aß42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or Aß42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma Aß42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher Aß42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and Aß42. Lowering Aß42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [18 F]GE-179 for the clinical study of activated NMDA receptors.

N-(2-chloro-5-(S-2-[18 F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([18 F]GE-179), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [18 F]GE-179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8. The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 µg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18 F]GE-179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.

Mainstreaming gender into global health programming to improve women's health.

In this paper, a case is made for mainstreaming gender into global women's health programming and policies. The potential implications of conflating "gender" with "women'" in the design and evaluation of women's health programming are first considered. HIV/AIDS case studies are then used to depict examples of (a) where gender has been well integrated and (b) where policies fall short of gender mainstreaming. Finally, practical approaches to mainstream gender in a meaningful way into the design and evaluation of women's health programming and policies are provided for practitioners and researchers.

Strain differences in hearing in song canaries.

Belgian Waterslager song canaries, bred for hundreds of years for a low-pitched song, have also acquired an inherited high-frequency hearing loss associated with hair cell abnormalities. Here, auditory thresholds measured using auditory brainstem responses and psychophysical methods in three different strains of canaries are compared: Belgian Waterslagers, American Singers, and Borders. Border canaries have not been bred for song characteristics while American Singer canaries have been bred for song only since the 1930s. Results show that American Singer canaries also have elevated high frequency thresholds that are similar to those of the Belgian Waterslager, while Border canaries have normal thresholds. These results strengthen the case that song canary breeders in selecting for song characteristics may have inadvertently selected for hearing abnormalities.

Concordance of Child and Parent Reports of Children's Screen Media Use.

OBJECTIVE: Little is known about the concordance of parent and child reports of children's media consumption, even though parents are often asked to report for their children in clinical care settings. Our objective was to understand how parent and child reports of children's media consumption differ in an era of changing screen media consumption via personal devices. METHODS: As part of a larger study about the reception of health-related cues from children's media, children ages 9 to 11 years (N = 114) and their parents independently completed identical questionnaires about specific media use and health behaviors. To examine concordance between child and parent reports of children's screen media use, we calculated the mean number of minutes per day and proportions reported by the child and parent and assessed concordance with t-tests and chi-square tests. RESULTS: On a typical day, children reported nearly an hour each of video and app game use, computer use, and television exposure. Overall, child and parent reports were similar, usually within 10 minutes of each other; however, among 3 measures of TV use, parents consistently reported less TV exposure than children. There was significant discordance in the percentages of parents and children reporting the presence of a TV in the child's room. CONCLUSIONS: Parent and child reports of children's media use were generally concordant; however, there were important disagreements, such as TV use in the child's room and during meals. We discuss possible causes of discrepancies and implications.

Discovery and lead optimisation of a potent, selective and orally bioavailable RARß agonist for the potential treatment of nerve injury.

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.