Automatic Assessment of Intelligibility in Noise in Parkinson Disease: Validation Study.

BACKGROUND: Most individuals with Parkinson disease (PD) experience a degradation in their speech intelligibility. Research on the use of automatic speech recognition (ASR) to assess intelligibility is still sparse, especially when trying to replicate communication challenges in real-life conditions (ie, noisy backgrounds). Developing technologies to automatically measure intelligibility in noise can ultimately assist patients in self-managing their voice changes due to the disease. OBJECTIVE: The goal of this study was to pilot-test and validate the use of a customized web-based app to assess speech intelligibility in noise in individuals with dysarthria associated with PD. METHODS: In total, 20 individuals with dysarthria associated with PD and 20 healthy controls (HCs) recorded a set of sentences using their phones. The Google Cloud ASR API was used to automatically transcribe the speakers' sentences. An algorithm was created to embed speakers' sentences in +6-dB signal-to-noise multitalker babble. Results from ASR performance were compared to those from 30 listeners who orthographically transcribed the same set of sentences. Data were reduced into a single event, defined as a success if the artificial intelligence (AI) system transcribed a random speaker or sentence as well or better than the average of 3 randomly chosen human listeners. These data were further analyzed by logistic regression to assess whether AI success differed by speaker group (HCs or speakers with dysarthria) or was affected by sentence length. A discriminant analysis was conducted on the human listener data and AI transcriber data independently to compare the ability of each data set to discriminate between HCs and speakers with dysarthria. RESULTS: The data analysis indicated a 0.8 probability (95% CI 0.65-0.91) that AI performance would be as good or better than the average human listener. AI transcriber success probability was not found to be dependent on speaker group. AI transcriber success was found to decrease with sentence length, losing an estimated 0.03 probability of transcribing as well as the average human listener for each word increase in sentence length. The AI transcriber data were found to offer the same discrimination of speakers into categories (HCs and speakers with dysarthria) as the human listener data. CONCLUSIONS: ASR has the potential to assess intelligibility in noise in speakers with dysarthria associated with PD. Our results hold promise for the use of AI with this clinical population, although a full range of speech severity needs to be evaluated in future work, as well as the effect of different speaking tasks on ASR.

Photocatalytic methods for amino acid modification.

Amino acid modification plays an important role across several fields, including synthetic organic chemistry, materials science, targeted drug delivery and the probing of biological function. Although a myriad of methods now exist for the modification of peptides or proteins, many of these target a handful of the most reactive proteinogenic amino acids. Photocatalysis has recently emerged as a mild approach for amino acid modification, generating a sizable toolbox of reactions capable of modifying almost all of the canonical amino acids. These reactions are characterised by their mild, physiologically compatible conditions, greatly enhancing their usefulness for amino acid modification. This review aims to introduce the field of photocatalytic amino acid modification and discusses the most recent advances.

Site-selective modification strategies in antibody-drug conjugates.

Antibody-drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.

OXTR rs53576 Variation with Breast and Nipple Pain in Breastfeeding Women.

BACKGROUND: Thirty percent of women who seek professional breastfeeding support require assistance with ongoing breast and nipple pain and < 50% of women report resolution of their pain. It is unknown if there is a molecular risk for ongoing breast and nipple pain during breastfeeding. Aim -To evaluate associations among breast and nipple pain sensitivity and candidate pain sensitivity single-nucleotide polymorphisms [SNPs], (COMT rs6269, rs4633, rs4818, rs4680 and OXTR rs2254298, rs53576) in breastfeeding women. Design - A secondary analysis of a pilot randomized controlled trial of a pain self-management intervention conducted over 6 weeks postpartum. Setting and Participants - Sixty women were recruited from two hospital settings after birth. Methods - All participants underwent standardized mechanical somatosensory testing for an assessment of pain sensitivity and provided baseline buccal swabs for genetic analysis. At 1, 2, and 6 weeks postpartum, women self-reported breast and nipple pain severity using a visual analogue scale. Results - Women with the minor allele OXTR rs53576 reported 8.18-fold higher breast and nipple pain severity over time. For every 1-unit increase in Mechanical detection threshold and windup ratio, women reported 16.51-fold and 4.82-fold higher breast and nipple pain severity respectively. Six women with the OXTR rs2254298 minor allele reported allodynia. Conclusion - The presence of OXTR alleles in women with enhanced pain sensitivity suggests a phenotype of genetic risk for ongoing breast and nipple with potential for pain-associated breastfeeding cessation. Somatosensory testing identified women who reported higher breast and nipple pain during the first weeks of breastfeeding.

Efficient and selective antibody modification with functionalised divinyltriazines.

A highly efficient disulfide rebridging strategy for the modification of monoclonal antibodies with substituted divinyltriazine linkers is reported. The reaction proceeds efficiently under mild conditions with near stoichiometric quantities of linker. This method of conjugation yields serum stable antibody conjugates with a controlled payload loading of 4.

General dual functionalisation of biomacromolecules via a cysteine bridging strategy.

Site-selective modification of peptides and proteins has resulted in the development of a host of novel tools for the study of cellular systems or the synthesis of enhanced biotherapeutics. There is a need for useful methodologies that enable site-selective modification of native peptides or proteins, which is even more prevalent when modification of the biomolecule with multiple payloads is desired. Herein, we report the development of a novel dual functional divinylpyrimidine (dfDVP) platform that enables robust and modular modification of peptides, antibody fragments and antibodies. These biomacromolecules could be easily functionalised with a range of functional payloads (e.g. fluorescent dyes, cytotoxic warheads or cell-penetrating tags). Importantly, the dual functionalised peptides and antibodies demonstrated exquisite bioactivity in a range of in vitro cellular assays, showcasing the enhanced utility of these bioactive conjugates.

Expeditious Total Synthesis of Hemiasterlin through a Convergent Multicomponent Strategy and Its Use in Targeted Cancer Therapeutics.

Hemiasterlin is an antimitotic marine natural product with reported sub-nanomolar potency against several cancer cell lines. Herein, we describe an expeditious total synthesis of hemiasterlin featuring a four-component Ugi reaction (Ugi-4CR) as the key step. The convergent synthetic strategy enabled rapid access to taltobulin (HTI-286), a similarly potent synthetic analogue. This short synthetic sequence enabled investigation of both hemiasterlin and taltobulin as cytotoxic payloads in antibody-drug conjugates (ADCs). These novel ADCs displayed sub-nanomolar cytotoxicity against HER2-expressing cancer cells, while showing no activity against antigen-negative cells. This study demonstrates an improved synthetic route to a highly valuable natural product, facilitating further investigation of hemiasterlin and its analogues as potential payloads in targeted therapeutics.

Efficacy of a Breastfeeding Pain Self-Management Intervention: A Pilot Randomized Controlled Trial.

BACKGROUND: Over 90% of women experience pain during breastfeeding initiation and lack strategies to self-manage breast and nipple pain. Guided by the Individual and Family Self-Management Theory, a breastfeeding self-management (BSM) intervention targeted women's knowledge, beliefs, and social facilitation to manage their breast and nipple pain and achieve their breastfeeding goals. OBJECTIVES: The purpose of this longitudinal pilot randomized control trial (RCT) was to test the preliminary efficacy of the BSM intervention on general and specific pain related to breastfeeding. METHODS: Sixty women intending to breastfeed were approached within 48 hours of delivery to participate in this pilot RCT (30 randomized to the BSM intervention and 30 randomized to the control group). All participants provided baseline data before discharge and pain and breastfeeding measures at 1, 2, and 6 weeks. Participants in the BSM intervention group received educational modules addressing breast and nipple pain and biweekly, text-based nurse coaching and completed a daily breastfeeding journal. RESULTS: Women in the BSM intervention group reported significantly less breast and nipple pain at 1 and 2 weeks using a visual analog scale (p < .014 and p < .006) and at 2 weeks using the Brief Pain Inventory intensity scale (p < .029), but no difference in breastfeeding duration. DISCUSSION: The BSM intervention pilot demonstrates a positive effect on breastfeeding specific and overall generalized pain. Future investigation is needed to identify at-risk women of ongoing breastfeeding pain and develop precision interventions to sustain this beneficial health behavior for mothers and infants.

Interactions of social, terrestrial, and marine sub-systems in the Galapagos Islands, Ecuador.

Galapagos is often cited as an example of the conflicts that are emerging between resource conservation and economic development in island ecosystems, as the pressures associated with tourism threaten nature, including the iconic and emblematic species, unique terrestrial landscapes, and special marine environments. In this paper, two projects are described that rely upon dynamic systems models and agent-based models to examine human-environment interactions. We use a theoretical context rooted in complexity theory to guide the development of our models that are linked to social-ecological dynamics. The goal of this paper is to describe key elements, relationships, and processes to inform and enhance our understanding of human-environment interactions in the Galapagos Islands of Ecuador. By formalizing our knowledge of how systems operate and the manner in which key elements are linked in coupled human-natural systems, we specify rules, relationships, and rates of exchange between social and ecological features derived through statistical functions and/or functions specified in theory or practice. The processes described in our models also have practical applications in that they emphasize how political policies generate different human responses and model outcomes, many detrimental to the social-ecological sustainability of the Galapagos Islands.

Climate Shocks and Migration: An Agent-Based Modeling Approach.

This is a study of migration responses to climate shocks. We construct an agent-based model that incorporates dynamic linkages between demographic behaviors, such as migration, marriage, and births, and agriculture and land use, which depend on rainfall patterns. The rules and parameterization of our model are empirically derived from qualitative and quantitative analyses of a well-studied demographic field site, Nang Rong district, Northeast Thailand. With this model, we simulate patterns of migration under four weather regimes in a rice economy: 1) a reference, 'normal' scenario; 2) seven years of unusually wet weather; 3) seven years of unusually dry weather; and 4) seven years of extremely variable weather. Results show relatively small impacts on migration. Experiments with the model show that existing high migration rates and strong selection factors, which are unaffected by climate change, are likely responsible for the weak migration response.

Changing crops in response to climate: virtual Nang Rong, Thailand in an agent based simulation.

The effects of extended climatic variability on agricultural land use were explored for the type of system found in villages of northeastern Thailand. An agent based model developed for the Nang Rong district was used to simulate land allotted to jasmine rice, heavy rice, cassava, and sugar cane. The land use choices in the model depended on likely economic outcomes, but included elements of bounded rationality in dependence on household demography. The socioeconomic dynamics are endogenous in the system, and climate changes were added as exogenous drivers. Villages changed their agricultural effort in many different ways. Most villages reduced the amount of land under cultivation, primarily with reduction in jasmine rice, but others did not. The variation in responses to climate change indicates potential sensitivity to initial conditions and path dependence for this type of system. The differences between our virtual villages and the real villages of the region indicate effects of bounded rationality and limits on model applications.

Ketamine produces no detectable long-term positive or negative effects on cognitive flexibility or reinforcement learning of male rats.

RATIONALE: Patients with major depressive disorder (MDD) often experience abnormalities in behavioral adaptation following environmental changes (i.e., cognitive flexibility) and tend to undervalue positive outcomes but overvalue negative outcomes. The probabilistic reversal learning task (PRL) is used to study these deficits across species and to explore drugs that may have therapeutic value. Selective serotonin-reuptake inhibitors (SSRIs) have limited effectiveness in treating MDD and produce inconsistent effects in non-human versions of the PRL. As such, ketamine, a novel and potentially rapid-acting therapeutic, has begun to be examined using the PRL. Two previous studies examining the effects of ketamine in the PRL have shown conflicting results and only examined short-term effects of ketamine. OBJECTIVE: This experiment examined PRL performance across a 2-week period following a single exposure to a ketamine dose that varied across groups. METHODS: After five sessions of PRL training, groups of rats received an injection of either 0, 10, 20 or 30 mg/kg ketamine. One-hour post-injection, rats engaged in the PRL, and subsequently sessions continued daily for 2 weeks. Traditional behavioral and computational reinforcement learning-derived measures were examined. RESULTS: Results showed that ketamine had acute effects 1-h post-injection, including a significant decrease in the value of the punishment learning rate. Beyond 1 h, ketamine produced no detectable improvements nor decrements in performance across 2 weeks. CONCLUSION: Overall, the present results suggest that the range of ketamine doses examined do not have long-term positive or negative effects on cognitive flexibility or reward processing in healthy rats as measured by the PRL.

Perceptual consequences of online group speech treatment for individuals with Parkinson's disease: A pilot study case series.

PURPOSE: We examined perceptual changes in the domains of ease of understanding, naturalness, and speech severity, as well as changes in self-perceptions of voice disability, following an online group speech treatment program for people with Parkinson's disease (PD) conducted during the COVID-19 pandemic. METHOD: Seven speakers with hypokinetic dysarthria associated with PD participated in a university and community-based online group speech program for 10 weeks. Speech recordings occurred remotely 1 week before and 1 week after the online program. Thirty naïve listeners rated ease of understanding, naturalness, and speech severity based on the speech recordings. Speakers' self-perceptions of voice disability were also obtained at both time points. RESULT: Individual analysis of the speech data showed that for most speakers with dysarthria, ease of understanding and perceptions of severity were rated the same or better pre- to post-treatment. Naturalness, however, was only perceived to be the same or better post-treatment in three out of seven speakers. Over half of the speakers reported improvements in their self-perception of voice disability. CONCLUSION: This pilot study highlighted the individual variability among speakers with dysarthria and the potential of online group speech treatment to maintain and/or improve speech function in this population.

¿Notas La Diferencia? [Do You Hear the Difference?]: Perceptual Consequences of Intensive Voice Treatment in Spanish Speakers With Parkinson's Disease.

PURPOSE: The primary objective of this study was to explore the effects of intensive voice-focused treatment on speech parameters in Spanish speakers with dysarthria associated with Parkinson's disease (PD) as perceived by naïve listeners. METHOD: Fifteen Spanish speakers with dysarthria associated with PD received the Lee Silverman Voice Treatment (LSVT LOUD) for a month. Voice and speech recordings were conducted pretreatment, posttreatment, and at a 1-month follow-up. Thirty naïve adult listeners rated the perceptual dimensions of ease of understanding (EoU), resonance, articulatory precision, prosody, and voice quality from sentences extracted from an emotional monologue on a visual analogue scale. RESULTS: EoU, resonance, articulatory precision, and voice quality significantly improved pre- to posttreatment, but gains were not maintained at follow-up. Speech severity was a significant source of variance in mean listener response for all perceptual dimensions, although the interaction between speech severity and time was only significant for resonance and voice quality. CONCLUSIONS: LSVT LOUD may be beneficial to improve perceptual speech domains affected by PD in Spanish speakers with dysarthria. Its impact on the different speech subsystems may reflect a universal distribution of effects when directly targeting the glottal source. Language-specific contributions of each perceptual domain to speech intelligibility should be explored in further research to determine linguistically sensitive treatment targets.

Towards the Targeted Protein Degradation of PRMT1.

Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase 1 clinical trial for GSK3368715, the first PRMT1 inhibitor to enter the clinic, was terminated early due to a lack of clinical efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. The incidence of the latter two events may be associated with inhibition-driven pharmacology as a high and sustained concentration of inhibitor is required for therapeutic effect. The degradation of PRMT1 using a proteolysis targeting chimera (PROTAC) may be superior to inhibition as proceeds via event-driven pharmacology where a PROTAC acts catalytically at a low dose. PROTACs containing the same pharmacophore as GSK3368715, combined with a motif that recruits the VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability and target engagement were shown for selected candidates by the detection of downstream effects of PRMT1 inhibition and by a NanoBRET assay for E3-ligase binding, however the candidates did not induce PRMT1 degradation. This paper is the first reported investigation of PRMT1 for targeted protein degradation and provides hypotheses and insights to assist the design of PROTACs for PRMT1 and other novel target proteins.

Novel immunotherapeutics against LGR5 to target multiple cancer types.

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Design of an Agent-Based Model to Examine Population-Environment Interactions in Nang Rong District, Thailand.

The design of an Agent-Based Model (ABM) is described that integrates Social and Land Use Modules to examine population-environment interactions in a former agricultural frontier in Northeastern Thailand. The ABM is used to assess household income and wealth derived from agricultural production of lowland, rain-fed paddy rice and upland field crops in Nang Rong District as well as remittances returned to the household from family migrants who are engaged in off-farm employment in urban destinations. The ABM is supported by a longitudinal social survey of nearly 10,000 households, a deep satellite image time-series of land use change trajectories, multi-thematic social and ecological data organized within a GIS, and a suite of software modules that integrate data derived from an agricultural cropping system model (DSSAT - Decision Support for Agrotechnology Transfer) and a land suitability model (MAXENT - Maximum Entropy), in addition to multi-dimensional demographic survey data of individuals and households. The primary modules of the ABM are the Initialization Module, Migration Module, Assets Module, Land Suitability Module, Crop Yield Module, Fertilizer Module, and the Land Use Change Decision Module. The architecture of the ABM is described relative to module function and connectivity through uni-directional or bi-directional links. In general, the Social Modules simulate changes in human population and social networks, as well as changes in population migration and household assets, whereas the Land Use Modules simulate changes in land use types, land suitability, and crop yields. We emphasize the description of the Land Use Modules - the algorithms and interactions between the modules are described relative to the project goals of assessing household income and wealth relative to shifts in land use patterns, household demographics, population migration, social networks, and agricultural activities that collectively occur within a marginalized environment that is subjected to a suite of endogenous and exogenous dynamics.

Acoustic Predictors of Ease of Understanding in Spanish Speakers With Dysarthria Associated With Parkinson's Disease.

PURPOSE: The purpose of this study was to examine selected baseline acoustic features of hypokinetic dysarthria in Spanish speakers with Parkinson's disease (PD) and identify potential acoustic predictors of ease of understanding in Spanish. METHOD: Seventeen Spanish-speaking individuals with mild-to-moderate hypokinetic dysarthria secondary to PD and eight healthy controls were recorded reading a translation of the Rainbow Passage. Acoustic measures of vowel space area, as indicated by the formant centralization ratio (FCR), envelope modulation spectra (EMS), and articulation rate were derived from the speech samples. Additionally, 15 healthy adults rated ease of understanding of the recordings on a visual analogue scale. A multiple linear regression model was implemented to investigate the predictive value of the selected acoustic parameters on ease of understanding. RESULTS: Listeners' ease of understanding was significantly lower for speakers with dysarthria than for healthy controls. The FCR, EMS from the first 10 s of the reading passage, and the difference in EMS between the end and the beginning sections of the passage differed significantly between the two groups of speakers. Findings indicated that 67.7% of the variability in ease of understanding was explained by the predictive model, suggesting a moderately strong relationship between the acoustic and perceptual domains. CONCLUSIONS: Measures of envelope modulation spectra were found to be highly significant model predictors of ease of understanding of Spanish-speaking individuals with hypokinetic dysarthria associated with PD. Articulation rate was also found to be important (albeit to a lesser degree) in the predictive model. The formant centralization ratio should be further examined with a larger sample size and more severe dysarthria to determine its efficacy in predicting ease of understanding.

A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.

Stapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment.

Peroxide-cleavable linkers for antibody-drug conjugates.

Antibody-drug conjugates containing peroxide-cleavable arylboronic acid linkers are described, which target the high levels of reactive oxygen species (ROS) in cancer. The arylboronic acid linkers rapidly release a payload in the presence of hydrogen peroxide, but remain stable in plasma. Anti-HER2 and PD-L1 peroxide-cleavable ADCs exhibited potent cytotoxicity in vitro.