Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the -terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease.

An international core outcome set for primary progressive aphasia (COS-PPA): Consensus-based recommendations for communication interventions across research and clinical settings.

Introduction: Interventions to treat speech-language difficulties in primary progressive aphasia (PPA) often use word accuracy as a highly comparable outcome. However, there are more constructs of importance to people with PPA that have received less attention.

Methods: Following Core Outcome Set Standards for Development Recommendations (COSSTAD), this study comprised: Stage 1 - systematic review to identify measures; Stage 2 - consensus groups to identify important outcome constructs for people with PPA (n = 82) and care partners (n = 91); Stage 3 - e-Delphi consensus with 57 researchers.

The role of advocacy in sustaining male contraceptive research and development.

Novel male contraceptives have been in development for well over half a century, and despite a robust predicted global market for new methods, funding for research and development has been extremely limited. While the pharmaceutical industry previously supported male contraceptive research and development, industry partners are only spectators in the current space, awaiting a product that has been de-risked by the public sector before re-entering the field. Current male contraceptive development efforts are thus primarily funded by nonprofit, non-governmental, and government agencies who also act as the primary advocates for the field.

Naming in a multilingual context: Norms for the ICMR-Manipal colour picture corpus in Kannada from the Indian context.

There have been many published picture corpora. However, more than half of the world's population speaks more than one language and, as language and culture are intertwined, some of the items from a picture corpus designed for a given language in a particular culture may not fit another culture (with the same or different language). There is also an awareness that language research can gain from the study of bi-/multilingual individuals who are immersed in multilingual contexts that foster inter-language interactions.

Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target.

Why is a named as and as ? Understanding the relationship between targets and errors in a speeded picture naming task.

Speakers sometimes make word production errors, such as mistakenly saying instead of flamingo. This study explored which properties of an error influence the likelihood of its selection over the target word. Analysing real-word errors in speeded picture naming, we investigated whether, relative to the target, naming errors were more typical representatives of the semantic category, were associated with more semantic features, and/or were semantically more closely related to the target than its near semantic neighbours were on average.

Nonhormonal Male Contraceptive Development-Strategies for Progress.

Despite the widely demonstrated public health benefits of contraception, limited contraceptive options are available for men, placing both the contraceptive burden and opportunity solely on women. This review outlines the need for an increased focus on male contraceptive development and highlights several related topics, including the perspectives of women and men on male contraceptives, historical challenges, and reasons behind the persistent delays in male contraceptive development. It also discusses the importance of serendipitous observations in drug discovery and the limitations of depleting sperm or spermatogenic cells as a contraceptive approach.

Common ground: the opportunity of male contraceptives as MPTs.

Multipurpose prevention technologies (MPTs) and male contraceptive methods are currently in development to address unique and critical needs facing the global reproductive health community. Currently, MPT products in development are exclusively female-focused due to the readily available nature and regulatory precedent offered by female contraceptive active pharmaceutical ingredients (APIs); however, the opportunity to explore codevelopment with male contraceptive methods, which are at a comparatively early stage of development, should not be overlooked. These fields face parallel challenges including research and development, commercialization, regulatory approval, and market uptake, and these parallels can inform strategic alignment between the fields.

Quality of Life Ratings and Proxy Bias in Primary Progressive Aphasia: Two Sides to the Story?

A valid measure of quality of life is important for clinical goal setting and for evaluating interventions. In the amnestic dementias, proxy-raters (e.g.

Developing a machine learning model to detect diagnostic uncertainty in clinical documentation.

Background And Objective: Diagnostic uncertainty, when unrecognized or poorly communicated, can result in diagnostic error. However, diagnostic uncertainty is challenging to study due to a lack of validated identification methods. This study aims to identify distinct linguistic patterns associated with diagnostic uncertainty in clinical documentation.

Examining Dose Frameworks to Improve Aphasia Rehabilitation Research.

The effect of treatment dose on recovery of post-stroke aphasia is not well understood. Inconsistent conceptualization, measurement, and reporting of the multiple dimensions of dose hinders efforts to evaluate dose-response relations in aphasia rehabilitation research. We review the state of dose conceptualization in aphasia rehabilitation and compare the applicability of 3 existing dose frameworks to aphasia rehabilitation research-the Frequency, Intensity, Time, and Type (FITT) principle, the Cumulative Intervention Intensity (CII) framework, and the Multidimensional Dose Articulation Framework (MDAF).

Semantic impairment in aphasia: A problem of control?

Purpose: The relationship between cognitive processes and language ability in aphasia has recently gained increasing attention, with some authors suggesting that control impairments may underlie difficulties with semantic tasks in aphasia. This paper aims to present an overview of the current research on the involvement of cognitive processes in semantic processing tasks and discuss the proposed relationship between cognitive control and semantic processing in aphasia.

Method: The role of cognitive processes in semantic processing tasks commonly used in the aphasiology literature is discussed and two theoretical approaches to semantic processing that contribute to the understanding of the nature of semantic breakdown in aphasia are outlined.

The effect of processing semantic features on spoken word retrieval in a case series of people with aphasia.

: There is a growing body of evidence showing the benefit of Semantic Feature Analysis in the treatment of word finding abilities in people with aphasia. The original technique was grounded in the hypothesis that the activation of semantic features spreads to the target and thereby facilitates its subsequent retrieval. However, it remains unclear the extent to which the focus on semantic features influences the treatment effects.

Investigating the influence of semantic factors on word retrieval: Reservations, results and recommendations.

There is consensus that word retrieval starts with activation of semantic representations. However, in adults without language impairment, relatively little attention has been paid to the effects of the semantic attributes of to-be-retrieved words. This paper, therefore, addresses the question of which item-inherent semantic factors influence word retrieval.

Are they really stronger? Comparing effects of semantic variables in speeded deadline and standard picture naming.

Investigations of effects of semantic variables on picture naming have often been inconclusive, with some studies reporting significant and others non-significant effects. One potential explanation may relate to the specific naming tasks used: While most previous studies have used standard picture naming, others have used speeded naming that requires participants to prioritise naming speed over accuracy. Speeded naming has been suggested to cause enhanced effects of item-inherent word characteristics due to disruptions of cognitive control and resulting modulations of responsiveness to input.

Results of the COMPARE trial of Constraint-induced or Multimodality Aphasia Therapy compared with usual care in chronic post-stroke aphasia.

Background: While meta-analyses confirm treatment for chronic post-stroke aphasia is effective, a lack of comparative evidence for different interventions limits prescription accuracy. We investigated whether Constraint-Induced Aphasia Therapy Plus (CIAT-plus) and/or Multimodality Aphasia Therapy (M-MAT) provided greater therapeutic benefit compared with usual community care and were differentially effective according to baseline aphasia severity.

Methods: We conducted a three-arm, multicentre, parallel group, open-label, blinded endpoint, phase III, randomised-controlled trial.

Dual-Task nTMS Mapping to Visualize the Cortico-Subcortical Language Network and Capture Postoperative Outcome-A Patient Series in Neurosurgery.

Background: Perioperative assessment of language function in brain tumor patients commonly relies on administration of object naming during stimulation mapping. Ample research, however, points to the benefit of adding verb tasks to the testing paradigm in order to delineate and preserve postoperative language function more comprehensively. This research uses a case series approach to explore the feasibility and added value of a dual-task protocol that includes both a noun task (object naming) and a verb task (action naming) in perioperative delineation of language functions.

A Multicenter, Prospective Study Comparing Subxiphoid and Parasternal Views During Brief Echocardiography: Effect on Image Quality, Acquisition Time, and Visualized Anatomy.

Background: Recent literature has suggested echocardiography (echo) may prolong pauses in chest compressions during cardiac arrest.

Objectves: We sought to determine the impact of the sonographic approach (subxiphoid [SX] vs. parasternal long [PSL]) on time to image completion, image quality, and visualization of cardiac anatomy during echo, as performed during Advanced Cardiac Life Support.

Semantic Variant Primary Progressive Aphasia: Practical Recommendations for Treatment from 20 Years of Behavioural Research.

People with semantic variant primary progressive aphasia (svPPA) present with a characteristic progressive breakdown of semantic knowledge. There are currently no pharmacological interventions to cure or slow svPPA, but promising behavioural approaches are increasingly reported. This article offers an overview of the last two decades of research into interventions to support language in people with svPPA including recommendations for clinical practice and future research based on the best available evidence.

Semantic variables both help and hinder word production: Behavioral evidence from picture naming.

This research investigated how word production is influenced by six feature-based semantic variables (number of semantic features, intercorrelational density, number of near semantic neighbors, semantic similarity, typicality, and distinctiveness). We simultaneously investigated effects of the six semantic variables on spoken picture naming in a large group of participants ( = 87), while controlling for other psycholinguistic variables. Across analyses, number of semantic features was the most consistent predictor with a facilitatory effect on naming latency and accuracy.

No negative impact of word retraining on vocabulary use or clarity of communication in semantic dementia.

Word retraining techniques can improve picture naming of treated items in people with semantic dementia (SD). The utility of this, however, has been questioned given the propensity for under- and overgeneralization errors in naming in SD. Few studies have investigated the occurrence of such errors.

Catalyzing momentum in male contraceptive development†.

Globally, nearly half of all pregnancies are unplanned. Male contraceptives offer the potential to decrease unintended pregnancy and introduce contraceptive equity, but decades of research have yet to bring a novel product to market. New funding avenues from the philanthropic sector seek to stimulate research in male contraceptives through investments, grants, and support for trainees alongside other programs that encourage product development and ultimately commercialization.