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In response to Vivanti’s ‘Ask The Editor…’ paper [Journal of Autism and Developmental Disorders, 50(2), 691–693], we argue that the use of language in autism research has material consequences for autistic people including stigmatisation, dehumanisation, and violence. Further, that the debate in the use of person-first language versus identity-first language should centre first and foremost on the needs, autonomy, and rights of autistic people, so in to preserve their rights to self-determination. Lastly, we provide directions for future research.

The stigmatization of people with pedophilic sexual interests is a topic of growing academic and professional consideration, owing to its potential role in moderating pedophiles’ emotional well-being, and motivation and engagement in child abuse prevention schemes. Thus, improving attitudes and reducing stigmatization toward this group is of paramount importance. Prior research has suggested that narrative humanization—presenting personal stories of self-identified non-offending pedophiles—could be one route to doing this. However, this work has only been conducted with students or trainee psychotherapists, meaning the public generalizability of this method is still unknown. In this study, we compared two stigma interventions to test whether narratives reduce stigma toward people with pedophilic interests more effectively than an informative alternative (scientific information about pedophilia). Using a longitudinal experimental design with a lack of non-intervention control (initial N  = 950; final N  = 539), we found that narratives had consistently positive effects on all measured aspects of stigmatization (dangerousness, intentionality), whereas an informative alternative had mixed results, and actually increased perceptions of pedophiles’ levels of deviance. These effects were still present four months after the initial presentation. We discuss these data in relation to ongoing debates about treating pedophilia as a public health issue requiring a broad societal approach to well-being and child abuse prevention.

Genetic humanization, which involves replacing mouse genes with their human counterparts, can create powerful animal models for the study of human genes and diseases. One important example of genetic humanization involves mice humanized for their Ig genes, allowing for human antibody responses within a mouse background (HumAb mice) and also providing a valuable platform for the generation of fully human antibodies as therapeutics. However, existing HumAb mice do not have fully functional immune systems, perhaps because of the manner in which they were genetically humanized. Heretofore, most genetic humanizations have involved disruption of the endogenous mouse gene with simultaneous introduction of a human transgene at a new and random location (so-called KO-plus-transgenic humanization). More recent efforts have attempted to replace mouse genes with their human counterparts at the same genetic location (in situ humanization), but such efforts involved laborious procedures and were limited in size and precision. We describe a general and efficient method for very large, in situ, and precise genetic humanization using large compound bacterial artificial chromosome–based targeting vectors introduced into mouse ES cells. We applied this method to genetically humanize 3-Mb segments of both the mouse heavy and κ light chain Ig loci, by far the largest genetic humanizations ever described. This paper provides a detailed description of our genetic humanization approach, and the companion paper reports that the humoral immune systems of mice bearing these genetically humanized loci function as efficiently as those of WT mice.

Background Alzheimer's Disease (AD) risk variants APOE4 and TREM2‐R47H are known to impact glial cell functions and transcriptional profiles. TREM2‐mediated oligodendrocyte‐microglial crosstalk has not been revealed in previous research studies. Here, we present novel findings suggesting a TREM2‐dependent mediation of oligodendrocyte transcriptional profiles. Methods We investigated cell‐type specific transcriptional changes associated with humanized APOE4 and TREM2‐R47H genotypes in P301S+ mice versus background controls via single‐nuclei RNA‐sequencing of the frontal cortex. We investigated cell type subcluster abundance in association with genotype, sex and tau‐positivity. We classified subclusters through differentially expressed gene network modules and gene set enrichment analysis. We compared our findings in mice to a human cohort. The mouse cohort consisted of 52 humanized APOExTREM2 mice, with six‐to‐eight mice per genotype‐tau group, evenly split on sex. The human cohort consisted of 55 AD and control humans: APOE4‐carrier TREM2‐R47H (E4‐R47H) (n = 18), nonE4‐R47H (nonE4‐R47H) (n = 6), APOE4‐carrier TREM2‐common variant (E4‐CV) (n = 16), nonE4‐CV (n = 6). Results We found that APOE‐TREM2 status had sex‐ and tau‐independent TREM2‐R47H‐specific effects, and APOE4‐R47H synergistic effects on cell abundance in oligodendrocytes, oligodendrocyte progenitor cells (OPCs), and a subgroup of inhibitory neurons. Specifically, we identified OPC and oligodendrocyte subclusters that strongly associate with TREM2‐R47H in a tau‐independent manner, further exacerbated by APOE genotype. Of note, the human cohort also showed a strong synergistic effect of APOE4 and TREM2‐R47H on an oligodendrocyte subcluster that may be related to the TREM2‐R47H‐dependent oligodendrocyte subclusters identified in the mice. This finding of TREM2‐specific effects on oligodendrocyte transcriptional states in both mice and humans suggests possible TREM2‐mediated microglia‐oligodendrocyte crosstalk, or the presence of TREM2‐oligodendrocyte cell‐ligand interactions that merits further investigation. Conclusion In summary, this study suggests possible synergistic effects of APOE4‐carrier and TREM2‐R47H‐carrier status on OPC, oligodendrocyte, and inhibitory neuron abundance and transcriptional profiles. Specifically, OPCs and oligodendrocytes show a strong association with TREM2‐R47H that is exacerbated by APOE genotype, a finding that is reflected in the human cohort. Hence, further classification of differences between joint APOE‐TREM2 genotypes will improve our understanding of glial cell alterations in AD, and could lead to novel cell type‐specific therapeutic interventions for AD and other AD‐related dementia if broadly applied.

Background Alzheimer’s disease (AD) is a human specific neurodegenerative disorder characterized by loss of memory and cognitive functions associated with amyloid beta 1‐42 (Aβ1‐42) plaques and tau fibrils. In the brain, an elevated level of Aβ1‐42 leads to neuronal death, microglia activation and neuroinflammation. The α7 nicotinic acetylcholine receptor (α7nAChR) binds Aβ1‐42 with high affinity. CHRFAM7A, a human restricted fusion gene, incorporates into the α7nAChR pentamer creating a hypomorphic α7/CHRFAM7A nAChR. We examine how the humanized receptor affects Aβ1‐42 induced neuroinflammation. Method To study the effect of Aβ1‐42 on neuronal and immune cells two models were utilized: human isogenic iPSC model that includes medial ganglionic eminence (MGE) progenitors and microglia like cells (MGL) differentiated from CHRFAM7A null, CHRFAM7A nascent and isogenic CHRFAM7A_KI cell lines; and human AD and age matched control macrophages (28 donors). Result Consistent with a hypomorphic receptor, Aβ1‐42 uptake was mitigated in a dose‐dependent manner in CHRFAM7A carriers in both MGE progenitors and MGL as demonstrated by flow cytometry, ELISA, and immunofluorescence. Interestingly, a decreased Aβ1‐42 uptake resulted in significantly elevated innate immune cytokine expression (interleukin 1beta, interleukin 6, and tumor necrosis factor alpha) in CHRFAM7A carriers compared to null. This finding was consistent with release of the α7nAChR‐mediated anti‐inflammatory effect. Additionally, higher NF‐κB activation in CHRFAM7A carriers compared to null was observed in MGL as shown by a prolonged p65 translocation to the nucleus (immunofluorescence) and an increased p65 phosphorylation (immunoblot). Human variance of Aβ1‐42 effect was characterized in primary human macrophages. Similar to the iPSC model, Aβ1‐42 treatment led to an increased cytokine level in CHRFAM7A carriers compared to non‐carriers. Conclusion We found dual effect of CHRFAM7A on Aβ1‐42 associated pathology in AD: it provides protection against toxic concentration of Aβ1‐42 by decreased uptake through the humanized α7/CHRFAM7A nAChR and increases the innate immune response by switching the α7nAChR from an anti‐inflammatory to pro‐inflammatory transducer. Our iPSC model presents an opportunity to elucidate the molecular mechanism of these processes and establish high throughput screens.

Background The TREM2 R47H (rs75932628) coding variant has been identified as one of the most strongly associated genetic risk factors for late‐onset Alzheimer's disease (LOAD). Previous studies revealed that this missense mutation causes microglia to be less reactive to the amyloid beta (Aβ) plaques, which might exacerbate the progression of Alzheimer's disease (AD) pathologies. In an effort to develop mouse models for LOAD, we have generated human TREM2 (hTREM2) knock‐in and hTREM2‐R47H knock‐in mouse lines, fully replacing the murine Trem2 (mTrem2) sequence with its human TREM2 counterpart between start and stop codons, and crossed them with 5xFAD mouse line, a commonly used AD mouse model with robust amyloid‐beta pathology. We anticipate that these mouse models will shed light on the impact of microglial TREM2‐R47H variant in AD pathology development. Method 6 genotype groups were developed (WT, WT;hTREM2, WT;hTREM2‐R47H, 5xFAD, 5xFAD;hTREM2, 5xFAD;hTREM2‐R47H) with two age time points (4mo, 12mo). Mouse brains were isolated and cut in half; one hemisphere for immunohistochemistry (IHC) and the other for spatial transcriptomic analysis. Amyloid pathology and glial responses were measured via IHC. In spatial transcriptomic analysis using CosMx, transcriptomic characteristics and changes in each glial cell type were analyzed. Result At 4 months of age, 5xFAD mice with the hTREM2‐R47H variant showed increased amyloid plaque load in subiculum, and a significant spread of amyloid plaque burden in cortex area relative to both 5xFAD with murine Trem2, as well as with hTREM2. Microglia also failed to respond to plaques. CosMx results indicated that hTREM2‐R47H knock‐in microglia failed to downregulate homeostatic gene expression (i.e., P2ry12, Csf1r, Tgfbr1, and Tmem119) compared to hTREM2 knock‐in line. Conclusion Microglial reactivity to amyloid plaques was less in hTREM2 knock‐in line compared to mTrem2, suggesting that hTREM2 itself is not fully functional in the murine biologic system. Nevertheless, compared to mTrem2 and hTREM2, hTREM2‐R47H microglia do not down‐regulate their homeostatic genes in response to amyloid‐beta. Further, the magnitude of the effect of R47H in hTREM2 appears stronger than R47H in mTREM2, suggesting that humanization of disease relevant genes offers additional insights into disease mechanisms.

Background Genome‐Wide Association Studies (GWAS) identified ApoE4 as the strongest genetic risk factor for late‐onset Alzheimer's Disease (LOAD). As part of our efforts to develop mouse models that better recapitulate LOAD, at Model Organism Development & Evaluation for Late‐Onset Alzheimer's Disease (MODEL‐AD) consortium at University of California – Irvine, we have created a triple homozygous mouse model that combines our previously developed hAb‐KIloxP mice (Jackson Lab #031050), a humanized ApoE4, which replaces part of the murine ApoE locus, (Jackson Lab #027894) and a humanized MAPT‐GR (H2). This newly developed mouse model (MAD1; Jackson Lab #038104) will allow us to evaluate the interactions between aging, hAPOE4, hTau and hAb. Method Mice were aged to 4, 12, 18 and 24 months of age (hAb‐KIloxP HO;hApoE4 HO cohort) or 4 and 12 months of age (MAD1 cohort). At these timepoints, coronal hippocampal slices were prepared, and long‐term potentiation recordings were obtained. Synaptic density and microglial synaptic engulfment were also assessed by super‐resolution microscopy in different brain regions. Result hAb‐KIloxP mice showed a significant reduction in mean potentiation 50‐60 minutes post TBS, when compared to WT mice, indicative of an LTP deficit associated to human Ab. Interestingly, the presence of hAPOE4 rescued the LTP deficits observed on the hAb‐KIloxP mice from 4 months of age. Additionally, we observed a significant pre‐synaptic loss on the hAb‐KIloxP mice and hAb‐KIloxP HO;hMAPT HO (vs WT) that was prevented by hAPOE4. Interestingly, this pre‐synaptic loss correlated with increased microglial synaptic pruning in the hAb‐KIloxP mice, which was then reduced by the presence of hAPOE4. Conclusion hAb induces robust LTP deficits that are prevent by hAPOE4, from 4 months of age. These results are in agreement with the excessive synaptic loss observed in the hAb‐KIloxP mice, which is also rescued by the addition of the hAPOE4 variant. Further studies are needed to fully understand the differences between murine and human APOE4 and how this could be modulating the effects of hAb on synaptic integrity and function.

Purpose This study explores whether the full potential of physiotherapy is reaching cancer patients and their caregivers at all stages of the oncological process, aiming to identify gaps and opportunities for improving care. Methods The World Cafe co-design methodology facilitated discussions among cancer patients and caregivers. This dynamic, inclusive, and engaging approach fostered diverse perspectives and deeper insights through collaborative and flexible discussions. Sessions were recorded, transcribed, and qualitatively analyzed. Results Sixteen participants were involved (eight cancer survivors and eight caregivers). The mean age of cancer survivors was 63.8 years, while the average age of caregivers was 59.3 years. Breast cancer was the most prevalent diagnosis among patients, and most caregivers had lost their family members to cancer. Analysis revealed two primary themes: “feeling cared for” and “the role of physiotherapy in the oncological process.” Key findings highlight the need for more humanized healthcare, with professionals providing support through effective communication and empathy. Significant gaps were detected in both systematic referrals to physiotherapists and their integration into care teams. Testimonies highlighted the lack of knowledge about the full potential of physiotherapy in oncology, hindering access. There was also a demand for recognizing specialized oncological physiotherapists. Conclusions These findings highlight significant gaps in physiotherapy care for cancer survivors and caregivers, including unmet needs due to the lack of information, resources, and effective communication. Future efforts should focus on increasing the visibility of physiotherapy, integrating specialized physiotherapists into oncology teams, and enhancing the emotional education of healthcare professionals to provide more humanized care.

One of the significant factors in the sustainability of education is the development of inclusive education. An inclusive educational space implies openness and accessibility of education for students, regardless of their educational needs. Inclusive education also means a partnership between students and teachers. A teacher is a living person whose socio-emotional skills and professional abilities are the basis for the sustainability of education and student development. This article is devoted to studying teachers’ competence and psychological readiness at schools and higher educational institutions to work with students with special educational needs. This article includes the results of a sociological study conducted in September 2022 and is devoted to the readiness of schoolteachers and university professors for inclusive education (N = 125). The general statistical calculation was carried out based on information processing using the Vortex program version 10.0. Universities and schools are located in large administrative centers of Russian regions with a population of about a million. The relevance of this study is due to the relationship of sustainability with the ideas of inclusive education, manifested in its goal of achieving students’ educational levels established by the state and the humanistic concept of equality of opportunity in the process of professional implementation and self-determination of the individual.

The brand relationship literature shows that the humanizing of brands and products generates more favorable consumer attitudes and thus enhances brand performance. However, the authors propose negative downstream consequences of brand humanization; that is, the anthropomorphization of a brand can negatively affect consumers' brand evaluations when the brand faces negative publicity caused by product wrongdoings. They find that consumers who believe in personality stability (i.e., entity theorists) view anthropomorphized brands that undergo negative publicity less favorably than nonanthropomorphized brands. In contrast, consumers who advocate personality malleability (i.e., incremental theorists) are less likely to devalue an anthropomorphized brand from a single instance of negative publicity. Finally, the authors explore three firm response strategies (i.e., denial, apology, and compensation) that can affect the evaluations of anthropomorphized brands for consumers with different implicit theory perspectives. They find that entity theorists have more difficulty in combating the adverse effects of brand anthropomorphization than incremental theorists. Furthermore, they demonstrate that compensation (vs. denial or apology) is the only effective response among entity theorists.