Cerebellar alterations in a model of Down syndrome: The role of the Dyrk1A gene

Down syndrome (DS) is characterized by a marked reduction in the size of the brain and cerebellum. These changes play an important role in the motor alterations and cognitive disabilities observed in this condition. The Ts65Dn (TS) mouse, the most commonly used model of DS, reflects many DS phenotypes, including alterations in cerebellar morphology. One of the genes that is overexpressed in both individuals with DS and TS mice is DYRK1A/Dyrk1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which has been implicated in the altered cerebellar structural and functional phenotypes observed in both populations. The aim of this study was to evaluate the effect of Dyrk1A on different alterations observed in the cerebellum of TS animals. TS mice were crossed with Dyrk1A +/- KO mice to obtain mice with a triplicate segment of Mmu16 that included Dyrk1A (TS +/+/+), mice with triplicate copies of the same genes that carried only two copies of Dyrk1A (TS +/+/-), euploid mice that expressed a normal dose of Dyrk1A (CO +/+) and CO animals with a single copy of Dyrk1A (CO +/-). Male mice were used for all experiments. The normalization of the Dyrk1A gene dosage did not rescue the reduced cerebellar volume. However, it increased the size of the granular and molecular layers, the densities of granular and Purkinje cells, and dendritic arborization. Furthermore, it improved the excitatory/inhibitory balance and walking pattern of TS +/+/- mice. These results support the hypothesis that Dyrk1A is involved in some of the structural and functional cerebellar phenotypes observed in the TS mouse model.This work was supported by grants from the Jerome Lejeune Foundation and Fundación Tatiana Pérez de Guzmán el Bueno and the Spanish Ministry of Economy and Competitiveness (PSI-2016-76194-R, AEI/FEDER, EU) and “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, CB06/05/0037)” from Spain

Early neurological deterioration after subarachnoid haemorrhage: risk factors and impact on outcome

Background Early neurological deterioration occurs frequently after subarachnoid haemorrhage (SAH). The impact on hospital course and outcome remains poorly defined. Methods We identified risk factors for worsening on the Hunt–Hess grading scale within the first 24 h after admission in 609 consecutively admitted aneurysmal SAH patients. Admission risk factors and the impact of early worsening on outcome was evaluated using multivariable analysis adjusting for age, gender, admission clinical grade, admission year and procedure type. Outcome was evaluated at 12 months using the modified Rankin Scale (mRS). Results 211 patients worsened within the first 24 h of admission (35%). In a multivariate adjusted model, early worsening was associated with older age (OR 1.02, 95% CI 1.001 to 1.03; p=0.04), the presence of intracerebral haematoma on initial CT scan (OR 2.0, 95% CI 1.2 to 3.5; p=0.01) and higher SAH and intraventricular haemorrhage sum scores (OR 1.05, 95% CI 1.03 to 1.08 and 1.1, 95% CI 1.01 to 1.2; p less than 0.001 and 0.03, respectively). Early worsening was associated with more hospital complications and prolonged length of hospital stay and was an independent predictor of death (OR 12.1, 95% CI 5.7 to 26.1; p less than 0.001) and death or moderate to severe disability (mRS 4–6, OR 8.4, 95% CI 4.9 to 14.5; p=0.01) at 1 year. Conclusions Early worsening after SAH occurs in 35% of patients, is predicted by clot burden and is associated with mortality and poor functional outcome at 1 year

From Human Days to Machine Seconds: Automatically Answering and Generating Machine Learning Final Exams

A final exam in machine learning at a top institution such as MIT, Harvard, or Cornell typically takes faculty days to write, and students hours to solve. We demonstrate that large language models pass machine learning finals at a human level, on finals available online after the models were trained, and automatically generate new human-quality final exam questions in seconds. Previous work has developed program synthesis and few-shot learning methods to solve university-level problem set questions in mathematics and STEM courses. In this work, we develop and compare methods that solve final exams, which differ from problem sets in several ways: the questions are longer, have multiple parts, are more complicated, and span a broader set of topics. We curate a dataset and benchmark of questions from machine learning final exams available online and code for answering these questions and generating new questions. We show how to generate new questions from other questions and course notes. For reproducibility and future research on this final exam benchmark, we use automatic checkers for multiple-choice, numeric, and questions with expression answers. We perform ablation studies comparing zero-shot learning with few-shot learning and chain-of-thought prompting using GPT-3, OPT, Codex, and ChatGPT across machine learning topics and find that few-shot learning methods perform best. We highlight the transformative potential of language models to streamline the writing and solution of large-scale assessments, significantly reducing the workload from human days to mere machine seconds. Our results suggest that rather than banning large language models such as ChatGPT in class, instructors should teach students to harness them by asking students meta-questions about correctness, completeness, and originality of the responses generated, encouraging critical thinking in academic studies.Comment: 9 page

Fine Mapping of 10q and 18q for Familial Alzheimer's Disease in Caribbean Hispanics

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18

Síndrome de Behcet: Presentación de un caso

Se presentó un paciente joven masculino que acudió a Consulta de Reumatología por presentar aumento de volumen articular asociado a úlceras en el escroto y aftas orales, se interpretó inicialmente como un síndrome de Reiter. En el curso del ingreso se constató la presencia de foliculitis en piel de miembros superiores, tórax y cara e iridoconjuntivitis bilateral, en los rayos X sólo se observó el aumento de partes blandas en la articulación comprometida, el resto de los exámenes complementarios sólo mostraron de interés una aceleración moderada de la velocidad de sedimentación globular. Se rediscutió nuevamente y se observó que presentaba los 4 criterios mayores para el diagnóstico de síndrome de Behcet completo.A young male patient is presented, who went to Rheumatology Medical Service because he had an increased articular volume caused by scrotum ulcers and aphthous ulcers. This case was initially regarded as Reiter´s Syndrome. In the course of the admission, foliculitis in upper limbs, thorax and face skin as well as bilateral iridioconjunctivitis were found; X-ray test showed increased soft parts in the compromised articulation. The rest of the supplementary tests only showed a moderate acceleration of globular sedimentation speed. The case was re-discussed and it was observed that the four main criteria for the diagnosis of a full Behcet´s Syndrome were present

Familial Alzheimer Disease Among Caribbean Hispanics: A Reexamination of Its Association With APOE

Objectives: To reexamine the association between the apolipoprotein E ϵ4 allele (APOE ϵ4) and familial Alzheimer disease (AD), and to search for novel genes that may be associated with susceptibility in Caribbean Hispanic families with a history of AD. Methods: Families were identified in Caribbean Hispanic communities in the greater New York City area, the Dominican Republic, and Puerto Rico. Each family in the study cohort included at least 2 living relatives with a history of dementia. All family members underwent neuropsychological testing and medical and neurological examinations to establish the presence or absence of dementia and to specify the type of dementia. Results: Over a 2½-year period, 203 families were identified. Of these, 19 families had at least 1 family member with onset of dementia before age 55 years, with 8 of the 19 families showing an association with a previously unreported presenilin mutation. Multiple cases of AD were identified in 29 families. Overall, there were 236 affected sibling pairs with AD available for analysis. The average age at onset was 74 years. The presence of APOE ϵ4 was strongly associated with AD. Conclusions: Both early-onset and late-onset familial AD occur in Caribbean Hispanics. In contrast to sporadic AD, late-onset familial AD among Caribbean Hispanics is strongly associated with APOE ϵ4. Future attempts to identify additional susceptibility genes should consider the effects of APOE ϵ4. A FAMILY HISTORY of Alzheimer disease (AD) is one of the strongest risk factors for the disease. The lifetime risk of AD for family members of patients approaches 50% in some studies, which suggests an age-dependent autosomal dominant mode of inheritance.1,2 Mutations in genes on chromosomes 1, 14, and 21 are associated with familial early-onset AD, often with an autosomal dominant pattern of inheritance.3,4 However, these genes account for only 10% of all AD. The discovery that a polymorphism in the APOE (apolipoprotein E) gene on chromosome 19 was associated with susceptibility to both sporadic and familial late-onset AD5 led to the search for other potential susceptibility genes. Sites for potential susceptibility genes on chromosome 12 have been identified,6 and, more recently, sites on chromosome 10 have also been identified.7-9 Attempts to confirm the linkage between chromosome 12 and AD have been variable,10-12 and the association with α2-macroglobulin, a candidate gene in the area, has also been inconsistent.13-16 Familial AD may be the result of complex inheritance involving many genes with incomplete penetrance or a combination of genetic and environmental factors. Hispanics are one of the most rapidly increasing ethnic groups in the United States. The elderly Hispanic population is expected to double in the United States by the year 2010 and increase 11-fold by 2050.17 Compared with other ethnic groups, Caribbean Hispanics have an increased prevalence and incidence of AD,18-20 as do Mexican Americans.21 Yet the reason for this increase in disease frequency is unknown. No specific environmental factors have been identified, which suggests a genetic explanation. The association between AD and the APOE ϵ4 allelic polymorphism has been weaker in late-onset AD among Caribbean Hispanics compared with whites in New York City20,22,23 but not in Miami, Fla.24,25 We began the family study not only to identify the chromosomal location of additional susceptibility genes in Caribbean Hispanics, but also to reinvestigate the heterogeneity of the APOE association in this population

A Dataset for Learning University STEM Courses at Scale and Generating Questions at a Human Level

We present a new dataset for learning to solve, explain, and generate university-level STEM questions from 27 courses across a dozen departments in seven universities. We scale up previous approaches to questions from courses in the departments of Mechanical Engineering, Materials Science and Engineering, Chemistry, Electrical Engineering, Computer Science, Physics, Earth Atmospheric and Planetary Sciences, Economics, Mathematics, Biological Engineering, Data Systems, and Society, and Statistics. We visualize similarities and differences between questions across courses. We demonstrate that a large foundation model is able to generate questions that are as appropriate and at the same difficulty level as human-written questions