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Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers.
PurposeWe determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene.MethodsA total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis.ResultsSeveral distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]).ConclusionsThe PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets
Feasibility of Blood Flow Restriction Exercise in Adults with a Non-surgically Treated Achilles Tendon Rupture; a Case Series
International Journal of Exercise Science 17(3): 140-153, 2024. Blood flow restriction exercise (BFRE) appears to provide a unique opportunity to preserve lower limb muscle and function in patients with an Achilles tendon rupture. The purpose of this study was to investigate the feasibility of BFRE in patients with an Achilles tendon rupture. Additionally, to evaluate muscle volume and patient-reported ankle function, symptoms, complications, and physical activity following 12 weeks of BFRE. Feasibility was measured by adherence to training sessions, drop-out rate, intervention acceptability, ankle pain exacerbation (NRS), and adverse events. At baseline and 12-weeks follow-up, patients completed the Achilles Tendon Total Rupture Score questionnaire and had their thigh and calf circumference measured. At follow-up, patientsâ ability to perform a single-leg heel rise was tested. Sixteen of 18 patients completed the intervention and for those, adherence to training sessions was 88% ±16%. The mean NRS following BFRE sessions was 1.1 (95%CI: 1; 1.2). Three adverse events occurred during the 12 weeks. Two re-ruptures after completion of the BFRE program and one deep venous thrombosis following cast removal. BFRE was found to be feasible in a subset of patients with an Achilles tendon rupture. However, with three adverse events in a population of 18 patients, the effectiveness and safety of BFRE warrants further investigation
The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis
Summary:
Expression of the initiator methionine tRNA (tRNAi
Met)
is deregulated in cancer. Despite this fact, it is not
currently known how tRNAi
Met expression levels influence
tumor progression. We have found that tRNAi
Met
expression is increased in carcinoma-associated
fibroblasts, implicating deregulated expression of
tRNAi
Met in the tumor stroma as a possible contributor
to tumor progression. To investigate how elevated
stromal tRNAi
Met contributes to tumor progression,
we generated a mouse expressing additional copies
of the tRNAi
Met gene (2+tRNAi
Met mouse). Growth
and vascularization of subcutaneous tumor allografts
was enhanced in 2+tRNAi
Met mice compared with
wild-type littermate controls. Extracellular matrix
(ECM) deposited by fibroblasts from 2+tRNAi
Met
mice supported enhanced endothelial cell and fibroblast
migration. SILAC mass spectrometry indicated
that elevated expression of tRNAi
Met significantly
increased synthesis and secretion of certain types of
collagen, in particular type II collagen. Suppression
of type II collagen opposed the ability of tRNAi
Metoverexpressing
fibroblasts to deposit pro-migratory
ECM. We used the prolyl hydroxylase inhibitor ethyl-
3,4-dihydroxybenzoate (DHB) to determine whether
collagen synthesis contributes to the tRNAi
Met-driven
pro-tumorigenic stroma in vivo. DHB had no effect
on the growth of syngeneic allografts in wild-type
mice but opposed the ability of 2+tRNAi
Met mice to
support increased angiogenesis and tumor growth.
Finally, collagen II expression predicts poor prognosis
in high-grade serous ovarian carcinoma. Taken
together, these data indicate that increased tRNAi
Met
levels contribute to tumor progression by enhancing
the ability of stromal fibroblasts to synthesize and
secrete a type II collagen-rich ECM that supports
endothelial cell migration and angiogenesis
North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene
PURPOSE: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). METHODS: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. RESULTS: Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13. The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. CONCLUSIONS: The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13, not CCNC, is the cause of NCMD mapped to the MCDR1 locus
Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia
In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5âyears after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists
Learning to Eat Vegetables in Early Life: The Role of Timing, Age and Individual Eating Traits
Vegetable intake is generally low among children, who appear to be especially fussy during the pre-school years. Repeated exposure is known to enhance intake of a novel vegetable in early life but individual differences in response to familiarisation have emerged from recent studies. In order to understand the factors which predict different responses to repeated exposure, data from the same experiment conducted in three groups of children from three countries (nâ=â332) aged 4â38 m (18.9±9.9 m) were combined and modelled. During the intervention period each child was given between 5 and 10 exposures to a novel vegetable (artichoke puree) in one of three versions (basic, sweet or added energy). Intake of basic artichoke puree was measured both before and after the exposure period. Overall, younger children consumed more artichoke than older children. Four distinct patterns of eating behaviour during the exposure period were defined. Most children were âlearnersâ (40%) who increased intake over time. 21% consumed more than 75% of what was offered each time and were labelled âplate-clearersâ. 16% were considered ânon-eatersâ eating less than 10 g by the 5th exposure and the remainder were classified as âothersâ (23%) since their pattern was highly variable. Age was a significant predictor of eating pattern, with older pre-school children more likely to be non-eaters. Plate-clearers had higher enjoyment of food and lower satiety responsiveness than non-eaters who scored highest on food fussiness. Children in the added energy condition showed the smallest change in intake over time, compared to those in the basic or sweetened artichoke condition. Clearly whilst repeated exposure familiarises children with a novel food, alternative strategies that focus on encouraging initial tastes of the target food might be needed for the fussier and older pre-school children
The "ram effect": new insights into neural modulation of the gonadotropic axis by male odors and socio-sexual interactions
Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate LH secretion and eventually reinstate cyclicity. This is known as the ram effect and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a pheromone-like effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naĂŻve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the spe
Reflections from the Workshop on AI-Assisted Decision Making for Conservation
In this white paper, we synthesize key points made during presentations and
discussions from the AI-Assisted Decision Making for Conservation workshop,
hosted by the Center for Research on Computation and Society at Harvard
University on October 20-21, 2022. We identify key open research questions in
resource allocation, planning, and interventions for biodiversity conservation,
highlighting conservation challenges that not only require AI solutions, but
also require novel methodological advances. In addition to providing a summary
of the workshop talks and discussions, we hope this document serves as a
call-to-action to orient the expansion of algorithmic decision-making
approaches to prioritize real-world conservation challenges, through
collaborative efforts of ecologists, conservation decision-makers, and AI
researchers.Comment: Co-authored by participants from the October 2022 workshop:
https://crcs.seas.harvard.edu/conservation-worksho
SARS and Pregnancy: A Case Report
We report a laboratory-confirmed case of severe acute respiratory syndrome (SARS) in a pregnant woman. Although the patient had respiratory failure, a healthy infant was subsequently delivered, and the mother is now well. There was no evidence of viral shedding at delivery. Antibodies to SARS virus were detected in cord blood and breast milk
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