mutations provide genetic vulnerability to copper ionophores in human acute myeloid leukemia.

In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward -mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis.

ArHsp90 is important in stress tolerance and embryo development of the brine shrimp, Artemia franciscana.

Females of the extremophile crustacean, Artemia franciscana, either release motile nauplii via the ovoviviparous pathway or encysted embryos (cysts) via the oviparous pathway. Cysts contain an abundant amount of the ATP-independent small heat shock protein that contributes to stress tolerance and embryo development, however, little is known of the role of ATP-dependent molecular chaperone, heat shock protein 90 (Hsp90) in the two processes. In this study, a hsp90 was cloned from A.

Speech-language pathologists' practices and perceptions of parent involvement in paediatric services funded by the NDIS in Australia.

: There has been concern that a shift in disability funding to the National Disability Insurance Scheme (NDIS) in Australia may have influenced paediatric speech and language intervention to involve parents less in service delivery. This study aimed to describe paediatric speech-language pathologists' (SLPs) practices and perceptions of parent involvement in NDIS-funded speech and/or language intervention.: Seventy-two paediatric SLPs currently practicing in Australia with NDIS-funded speech and/or language clients completed an online survey.

Patient Reported Outcomes Following Triple Arthrodesis for Adult Acquired Flat Foot Deformity: Minimum Two Year Follow Up.

The aim of this study is to analyze patient-reported outcomes following this procedure as well as any demographics that may confer prognostic capability. A retrospective analysis was conducted of patients who underwent Triple Arthrodesis at our facility from 2014-2021. Patients were selected if they underwent an isolated triple arthrodesis.

Influence of Surgical Approach and Fixation on Complications in Talus Fractures: A Multicenter Review.

Fractures of the talus are infrequent injuries often associated with substantial morbidity and imperfect outcomes. We undertook a retrospective review of talus fractures at multiple level 1 trauma centers in order to identify common treatment patterns and potential predictors of complications. All cases of talar fractures meeting inclusion criteria at our institution were reviewed.

Variation in morpho-lexical development within and between diagnoses in children with neurodevelopmental disorders.

While primary diagnosis is only one aspect of the presentation of a child with neurodevelopmental delay/disorder, the degree to which early expressive language reflects diagnostic divisions must be understood in order to reduce the risk of obscuring clinically important differences and similarities across diagnoses. We present original data from the New Zealand MacArthur-Bates Communicative Development Inventory (NZCDI) from 88 English-speaking children aged 2;6 to 5;6 years receiving multidisciplinary intervention within a single family-centered program. The children had one of six pediatrician-assigned genetic or behaviorally determined diagnoses: Down syndrome (DS); motor disorders (cerebral palsy and developmental coordination disorder); global development delay; disorders of relating and communicating (R&C); other genetically defined diagnoses; or language delay due to premature (PREM) birth.

Frailty and genetic risk predict fracture after lung transplantation.

Fractures negatively impact quality of life and survival. We hypothesized that recipient frailty score and genetic profile measured before transplant would predict risk of fracture after lung transplant. We conducted a retrospective cohort study of bone mineral density (BMD) and fracture among lung transplant recipients at a single center.

Word type and modality in the emerging expressive vocabularies of preschool children with Down syndrome.

Background: Previous studies have explored the size and word type composition (nouns, predicates, etc.) of expressive vocabularies of preschool children with Down syndrome, both spoken and signed. Separately, overall preferences for modality of expression have also been explored.

Indocyanine Green Fluorescence Angiography in Minor Lower Extremity Amputations: A Useful Technique?

Complications remain despite conventional methods aimed at improving survivorship of lower extremity amputations. High rates of wound dehiscence, readmission, and revision surgery warrant the development of innovative methods to improve amputation survivorship. One such method employs the use of indocyanine green dye (ICG); an inert chemical injected intraoperatively which can be used to visualize dermal blood flow in real time.

Regulation, functions and transmission of bivalent chromatin during mammalian development.

Cells differentiate and progress through development guided by a dynamic chromatin landscape that mediates gene expression programmes. During development, mammalian cells display a paradoxical chromatin state: histone modifications associated with gene activation (trimethylated histone H3 Lys4 (H3K4me3)) and with gene repression (trimethylated H3 Lys27 (H3K27me3)) co-occur at promoters of developmental genes. This bivalent chromatin modification state is thought to poise important regulatory genes for expression or repression during cell-lineage specification.

HMGA2 expression defines a subset of human AML with immature transcriptional signature and vulnerability to G2/M inhibition.

High-mobility group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein that is normally expressed in stem cells of various tissues and aberrantly detected in several tumor types. We recently observed that one-fourth of human acute myeloid leukemia (AML) specimens express HMGA2, which associates with a very poor prognosis. We present results indicating that HMGA2+ AMLs share a distinct transcriptional signature representing an immature phenotype.

Predictors of Speech Severity and Inconsistency Over Time in Children With Token-to-Token Inconsistency.

Purpose: The aim of this study was to describe and explain changes in severity of speech sound disorder (SSD) and token-to-token inconsistency in children with high levels of inconsistency.

Method: Thirty-nine children (aged 4;6-7;11 [years;months]) with SSDs and high levels of token-to-token inconsistency were assessed every 6 months for 2 years (i.e.

Consonant Cluster Productions in Preschool Children Who Speak African American English.

Purpose: The aim of this study was to compare word-initial and word-final consonant cluster productions in young children who speak African American English (AAE) and compare their productions to what we know about cluster productions in children who speak Mainstream American English (MAE), in order to minimize misdiagnosis of speech sound disorders.

Method: Twenty-two children (ages 2;10-5;4 [years;months]) labeled pictures whose names contained at least one consonant cluster in word-initial and/or word-final position. Most two-element clusters of English were sampled, the majority in two or more words.

Vesicular trafficking is a key determinant of the statin response in acute myeloid leukemia.

Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability.

HLF expression defines the human hematopoietic stem cell state.

Hematopoietic stem cells (HSCs) sustain blood cell homeostasis throughout life and can regenerate all blood lineages after transplantation. Despite this clear functional definition, highly enriched isolation of human HSCs can currently only be achieved through combinatorial assessment of multiple surface antigens. Although several transgenic HSC reporter mouse strains have been described, no analogous approach to prospectively isolate human HSCs has been reported.

The deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development.

Pluripotent cells of the mammalian embryo undergo extensive chromatin rewiring to prepare for lineage commitment after implantation. Repressive H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), is reallocated from large blankets in pre-implantation embryos to mark promoters of developmental genes. The regulation of this global redistribution of H3K27me3 is poorly understood.

UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex.

Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacity when cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, most notably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylase LSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulates the CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activity of UM171. The mechanism underlying the UM171-mediated loss of CoREST function remains undetermined.

Short-term cold stress and heat shock proteins in the crustacean Artemia franciscana.

In their role as molecular chaperones, heat shock proteins (Hsps) mediate protein folding thereby mitigating cellular damage caused by physiological and environmental stress. Nauplii of the crustacean Artemia franciscana respond to heat shock by producing Hsps; however, the effects of cold shock on Hsp levels in A. franciscana have not been investigated previously.

Test performance evaluation of SARS-CoV-2 serological assays.

Background: Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data.

Method: We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies.

Integration of Podiatric Medicine Within the Fracture Liaison Services Model.

Underlying bone metabolic disorders are often neglected when managing acute fractures. The term fracture liaison services (FLS) refers to models of care with the designated responsibility of comprehensive fracture management, including the diagnosis and treatment of osteoporosis. Although there is evidence of the effectiveness of FLS in reducing health-care costs and improving patient outcomes, podiatric practitioners are notably absent from described FLS models.

UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal.

Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function.