The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation.

A time- and single-cell-resolved model of murine bone marrow hematopoiesis.

The paradigmatic hematopoietic tree model is increasingly recognized to be limited, as it is based on heterogeneous populations largely defined by non-homeostatic assays testing cell fate potentials. Here, we combine persistent labeling with time-series single-cell RNA sequencing to build a real-time, quantitative model of in vivo tissue dynamics for murine bone marrow hematopoiesis. We couple cascading single-cell expression patterns with dynamic changes in differentiation and growth speeds.

Trends in carbazole synthesis - an update (2013-2023).

The interest of scientists in the carbazole core has risen steadily over the last 30 years, particularly over the last decade given its presence in several active pharmaceutical ingredients, functional materials and a wide range of biologically active natural products. The continuous development of more efficient, more (regio-)selective and "greener" methodologies to access the carbazole core is thus imperative. This review compares and evaluates synthetic strategies towards the carbazole core that have been reported since 2013, with a focus on their applicability towards the total synthesis of carbazole-containing natural products.

Barriers and Translational Solutions to Improving Community Living Outcomes among People of Color with Disabilities with Opioid Use Disorder: A Focus Group Perspective.

This investigation examined vocational rehabilitation, substance abuse, and mental health service providers' perceptions about barriers and potentially translational solutions to poor community living outcomes for people of color with disabilities (i.e., African Americans, Latinx, Native Americans and Alaskan Natives, Asian Americans, and Pacific islanders) who have opioid use disorder.

Community Living Outcome Factors for People of Color with Disabilities and Concomitant Opioid Use Disorder: A Scoping Review.

This scoping review mapped the pertinent extant published and grey literature and policy to assess factors that promote positive community living outcomes among people of color with disabilities and concomitant opioid use disorder (OUD) in the United States (U.S.).

Factors in Utilization of Telehealth Treatment by Rural African-Americans with Opioid Use Disorder and Disabilities.

This study explored factors that impact telehealth service utilization for treatment of African Americans with disabilities with opioid use disorder in rural communities. A focus group was conducted involving 12 different mental health, substance use, and rehabilitation counseling professionals. The analysis was completed using NVivo (Version 12).

Assistive Technology Workplace Accommodation and Employment among Diverse Populations with Disabilities: Does Race/Ethnicity Matter?

The purpose of this study was to examine the relationship between assistive technology workplace accommodation (AT-WA) usage and employment status among racial/ethnic populations with disabilities. Chi-square tests and logistic regression were used to analyze secondary data from the 2015 Kessler Foundation National Employment and Disability Survey (KFNEDS). Results indicated that significantly more consumers who used AT-WA were currently working, and a significantly greater proportion of them were White.

CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.

Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging.

Race Differences in Postacute Physical Therapy Utilization and Patient-Reported Function After Total Knee Arthroplasty.

Objective: This observational cohort study included patients of Black and White race and non-Hispanic ethnicity with end-stage knee osteoarthritis who were scheduled to receive total knee arthroplasty (TKA) surgery. Our objective was to examine whether race differences exist in the use of physical therapy (PT) across all postacute settings and to examine patient-reported physical function following TKA.

Methods: We collected pre- and postoperative physical function data and postoperative rehabilitation data on 104 Black and White individuals undergoing TKA.

Exploring Race Differences in Satisfaction With Rehabilitation Following Total Knee Arthroplasty: A Qualitative Study.

Background: The purpose of this qualitative focus group study was to explore race differences in the rehabilitation experience and satisfaction with rehabilitation following total knee arthroplasty (TKA).

Method: We conducted a series of qualitative focus group discussions with groups of non-Hispanic White and non-Hispanic Black older adults who recently underwent TKA. We used grounded theory approach, which asks the researcher to develop theory from the data that are collected.

An entry to 2-(cyclobut-1-en-1-yl)-1-indoles through a cyclobutenylation/deprotection cascade.

A transition-metal-free strategy for the synthesis of 2-(cyclobut-1-en-1-yl)-1H-indoles under mild conditions is described herein. A series of substituted 2-(cyclobut-1-en-1-yl)-1H-indoles are accessed by a one-pot cyclobutenylation/deprotection cascade from N-Boc protected indoles. Preliminary experimental and density functional theory calculations suggest that a Boc-group transfer is involved in the underlying mechanism.

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells.

Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG-dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis.

Recent advances in the synthesis of α-amino ketones.

Due to the importance of the amino ketone motif in synthetic and medicinal chemistry, the number of protocols developed in recent years has considerably increased. This review serves to collate and critically evaluate novel methodologies published since 2011 towards this high value synthon. The chapters are divided by the requisite functionality in the starting material, and an emphasis is placed on discussing functional group compatibility and resultant product substitution patterns.

Oxidative Deconstruction of Azetidinols to α-Amino Ketones.

A silver-mediated synthesis of α-amino ketones via the oxidative deconstruction of azetidinols has been developed using a readily scalable protocol with isolated yields up to 80%. The azetidinols are easily synthesized in one step and can act as protecting groups for these pharmaceutically relevant synthons. Furthermore, mechanistic insights are presented and these data have revealed that the transformation is likely to proceed through the β-scission of an alkoxy radical, followed by oxidation and C-N cleavage of the resulting α-amido radical.

Transition-Metal-Free Access to Heteroaromatic-Fused 4-Tetralones by the Oxidative Ring Expansion of the Cyclobutanol Moiety.

Advances in the transition-metal-free cyclobutanol ring expansion to 4-tetralones under -bromosuccinimide mediation are described. We have expanded the scope of this ring expansion methodology and investigated the effect substituents on the aromatic ring, and the cyclobutanol moiety, have on the outcome of the reaction. Limitations with certain substituents on the cyclobutanol moiety are also described.

Targeting the RNA mA Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA mA reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse mA transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis.

Bloodstream Infection in a Boy With Pediatric Acute-Onset Neuropsychiatric Syndrome.

Background: With the advent of more sensitive culture and molecular diagnostic testing modalities, spp. infections have been documented in blood and/or cerebrospinal fluid specimens from patients with diverse neurological symptoms. Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by an unusually abrupt onset of cognitive, behavioral, or neurological symptoms.

Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring Expansion to 4-Tetralones.

A facile and transition-metal-free ring expansion of the cyclobutanol moiety to 4-tetralones fused to heteroaromatic systems is described. The oxidative ring expansion proceeds rapidly and regioselectively through mediation by N-bromosuccinimide and acetonitrile in satisfactory to good yields. The preparation of precursors and the ring expansion have proven to be scalable and are straightforward to carry out.

Why Public Health Researchers Should Consider Using Disability Data from the American Community Survey.

The United States (US) federal government allocates hundreds of billions of dollars to provide resources to Americans with disabilities, older adults, and the poor. The American Community Survey (ACS) influences the distribution of those resources. The specific aim of the project is to introduce health researchers to Public Use Microdata Sample file from 2009 to 2011.

An Approach to the Core of Lactonamycin.

A cascade reaction has been developed for the synthesis of lactonamycin. In this paper, we demonstrate that a transition-metal-free thermal ene-diyne cyclization can be used for the construction of the entire core of the antibiotic lactonamycin and anticancer agent lactonamycin Z.

Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure.

Development of the Telehealth Usability Questionnaire (TUQ).

Current telehealth usability questionnaires are designed primarily for older technologies, where telehealth interaction is conducted over dedicated videoconferencing applications. However, telehealth services are increasingly conducted over computer-based systems that rely on commercial software and a user supplied computer interface. Therefore, a usability questionnaire that addresses the changes in telehealth service delivery and technology is needed.

Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension.

A New Approach for the Synthesis of Highly Substituted Aromatic Rings: The Alkyne-Mediated Approach.

Pentasubstituted aromatic rings serve as templates for drug design and can be conveniently prepared by the thermolysis of suitably substituted alkynes under microwave conditions.