Inhibition of leucine-rich repeat kinase 2 (LRRK2) kinase activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. ...Herein, we describe the optimization of a novel series of potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1
-indazole type I (ATP competitive) LRRK2 inhibitors. Type I ATP-competitive kinase physicochemical properties were integrated with CNS drug-like properties through a combination of structure-based drug design and parallel medicinal chemistry enabled by sp
-sp
cross-coupling technologies. This resulted in the discovery of a unique sp
-rich spirocarbonitrile motif that imparted extraordinary potency, pharmacokinetics, and favorable CNS drug-like properties. The lead compound,
, demonstrated exceptional on-target potency in human peripheral blood mononuclear cells, excellent off-target kinase selectivity, and good brain exposure in rat, culminating in a low projected human dose and a pre-clinical safety profile that warranted advancement toward pre-clinical candidate enabling studies.
Peer acceptance has been consistently linked with academic performance. Acceptance, however, is often a measure of overall peers’ impressions of a child, and not their own interest in being friends. ...Friendship nominations reflect a stronger, more persistent, peer endorsement than acceptance, and rejection nominations, similarly, reflect more direct negative feelings. In addition, most data on these relationships are from schools with children from middle class backgrounds who are predominantly White. This study focuses on friendship and rejection nominations among a sample of predominantly African American children (N = 221) from low socioeconomic backgrounds in a large city in the Northeastern United States. All students in 10 classrooms from Grades 3 to 5 (n = 123) and 6–8 (n = 98), completed friendship and rejection measures, as well as standardized academic achievement tests, each Spring for 2 years. Reading and math scores increased for both groups over time. Friend and rejection nominations increased over time for younger students but decreased in the older group. Among younger students, friend nominations in the first year were related to reading performance in the second year. However, there were no relations between social variables in Year 1 and standardized test scores in Year 2 within the older grade group. Thus, focusing on both social and academic involvement in the elementary years may help improve student performance.
Anorectal malformations (ARM) are associated with congenital anomalies of the spine, but the impact of a minor spinal cord dysraphism (mSCD) on fecal continence in the setting of ARM remains unclear.
...A retrospective review was performed utilizing data from the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) registry. The patient cohort was reviewed for ARM type, mSCD screening/incidence/neurosurgical intervention and age-based BMP utilization.
987 patients with ARM were categorized into mild (38%), moderate (32%) or complex (19%). 694 (70%) had normal spinal (NS) status. 271 (27.5%) patients had mSCD. MRI alone (49%) was the most common screening test for mSCD. US screening had a positive predictive value of 86.3% and a negative predictive value of 67.1%. Surgical intervention rates for mSCD ranged between 13% and 77% at a median age of 0.6–5.2 years. 726 (73.6%) patients were prescribed BMP (74.4% NS, 77.5% mSCD). Laxatives were most utilized BMP in all groups <5yo. ≥5yo, enema utilization increased with ARM complexity independent of spine status (with or without neurosurgical intervention). Neurosurgical intervention did not affect BMP utilization at any age or with any ARM when mSCD was identified.
MSCD influence on bowel function in the setting ARM remains unclear. No significant impact of mSCD was noted on ARM patient bowel management program utilization. Variability exists within PCPLC site with screening and intervention for mSCD in patients with ARM. Future studies with standardized care may be needed to elucidate the true impact of mSCD on long term patient outcomes in ARM patients.
Retrospective Comparative Study.
III.
Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the ...functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care.
A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions.
Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic.
Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.
Contouring Collaborative for Consensus in Radiation Oncology (C3RO) is a crowdsourced challenge engaging radiation oncologists across various expertise levels in segmentation. An obstacle to ...artificial intelligence (AI) development is the paucity of multiexpert datasets; consequently, we sought to characterize whether aggregate segmentations generated from multiple nonexperts could meet or exceed recognized expert agreement.
Participants who contoured
region of interest (ROI) for the breast, sarcoma, head and neck (H&N), gynecologic (GYN), or gastrointestinal (GI) cases were identified as a nonexpert or recognized expert. Cohort-specific ROIs were combined into single simultaneous truth and performance level estimation (STAPLE) consensus segmentations.
ROIs were evaluated against
contours using Dice similarity coefficient (DSC). The expert interobserver DSC (
) was calculated as an acceptability threshold between
and
. To determine the number of nonexperts required to match the
for each ROI, a single consensus contour was generated using variable numbers of nonexperts and then compared to the
.
For all cases, the DSC values for
versus
were higher than comparator expert
for most ROIs. The minimum number of nonexpert segmentations needed for a consensus ROI to achieve
acceptability criteria ranged between 2 and 4 for breast, 3 and 5 for sarcoma, 3 and 5 for H&N, 3 and 5 for GYN, and 3 for GI.
Multiple nonexpert-generated consensus ROIs met or exceeded expert-derived acceptability thresholds. Five nonexperts could potentially generate consensus segmentations for most ROIs with performance approximating experts, suggesting nonexpert segmentations as feasible cost-effective AI inputs.
The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the ...Ptger3 gene, in the loss of functional β-cell mass in Type 2 diabetes (T2D). The primary endogenous EP3 ligand is the arachidonic acid metabolite prostaglandin E2 (PGE2). Expression of the pancreatic islet EP3 and PGE2 synthetic enzymes and/or PGE2 excretion itself have all been shown to be upregulated in primary mouse and human islets isolated from animals or human organ donors with established T2D compared to nondiabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.
Many Latinas encounter negative expectations regarding their chances of attending college in the United States. Dominant narratives legitimize these structural and relational negations by depicting ...Latinas as a group that voluntarily lowers their expectations of themselves as they move through the education pipeline. To increase the representation of Latinas on college campuses, postsecondary institutions are financially incented to become Hispanic-Serving Institutions (HSIs). Through the lens of resilient resistance, this qualitative study asks the following questions: (a) How do first-generation college-going Latinas define their educational expectations for postsecondary education? and (b) How do first-generation college-going Latinas enact their educational expectations through the practice of resilient resistance at a Hispanic-Serving Institution? Through the stories of four Latina undergraduates at a 4-year HSI in the American Southwest, this study contends that participants' refusal to accept other people's disbelief ignited their postsecondary education pursuits. As their own educational expectations were overrun by the expectational status quo, the participants utilized their cultural values of familismo to enact resilient resistance as they navigated in-between institutional spaces. This article calls upon universities to establish equitable conditions within Latinas' educational environments and to actively direct resources toward their ability to leverage human agency, build coalitions, and recenter their own expectations for college success.
Introduction
Strategies are needed to improve the efficacy of paraprofessional home visitors for pregnant women in the United States. This study evaluates the maternal and child outcomes when ...evidence-based practices (EBP) are replicated with flexibility, rather than fidelity to a manualized intervention.
Methods
Pregnant mothers (N = 203) in five clinics were recruited in the waiting rooms and randomized to standard clinic care as the control condition (n = 104) or standard care plus home visiting (n = 99). Home visitors (n = 9) were selected, trained in foundational skills common to EBP and four problem domains (weight control, breastfeeding, daily habits, and depression). Independent interviewers assessed targeted outcomes at birth (82%) and 6 months later (83%).
Results
: Home visitors, called Mentor Mothers MM, made an average of 14.9 home visits or telephone contacts (SD = 9; total contacts = 1491) addressing maternal daily habits, breastfeeding, and depression. Intervention and control mothers were similar in weight, Body Mass Index (BMI), depression and social support at baseline and 6 months later. The percentage of low birth weight babies was similar; intervention infants’ growth (weight/height Z score) tended to be significantly better compared to the control condition.
Discussion
: There are many explanations for the failure to find significant benefits: insufficient statistical power; the benefits of repeated assessments by warm, supportive peers to improve outcomes; or the failure of EBP and the need to maintain replication with fidelity. All study mothers had better outcomes than documented among comparable published samples of low-income, Latina and Korean–American mothers in Los Angeles, CA. ClinicalTrials.gov registration NCT01687634.
The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we ...describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound
1
by modifying the heteroaryl C-H hinge and linker regions. This resulted in compound
12
which advanced deep into our research operating plan (ROP) before heteroaryl aniline metabolite
14
was characterized as Ames mutagenic, halting its progression. Strategic modifications to our ROP were made to enable early de-risking of putative aniline metabolites or hydrolysis products for mutagenicity in Ames. This led to the discovery of 3,5-diaminopyridine
15
and 4,6-diaminopyrimidine
16
as low risk for mutagenicity (defined by a 3-strain Ames negative result). Analysis of key matched molecular pairs
17
and
18
led to the prioritization of the 3,5-diaminopyridine sub-series for further optimization due to enhanced rodent brain penetration. These efforts culminated in the discovery of ethyl trifluoromethyl pyrazole
23
with excellent LRRK2 potency and expanded selectivity
versus
off-target CLK2.
The evolution of picolinamide derived LRRK2 inhibitors with improved kinase off target selectivity and de-risked for AMES mutagenicity.
ABSTRACT
We present BVRI and unfiltered (Clear) light curves of 70 stripped-envelope supernovae (SESNe), observed between 2003 and 2020, from the Lick Observatory Supernova Search follow-up program. ...Our SESN sample consists of 19 spectroscopically normal SNe Ib, 2 peculiar SNe Ib, six SNe Ibn, 14 normal SNe Ic, 1 peculiar SN Ic, 10 SNe Ic-BL, 15 SNe IIb, 1 ambiguous SN IIb/Ib/c, and 2 superluminous SNe. Our follow-up photometry has (on a per-SN basis) a mean coverage of 81 photometric points (median of 58 points) and a mean cadence of 3.6 d (median of 1.2 d). From our full sample, a subset of 38 SNe have pre-maximum coverage in at least one passband, allowing for the peak brightness of each SN in this subset to be quantitatively determined. We describe our data collection and processing techniques, with emphasis toward our automated photometry pipeline, from which we derive publicly available data products to enable and encourage further study by the community. Using these data products, we derive host-galaxy extinction values through the empirical colour evolution relationship and, for the first time, produce accurate rise-time measurements for a large sample of SESNe in both optical and infrared passbands. By modelling multiband light curves, we find that SNe Ic tend to have lower ejecta masses and lower ejecta velocities than SNe Ib and IIb, but higher 56Ni masses.
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