Identifying the Influences on Network Formation in Structural Isomers of Multifunctional Epoxies Using Near-Infrared Spectroscopy.

The network formation of four epoxy-rich formulations of the structural isomers of triglycidyl aminophenol and diaminodiphenyl sulfone has been monitored by using two complementary techniques, near-infrared spectroscopy and resin temperature monitoring. The differences between these networks have been described using the concentration of epoxide, primary amine, secondary amine, and tertiary amine functional groups and the actual temperature of the resin compared to the oven temperature during the cure schedule. It was found that initially, the 3,3'-diaminodiphenyl sulfone (33'DDS) formulations were more reactive and primary amines were completely consumed before the 4,4'-diaminodiphenyl sulfone (44'DDS) formulations. Secondary amines were formed more quickly in 33'DDS formulations compared to 44'DDS. The triglycidyl-meta-aminophenol (TGmAP) formulations consumed secondary amines and produced tertiary amines faster than the triglycidyl-para-aminophenol (TGpAP) formulations, indicating higher levels of cross-linking occurred earlier in the curing reaction. Etherification occurred much earlier in the TGpAP formulations than in the TGmAP formulations. Results suggest that internal cyclization occurs in the three meta isomer-containing formulations, and a corresponding lack of this effect in TGpAP/44'DDS results in a more homogeneous cross-linked network.

Site of Service Disparities Exist for Total Joint Arthroplasty.

BACKGROUND: The rate of outpatient total joint arthroplasty procedures, including those performed at ambulatory surgical centers (ASCs) and hospital outpatient departments, is increasing. The purpose of this study was to analyze if type of insurance is associated with site of service (in-patient vs outpatient) for total joint arthroplasty and adverse outcomes. MATERIALS AND METHODS: We identified patients undergoing unicompartmental knee arthroplasty (UKA), total knee arthroplasty (TKA), or total hip arthroplasty (THA) using Current Procedural Terminology codes in a national administrative claims database. Eligible patients were stratified by type of insurance (Medicaid, Medicare, private). The primary outcome was site of service. Secondary outcomes included general complications, procedural complications, and revision procedures. We evaluated the associations using adjusted multivariable logistic regression models. RESULTS: We identified 951,568 patients for analysis; 46,703 (4.9%) patients underwent UKA, 607,221 (63.8%) underwent TKA, and 297,644 (31.3%) underwent THA. Overall, 9.6% of procedures were outpatient. Patients with Medicaid were less likely than privately insured patients to receive outpatient UKA or THA (UKA: odds ratio [OR], 0.729 [95% CI, 0.640-0.829]; THA: OR, 0.625 [95% CI, 0.557-0.702]) but more likely than patients with Medicare to receive outpatient TKA or THA (TKA: OR, 1.391 [95% CI, 1.315-1.472]; THA: OR, 1.327 [95% CI, 1.166-1.506]). Patients with Medicaid were more likely to experience complications and revision procedures. CONCLUSION: Differences in site of service and complication rates following hip and knee arthroplasty exist based on type of insurance, suggesting a disparity in care. Further exploration of drivers of this disparity is warranted and can inform interventions (eg, progressive value-based payments) to support equity in orthopedic services. [Orthopedics. 2024;47(3):179-184.].

Targeting the WASF3 complex to suppress metastasis.

Wiskott-Aldrich syndrome protein family members (WASF) regulate the dynamics of the actin cytoskeleton, which plays an instrumental role in cancer metastasis and invasion. WASF1/2/3 forms a hetero-pentameric complex with CYFIP1/2, NCKAP1/1 L, Abi1/2/3 and BRK1 called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF1/2/3. Activation of the WRC enables actin networking and provides the mechanical force required for the formation of lamellipodia and invadopodia. Although the WRC drives cell motility essential for several routine physiological functions, its aberrant deployment is observed in cancer metastasis and invasion. WASF3 expression is correlated with metastatic potential in several cancers and inversely correlates with overall progression-free survival. Therefore, disruption of the WRC may serve as a novel strategy for targeting metastasis. Given the complexity involved in the formation of the WRC which is largely comprised of large protein-protein interfaces, there are currently no inhibitors for WASF3. However, several constrained peptide mimics of the various protein-protein interaction interfaces within the WRC were found to successfully disrupt WASF3-mediated migration and invasion. This review explores the role of the WASF3 WRC in driving metastasis and how it may be selectively targeted for suppression of metastasis.

In Silico Optimized Stapled Peptides Targeting WASF3 in Breast Cancer.

Wiskott-Aldrich Syndrome Protein Family (WASF) members regulate actin cytoskeletal dynamics, and WASF3 is directly associated with breast cancer metastasis and invasion. WASF3 forms a heteropentameric complex with CYFIP, NCKAP, ABI, and BRK1, called the WASF Regulatory Complex (WRC), which cooperatively regulates actin nucleation by WASF3. Since aberrant deployment of the WRC is observed in cancer metastasis and invasion, its disruption provides a novel avenue for targeting motility in breast cancer cells. Here, we report the development of a second generation WASF3 mimetic peptide, WAHMIS-2, which was designed using a combination of structure-guided design, homology modeling, and in silico optimization to disrupt binding of WASF3 to the WRC. WAHMIS-2 was found to permeate cells and inhibit cell motility, invasion, and MMP9 expression with greater potency than its predecessor, WAHM1. Targeted disruption of WASF3 from the WRC may serve as a useful strategy for suppression of breast cancer metastasis.

A novel murine in vivo model for acute hereditary angioedema attacks.

Hereditary Angioedema (HAE) is a rare genetic disease generally caused by deficiency or mutations in the C1-inhibitor gene, SERPING1, a member of the Serpin family. HAE results in acute attacks of edema, vasodilation, GI pain and hypotension. C1INH is a key inhibitor of enzymes controlling complement activation, fibrinolysis and the contact system. In HAE patients, contact system activation leads to uncontrolled production of bradykinin, the vasodilator responsible for the characteristic symptoms of HAE. In this study, we present the first physiological in vivo model to mimic acute HAE attacks. We evaluate hypotension, one of the many hallmark symptoms of acute HAE attacks using Serping1 deficient mice (serping1-/-) and implanted telemetry. Attacks were induced by IV injection of a silica nanoparticle (SiNP) suspension. Blood pressure was measured in real time, in conscious and untethered mice using implanted telemetry. SiNP injection induced a rapid, reversible decrease in blood pressure, in the presence of angiotensin converting enzyme (ACE) inhibition. We also demonstrate that an HAE therapeutic, ecallantide, can prevent HAE attacks in this model. The in vivo murine model described here can facilitate the understanding of acute HAE attacks, support drug development and ultimately contribute to improved patient care.

Leveraging the Value of CDISC SEND Data Sets for Cross-Study Analysis: Incidence of Microscopic Findings in Control Animals.

Implementation of the Clinical Data Interchange Standards Consortium (CDISC)'s Standard for Exchange of Nonclinical Data (SEND) by the United States Food and Drug Administration Center for Drug Evaluation and Research (US FDA CDER) has created large quantities of SEND data sets and a tremendous opportunity to apply large-scale data analytic approaches. To fully realize this opportunity, differences in SEND implementation that impair the ability to conduct cross-study analysis must be addressed. In this manuscript, a prototypical question regarding historical control data (see Table of Contents graphic) was used to identify areas for SEND harmonization and to develop algorithmic strategies for nonclinical cross-study analysis within a variety of databases. FDA CDER's repository of >1800 sponsor-submitted studies in SEND format was queried using the statistical programming language R to gain insight into how the CDISC SEND Implementation Guides are being applied across the industry. For each component needed to answer the question (defined as "query block"), the frequency of data population was determined and ranged from 6 to 99%. For fields populated <90% and/or that did not have Controlled Terminology, data extraction methods such as data transformation and script development were evaluated. Data extraction was successful for fields such as phase of study, negative controls, and histopathology using scripts. Calculations to assess accuracy of data extraction indicated a high confidence in most query block searches. Some fields such as vehicle name, animal supplier name, and test facility name are not amenable to accurate data extraction through script development alone and require additional harmonization to confidently extract data. Harmonization proposals are discussed in this manuscript. Implementation of these proposals will allow stakeholders to capitalize on the opportunity presented by SEND data sets to increase the efficiency and productivity of nonclinical drug development, allowing the most promising drug candidates to proceed through development.

A high Q piezoelectric resonator as a portable VLF transmitter.

Very low frequency communication systems (3 kHz-30 kHz) enable applications not feasible at higher frequencies. However, the highest radiation efficiency antennas require size at the scale of the wavelength (here, >1 km), making portable transmitters extremely challenging. Facilitating transmitters at the 10 cm scale, we demonstrate an ultra-low loss lithium niobate piezoelectric electric dipole driven at acoustic resonance that radiates with greater than 300x higher efficiency compared to the previous state of the art at a comparable electrical size. A piezoelectric radiating element eliminates the need for large impedance matching networks as it self-resonates at the acoustic wavelength. Temporal modulation of this resonance demonstrates a device bandwidth greater than 83x beyond the conventional Bode-Fano limit, thus increasing the transmitter bitrate while still minimizing losses. These results will open new applications for portable, electrically small antennas.

GGF2 (Nrg1-ß3) treatment enhances NG2+ cell response and improves functional recovery after spinal cord injury.

The adult spinal cord contains a pool of endogenous glial precursor cells, which spontaneously respond to spinal cord injury (SCI) with increased proliferation. These include oligodendrocyte precursor cells that express the NG2 proteoglycan and can differentiate into mature oligodendrocytes. Thus, a potential approach for SCI treatment is to enhance the proliferation and differentiation of these cells to yield more functional mature glia and improve remyelination of surviving axons. We previously reported that soluble glial growth factor 2 (GGF2)- and basic fibroblast growth factor 2 (FGF2)-stimulated growth of NG2(+) cells purified from injured spinal cord in primary culture. This study examines the effects of systemic administration of GGF2 and/or FGF2 after standardized contusive SCI in vivo in both rat and mouse models. In Sprague-Dawley rats, 1 week of GGF2 administration, beginning 24 h after injury, enhanced NG2(+) cell proliferation, oligodendrogenesis, chronic white matter at the injury epicenter, and recovery of hind limb function. In 2',3'-cyclic-nucleotide 3'-phosphodiesterase-enhanced green fluorescent protein mice, GGF2 treatment resulted in increased oligodendrogenesis and improved functional recovery, as well as elevated expression of the stem cell transcription factor Sox2 by oligodendrocyte lineage cells. Although oligodendrocyte number was increased chronically after SCI in GGF2-treated mice, no evidence of increased white matter was detected. However, GGF2 treatment significantly increased levels of P0 protein-containing peripheral myelin, produced by Schwann cells that infiltrate the injured spinal cord. Our results suggest that GGF2 may have therapeutic potential for SCI by enhancing endogenous recovery processes in a clinically relevant time frame.

Pregnenolone sulfate induces NMDA receptor dependent release of dopamine from synaptic terminals in the striatum.

Neuromodulators that alter the balance between lower-frequency glutamate-mediated excitatory and higher-frequency GABA-mediated inhibitory synaptic transmission are likely to participate in core mechanisms for CNS function and may contribute to the pathophysiology of neurological disorders such as schizophrenia and Alzheimer's disease. Pregnenolone sulfate (PS) modulates both ionotropic glutamate and GABA(A) receptor mediated synaptic transmission. The enzymes necessary for PS synthesis and degradation are found in brain tissue of several species including human and rat, and up to 5 nM PS has been detected in extracts of postmortem human brain. Here, we ask whether PS could modulate transmitter release from nerve terminals located in the striatum. Superfusion of a preparation of striatal nerve terminals comprised of mixed synaptosomes and synaptoneurosomes with brief-duration (2 min) pulses of 25 nM PS demonstrates that PS increases the release of newly accumulated [3H]dopamine ([3H]DA), but not [14C]glutamate or [3H]GABA, whereas pregnenolone is without effect. PS does not affect dopamine transporter (DAT) mediated uptake of [3H]DA, demonstrating that it specifically affects the transmitter release mechanism. The PS-induced [3H]DA release occurs via an NMDA receptor (NMDAR) dependent mechanism as it is blocked by D-2-amino-5-phosphonovaleric acid. PS modulates DA release with very high potency, significantly increasing [3H]DA release at PS concentrations as low as 25 pM. This first report of a selective direct enhancement of synaptosomal dopamine release by PS at picomolar concentrations via an NMDAR dependent mechanism raises the possibility that dopaminergic axon terminals may be a site of action for this neurosteroid.