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Alzheimer's disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There is considerable variation in the progression of clinical symptoms and pathology in humans, highlighting the importance of genetic diversity in the study of AD. To address this, we analyze cell composition and amyloid-beta deposition of 6- and 14-month-old AD-BXD mouse brains. We utilize the analytical QUINT workflow- a suite of software designed to support atlas-based quantification, which we expand to deliver a highly effective method for registering and quantifying cell and pathology changes in diverse disease models. In applying the expanded QUINT workflow, we quantify near-global age-related increases in microglia, astrocytes, and amyloid-beta, and we identify strain-specific regional variation in neuron load. To understand how individual differences in cell composition affect the interpretation of bulk gene expression in AD, we combine hippocampal immunohistochemistry analyses with bulk RNA-sequencing data. This approach allows us to categorize genes whose expression changes in response to AD in a cell and/or pathology load-dependent manner. Ultimately, our study demonstrates the use of the QUINT workflow to standardize the quantification of immunohistochemistry data in diverse mice, - providing valuable insights into regional variation in cellular load and amyloid deposition in the AD-BXD model., (© 2024. The Author(s).)

Background: Dual airbags are required to be installed and available for use in all motor vehicles since 1997. The National Highway Traffic Safety Administration reported that 50,457 lives were saved by airbags from 1987 to 2017; however, airbag deployment can cause injuries, including thermal and chemical burns, hyperpigmentation, and dysaesthesia. There is little information available in the literature regarding differences in outcomes between promptly visiting a plastic surgeon and waiting for treatment, especially as an injury may not be immediately apparent or patients may not know that airbag burn injuries may be delayed in presenting., Methods: This is a retrospective cohort pilot study conducted among 14 patients who presented to a plastic surgeon between January 1, 2019 and June 30, 2022 owing to injuries from airbag deployment. An early visit was considered ≤30 days, and a late visit was >30 days. Other variables collected included age, sex, Fitzpatrick skin type, smoking status, comorbidities, type of injury, injury site, pain status, hyper/hypopigmentation, dysaesthesia, epithelialization, and improvements in pain, pigmentation, and dysaesthesia from treatment., Results: The mean age was 36.0 years (standard deviation (SD) 17.9). The majority were female (85.7%), non-smokers (87.5%), and not diabetic (75.0%). Only six patients (42.9%) visited their doctor within one month of injury. Most patients experienced dysaesthesia (85.7%) and pain (71.4%). Thirteen of the 14 patients had hyperpigmentation or hyperemia, and one had hypopigmentation. Full or slight epithelialization was seen in 35.7%, and nine of the 14 patients had no epithelialization. Ongoing issues were a factor for 64.3% of these patients; 42.9% had ongoing issues with hyperpigmentation. A full recovery was seen in 28.6% of the patients. The patients who saw the plastic surgeon by day 30 or less (early) from the time of injury had a 66.7% improvement in pigmentation and 33.3% resolution in pain. Of those who went to the surgeon beyond 30 days (late), 25% had improvement in pigmentation and 37.5% had resolution of pain. Improvement in dysaesthesia occurred in both groups, but those who saw the plastic surgeon early had 33.3% resolution, while 37.5% of those who went late improved. Of those who went late to the surgeon, only 12.5% had epithelialization, while 66.7% of those who went within 30 days showed signs of (full or slight) epithelialization., Conclusion: Patients involved in motor vehicle collisions (MVCs) should be informed of the delayed fashion in which airbag burns can develop. An ostensibly mild burn may portend long-term consequences, especially if such injuries are not addressed in a prompt manner. Our study demonstrates how airbag burn injuries and their sequelae are best addressed with early care., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Schalet et al.)

Purpose: Nonadherence is a significant issue in cancer care, especially as more oral therapies become available. Measuring and optimizing adherence to such therapies is challenging. In this study, we tested a novel technology that records real-time medication-taking behavior from a smart prescription bottle and can communicate with patients via text message to intervene in cases of nonadherence., Methods: We conducted a 28-patient pilot study to assess the feasibility of this technology in measuring and improving adherence in patients taking capecitabine, an oral chemotherapy agent with a complex, cyclical regimen. The study had a preintervention stage, during which patients were monitored, and an intervention stage, during which the text messaging intervention was enabled., Results: During preintervention, patients had an average self-adherence of 89%, and during post intervention, they had an average adherence of 90%. We defined three categories of patients by change in adherence: category 1 (> 8%), category 2 (-8% to 8%), and category 3 (< -8%). Patients in category 1 tended to live in regions with lower average household income (mean = $58,937 in US dollars [USD]) than those in category 2 (mean = $77,482 USD) and category 3 (mean = $90,972 USD). Of poststudy survey respondents, most indicated that they would want to continue using this technology and that they would recommend it to others., Conclusion: This novel technology is able to monitor, measure, and intervene for patients taking capecitabine in real time. Adherence overall was high, and some patients appeared to benefit more from text-message interventions. Future work should focus on patients deemed high risk for nonadherence., Competing Interests: Rachel De JesusStock and Other Ownership Interests: SMRxT Inc, AbbvieConsulting or Advisory Role: HivePath Michael J. HufferEmployment: SMRxT IncLeadership: SMRxT IncStock and Other Ownership Interests: SMRxT Inc Sarah S. MougalianStock and Other Ownership Interests: Gilead Sciences, Coronado Biosciences, RocheConsulting or Advisory Role: Eisai, Puma Biotechnology, CelgeneResearch Funding: Genentech, PfizerNo other potential conflicts of interest were reported.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6 . The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.

Background: Cannabis contains Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD) as the primary constituents responsible for pharmacological activity. However, there are numerous additional chemically-related structures to Δ 9 -THC and CBD that are pharmacologically active and may influence the pharmacological properties of Δ 9 -THC and CBD. This study chemically characterized the cannabinoid constituents in a series of cannabis chemovar extracts and investigated the potential cannabinoid entourage effect in two behavioral assays., Methods: Six chemovar extracts were compared to pure Δ 9 -THC, CBD and morphine for effects on the following behavioral assays in mice: hot plate and tail suspension. The battery of behavioral tests was conducted post intravenous administration of cannabis chemovar extract. Cannabinoid profiles of extracts were analyzed using high performance liquid chromatography. Cannabis extracts were administered at equal doses of Δ 9 -THC to investigate the role of their cannabinoid profiles in modulating the effects of Δ 9 -THC. Dose response curves were fit using a log[inhibitor] vs response three parameter model and differences between group means were determined using a one-way ANOVA followed by a post hoc test., Results: Cannabis chemovars tested in this study exhibited substantially different cannabinoid profiles. All chemovars produced dose-dependent immobility in the tail suspension assay and dose-dependent antinociception in the hot plate assay. The maximum antinociceptive effect and ED50 was comparable between cannabis chemovars and Δ 9 -THC. Two cannabis chemovars produced significantly greater immobility in the tail suspension test, with no significant differences in ED50., Conclusions: Commercially available cannabis chemovars vary widely in cannabinoid content, but when equalized for Δ 9 -THC content, they produce similar behavioral effects with two exceptions. These findings provide only limited support for the entourage hypothesis. Further studies are necessary to characterize the nature of these pharmacological differences between cannabis chemovars and pure Δ 9 -THC.

To interpret the environment, our brain must evaluate external stimuli against internal representations from past experiences. How primary (S1) and secondary (S2) somatosensory cortices process stimuli depending on recent experiences is unclear. Using simultaneous multi-area population imaging of projection neurons and focal optogenetic inactivation, we studied mice performing a whisker-based working memory task. We find that activity reflecting a current stimulus, the recollection of a previous stimulus (cued recall), and the stimulus category are distributed across S1 and S2. Despite this overlapping representation, S2 is important for processing cued recall responses and transmitting these responses to S1. S2 network properties differ from S1, wherein S2 persistently encodes cued recall and the stimulus category under passive conditions. Although both areas encode the stimulus category, only information in S1 is important for task performance through pathways that do not necessarily include S2. These findings reveal both distributed and segregated roles for S1 and S2 in context-dependent sensory processing., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

The Plasmodium proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors. Here, we report further a structure-activity relationship study of AsnEDAs for selective inhibition of Pf20S over human proteasomes. Additionally, we show new mutation that conferred resistance to AsnEDAs and collateral sensitivity to an inhibitor of the Pf20S β2 subunit, the same as previously identified resistant mutation. This resistance could be overcome through the use of the structure-guided inhibitor design. Collateral sensitivity to inhibitors among respective proteasome subunits underscores the potential value of treating malaria with combinations of inhibitors of different proteasome subunits to minimize the emergence of drug resistance.

Avulsion fractures involving the radial wrist extensor tendons are extremely rare. Only 8 avulsion fractures of the extensor carpi radialis longus and 7 avulsion fractures of the extensor carpi radialis brevis have been previously reported. We know of no case involving an isolated avulsion fracture of the base of the third metacarpal where the extensor carpi radialis brevis attachment to the fracture fragment was still completely intact. This article reports a patient with an isolated avulsion fracture of the extensor carpi radialis brevis insertion treated by open reduction and internal fixation. The avulsion fracture was the result of a poor punching technique. The patient healed uneventfully, and returned to full painless activity. The senior author (S.W.B.) of this article is a former Tae Kwon Doe instructor and includes some editorial comments on proper technique for punching to avoid injury.

A recombinant form of human rhIL-7 was overexpressed in Escherichia coli HMS174 (DE3) pLysS under the control of a T7 promoter. The resulting insoluble inclusion bodies were separated from cellular debris by cross-flow filtration and solubilized by homogenization with 6 M guanidine HCl. Attempts at refolding rhIL-7 from solubilized inclusion bodies without prior purification of monomeric, denatured rhIL-7 were not successful. Denatured, monomeric rhIL-7 was therefore initially purified by size-exclusion chromatography using Prep-Grade Pharmacia Superdex 200. Correctly folded rhIL-7 monomer was generated by statically refolding the denatured protein at a final protein concentration of 80-100 microg/ml in 100 mM Tris, 2mM EDTA, 500 mM L-arginine, pH 9.0, buffer with 0.55 g/l oxidized glutathione at 2-8 degrees C for at least 48 h. The refolded rhIL-7 was subsequently purified by low-pressure liquid chromatography, using a combination of hydrophobic interaction, cation-exchange, and size-exclusion chromatography. The purified final product was >95% pure by SDS-PAGE stained with Coomassie brilliant blue, high-pressure size-exclusion chromatography (SEC-HPLC), and reverse-phase HPLC. The endotoxin level was <0.05 EU/mg. The final purified product was biologically active in a validated IL-7 dependent pre-B-cell bioassay. In anticipation of human clinical trials, this material is currently being evaluated for safety and efficacy in non-human primate toxicology studies.

Bibliography database managers (BDMs) are used to manage information resources: specifically, to maintain a database of references and create bibliographies and reference lists for written works. This comparative review provides an overview of BDMs and capsule reviews of five programs: EndNote Plus 2.0; Library Master 3.0; Papyrus 7.0.11; Pro-Cite 2.2.1; and Reference Manager 6.02.