The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Crystal Structure of Caryolan-1-ol Synthase, a Sesquiterpene Synthase Catalyzing an Initial Anti-Markovnikov Cyclization Reaction.

In a continuing effort to understand reaction mechanisms of terpene synthases catalyzing initial anti-Markovnikov cyclization reactions, we solved the X-ray crystal structure of (+)-caryolan-1-ol synthase (CS) from Streptomyces griseus , with and without an inactive analog of the FPP substrate, 2-fluorofarnesyl diphosphate (2FFPP), bound in the active site of the enzyme. The CS-2FFPP complex was solved to 2.65 Å resolution and showed the ligand in a linear, elongated orientation, incapable of undergoing the initial cyclization event to form a bond between carbons C1 and C11. Intriguingly, the apo CS structure (2.2 Å) also had electron density in the active site, in this case density that was well fit with a curled-up tetraethylene glycol molecule presumably recruited from the crystallization medium. The density was also well fit by a molecule of farnesene suggesting that the structure may mimic an intermediate along the reaction coordinate. The curled-up conformation of tetraethylene glycol was accompanied by dramatic rotamer shifts among active-site residues. Most notably, W56 was observed to undergo a 90° rotation between the 2FFPP complex and apo-enzyme structures, suggesting that it contributes to steric interactions that help curl the tetraethylene glycol molecule in the active site, and by extension perhaps also a derivative of the FPP substrate in the normal course of the cyclization reaction. In support of this proposal, the CS W56L variant lost the ability to cyclize the FPP substrate and produced only the linear terpene products farnesol and α- and ß-farnesene.

Sleep Quality Moderates the Associations between Cardiorespiratory Fitness and Hippocampal and Entorhinal Volume in Middle-Aged and Older Adults.

INTRODUCTION/PURPOSE: As individuals age, the entorhinal cortex (ERC) and hippocampus-crucial structures for memory-tend to atrophy, with related cognitive decline. Simultaneously, lifestyle factors that can be modified, such as exercise and sleep, have been separately linked to slowing of brain atrophy and functional decline. Yet, the synergistic impact of fitness and sleep on susceptible brain structures in aging adults remains uncertain. METHODS: We examined both independent and interactive associations of fitness and subjective sleep quality with regard to ERC thickness and hippocampal volume in 598 middle-aged and older adults from the Human Connectome Lifespan Aging Project. Cardiorespiratory fitness was assessed using the 2-minute walk test (2MWT), while subjective sleep quality was measured with the continuous Pittsburgh Sleep Quality Index (PSQI) global score. High-resolution structural magnetic resonance imaging was used to examine mean ERC thickness and bilateral hippocampal volume. Through multiple linear regression analyses, we investigated the moderating effects of subjective sleep quality on the association between fitness and brain structure, accounting for age, sex, education, body mass index, gait speed, and subjective physical activity. RESULTS: We found that greater cardiorespiratory fitness, but not subjective sleep quality, was positively associated with bilateral hippocampal volume and ERC thickness. Notably, significant interaction effects suggest poor subjective sleep quality was associated with a weaker association between fitness and both hippocampal volume and ERC thickness. CONCLUSIONS: Findings suggest the potential importance of both cardiorespiratory fitness and subjective sleep quality in preserving critical, age-vulnerable brain structures. Interventions targeting brain health should consider potential combined effects of sleep and fitness on brain health.

Hackflex library preparation enables low-cost metagenomic profiling.

Shotgun metagenomic sequencing provides valuable insights into microbial communities, but the high cost of library preparation with standard kits and protocols is a barrier for many. New methods such as Hackflex use diluted commercially available reagents to greatly reduce library preparation costs. However, these methods have not been systematically validated for metagenomic sequencing. Here, we evaluate Hackflex performance by sequencing metagenomic libraries from known mock communities as well as mouse fecal samples prepared by Hackflex, Illumina DNA Prep, and Illumina TruSeq methods. Hackflex successfully recovered all members of the Zymo mock community, performing best for samples with DNA concentrations <1 ng/uL. Furthermore, Hackflex was able to delineate microbiota of individual inbred mice from the same breeding stock at the same mouse facility, and statistical modeling indicated that mouse ID explained a greater fraction of the variance in metagenomic composition than did library preparation method. These results show that Hackflex is suitable for generating inventories of bacterial communities through metagenomic sequencing.

The histamine H3 receptor inverse agonist SAR-152954 reverses deficits in long-term potentiation associated with moderate prenatal alcohol exposure.

Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.

Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death.

Importance: Age-standardized dementia mortality rates are on the rise. Whether long-term consumption of olive oil and diet quality are associated with dementia-related death is unknown. Objective: To examine the association of olive oil intake with the subsequent risk of dementia-related death and assess the joint association with diet quality and substitution for other fats. Design, Setting, and Participants: This prospective cohort study examined data from the Nurses' Health Study (NHS; 1990-2018) and Health Professionals Follow-Up Study (HPFS; 1990-2018). The population included women from the NHS and men from the HPFS who were free of cardiovascular disease and cancer at baseline. Data were analyzed from May 2022 to July 2023. Exposures: Olive oil intake was assessed every 4 years using a food frequency questionnaire and categorized as (1) never or less than once per month, (2) greater than 0 to less than or equal to 4.5 g/d, (3) greater than 4.5 g/d to less than or equal to 7 g/d, and (4) greater than 7 g/d. Diet quality was based on the Alternative Healthy Eating Index and Mediterranean Diet score. Main Outcome and Measure: Dementia death was ascertained from death records. Multivariable Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% CIs adjusted for confounders including genetic, sociodemographic, and lifestyle factors. Results: Of 92 383 participants, 60 582 (65.6%) were women and the mean (SD) age was 56.4 (8.0) years. During 28 years of follow-up (2 183 095 person-years), 4751 dementia-related deaths occurred. Individuals who were homozygous for the apolipoprotein ε4 (APOE ε4) allele were 5 to 9 times more likely to die with dementia. Consuming at least 7 g/d of olive oil was associated with a 28% lower risk of dementia-related death (adjusted pooled HR, 0.72 [95% CI, 0.64-0.81]) compared with never or rarely consuming olive oil (P for trend < .001); results were consistent after further adjustment for APOE ε4. No interaction by diet quality scores was found. In modeled substitution analyses, replacing 5 g/d of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8% (95% CI, 4%-12%) to 14% (95% CI, 7%-20%) lower risk of dementia mortality. Substitutions for other vegetable oils or butter were not significant. Conclusions and Relevance: In US adults, higher olive oil intake was associated with a lower risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings extend the current dietary recommendations of choosing olive oil and other vegetable oils for cognitive-related health.

Circadian transcriptome of pancreatic adenocarcinoma unravels chronotherapeutic targets.

Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer characterized by a poor outcome and an increasing incidence. A significant majority (>80%) of newly diagnosed cases are deemed unresectable, leaving chemotherapy as the sole viable option, though with only moderate success. This necessitates the identification of improved therapeutic options for PDA. We hypothesized that there are temporal variations in cancer-relevant processes within PDA tumors, offering insights into the optimal timing of drug administration - a concept termed chronotherapy. In this study, we explored the presence of the circadian transcriptome in PDA using patient-derived organoids and validated these findings by comparing PDA data from The Cancer Genome Atlas with noncancerous healthy pancreas data from GTEx. Several PDA-associated pathways (cell cycle, stress response, Rho GTPase signaling) and cancer driver hub genes (EGFR and JUN) exhibited a cancer-specific rhythmic pattern intricately linked to the circadian clock. Through the integration of multiple functional measurements for rhythmic cancer driver genes, we identified top chronotherapy targets and validated key findings in molecularly divergent pancreatic cancer cell lines. Testing the chemotherapeutic efficacy of clinically relevant drugs further revealed temporal variations that correlated with drug-target cycling. Collectively, our study unravels the PDA circadian transcriptome and highlights a potential approach for optimizing chrono-chemotherapeutic efficacy.

Learning Curve of Robotic End-to-Side Microanastomoses.

BACKGROUND AND OBJECTIVES: Robotics are becoming increasingly widespread within various neurosurgical subspecialties, but data pertaining to their feasibility in vascular neurosurgery are limited. We present our novel attempt to evaluate the learning curve of a robotic platform for microvascular anastomoses. METHODS: One hundred and sixty one sutures were performed and assessed. Fourteen anastomoses (10 robotic [MUSA-2 Microsurgical system; Microsure] and 4 hand-sewn) were performed by the senior author on 1.5-mm caliber tubes and recorded with the Kinevo 900 (Zeiss) operative microscope. We separately compared interrupted sutures (from needle insertion until third knot) and running sutures (from needle insertion until loop pull-down). Average suture timing across all groups was compared using an unpaired Student's t test. Exponential smoothing (α = 0.2) was then applied to the robotic data sets for validation and a second set of t tests were performed. RESULTS: We compared 107 robotic sutures with 54 hand-sewn sutures. There was a significant difference between the average time/stitch for the robotic running sutures (n = 55) and the hand-sewn running sutures (n = 31) (31.2 seconds vs 48.3 seconds, respectively; P-value = .00052). Exponential smoothing (α = 0.2) reinforced these results (37.6 seconds vs 48.3 seconds; P-value = .014625). Average robotic running times surpassed hand-sewn by the second anastomosis (38.8 seconds vs 48.3 seconds) and continued to steadily decrease with subsequent stitches. The average of the robotic interrupted sutures (n = 52) was significantly longer than the hand-sewn (n = 23) (171.3 seconds vs 70 seconds; P = .000024). Exponential smoothing (α = 0.2) yielded similar results (196.7 seconds vs 70 seconds; P = .00001). However, average robotic interrupted times significantly decreased from the first to the final anastomosis (286 seconds vs 105.2 seconds; P = .003674). CONCLUSION: Our results indicate the learning curve for robotic microanastomoses is short and encouraging. The use of robotics warrants further study for potential use in cerebrovascular bypass procedures.

Severe Drug-Induced Liver Injury Due to Self-administration of the Veterinary Anthelmintic Medication, Fenbendazole.

Fenbendazole is an anthelmintic agent approved for veterinary applications. Even though it is not approved by the US Food and Drug Administration for human use, such use appears to be increasing due to the popularization of fenbendazole's potential anticancer effects by social media. We describe the first case of histologically confirmed severe drug-induced liver injury, hepatocellular pattern, associated with the self-administration of fenbendazole in a 67-year-old woman who presented with 2 weeks of jaundice. Liver function tests normalized in 3 months after the cessation of fenbendazole.

Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy.

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.

Do people know how suicidal they will be? Understanding suicidal prospection.

INTRODUCTION: Little research has been done on how people mentally simulate future suicidal thoughts and urges, a process we term suicidal prospection. METHODS: Participants were 94 adults with recent suicidal thoughts. Participants completed a 42-day real-time monitoring study and then a follow-up survey 28 days later. Each night, participants provided predictions for the severity of their suicidal thoughts the next day and ratings of the severity of suicidal thoughts over the past day. We measured three aspects of suicidal prospection: predicted levels of desire to kill self, urge to kill self, and intent to kill self. We generated prediction errors by subtracting participants' predictions of the severity of their suicidal thoughts from their experienced severity. RESULTS: Participants tended to overestimate (although the average magnitude was small and the modal error was zero) the severity of their future suicidal thoughts. The best fitting models suggested that participants used both their current suicidal thinking and previous predictions of their suicidal thinking to generate predictions of their future suicidal thinking. Finally, the average severity of predicted future suicidal thoughts predicted the number of days participants thought about suicide during the follow-up period. CONCLUSIONS: This study highlights prospection as a psychological process to better understand suicidal thoughts and behaviors.

Anti-tumor activity of a novel LAIR1 antagonist in combination with anti-PD-1 to treat collagen-rich solid tumors.

We recently reported that resistance to PD-1-blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist monoclonal antibody, elicits myeloid inflammation and allogeneic T cell responses by binding to LAIR1 and blocking collagen engagement. Further, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV­2 Mpro).

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.

Requirements for efficient endosomal escape by designed mini-proteins.

ZF5.3 is a compact, rationally designed mini-protein that escapes efficiently from the endosomes of multiple cell types. Despite its small size (27 amino acids), ZF5.3 can be isolated intact from the cytosol of treated cells and guides multiple classes of proteins into the cytosol and/or nucleus. In the best cases, delivery efficiencies reach or exceed 50% to establish nuclear or cytosolic concentrations of 500 nM or higher. But other than the requirement for unfoldable cargo and an intact HOPS complex, there is little known about how ZF5.3 traverses the limiting endocytic membrane. Here we delineate the attributes of ZF5.3 that enable efficient endosomal escape. We confirm that ZF5.3 is stable at pH values between 5.5 and 7.5, with no evidence of unfolding even at temperatures as high as 95 °C. The high-resolution NMR structure of ZF5.3 at pH 5.5, also reported here, shows a canonical p zinc-finger fold with the penta-arg motif integrated seamlessly into the C-terminal α-helix. At lower pH, ZF5.3 unfolds cooperatively as judged by both circular dichroism and high-resolution NMR. Unfolding occurs upon protonation of a single Zn(II)-binding His side chain whose pKa corresponds almost exactly to that of the late endosomal lumen. pH-induced unfolding is essential for endosomal escape, as a ZF5.3 analog that remains folded at pH 4.5 fails to efficiently reach the cytosol, despite high overall uptake. Finally, using reconstituted liposomes, we identify a high-affinity interaction of ZF5.3 with a specific lipid-BMP-that is selectively enriched in the inner leaflet of late endosomal membranes. This interaction is 10-fold stronger at low pH than neutral pH, providing a molecular picture for why escape occurs preferentially and in a HOPS-dependent manner from late endosomal compartments. The requirements for programmed endosomal escape identified here should aid and inform the design of proteins, peptidomimetics, and other macromolecules that reach cytosolic or nuclear targets intact and at therapeutically relevant concentrations.

Cas9 RNP Physiochemical Analysis for Enhanced CRISPR-AuNP Assembly and Function.

CRISPR therapy for hematological disease has proven effective for transplant dependent beta thalassemia and sickle cell anemia, with additional disease targets in sight. The success of these therapies relies on high rates of CRISPR-induced double strand DNA breaks in hematopoietic stem and progenitor cells (HSPC). To achieve these levels, CRISPR complexes are typically delivered by electroporation ex vivo which is toxic to HSPCs. HSPCs are then cultured in stimulating conditions that promote error-prone DNA repair, requiring conditioning with chemotherapy to facilitate engraftment after reinfusion. In vivo delivery by nanocarriers of CRISPR gene editing tools has the potential to mitigate this complexity and toxicity and make this revolutionary therapy globally available. To achieve in vivo delivery, the inherent restriction factors against oligonucleotide delivery into HSPCs, that make ex vivo manipulation including electroporation and stimulation essential, must be overcome. To this end, our group developed a CRISPR carrying gold nanoparticle (CRISPR-AuNP) capable of delivering either Cas9 or Cas12a CRISPRs as ribonucleoprotein complexes (RNP) without compromising HSPC fitness. However, the most commonly used CRISPR, Cas9, demonstrated inconsistent activity in this delivery system, with lower activity relative to Cas12a. Investigation of Cas9 RNP biophysics relative to Cas12a revealed duplex RNA instability during the initial loading onto Au cores, resulting in undetectable Cas9 loading to the particle surface. Here we demonstrate preformation of RNP before loading, coupled with optimization of the loading chemistry and conditions, resulted in 39.6 ± 7.0 Cas9 RNP/AuNP without compromising RNP activity in both in vitro assays and primary human HSPC. The same alterations improved Cas12a RNP/AuNP loading 10-fold over previously reported levels. To achieve particle stability, the reported polyethyleneimine outer coating was altered to include PEGylation and the resulting 2nd generation CRISPR-AuNP demonstrates favorable nanoformulation characteristics for in vivo administration, with a hydrophilic, more neutral nanoparticle surface. Direct treatment of HSPC in vitro showed 72.5 ± 7.37% uptake of 2nd generation CRISPR-AuNP in primary human HSPC, but with endosomal accumulation and low rates of gene editing consistent with low levels of endosomal escape.

Organization of spontaneous spatial behaviors under dark conditions is unaffected in adult male and female long-Evans rats after moderate prenatal alcohol exposure.

Prenatal alcohol exposure can produce disruptions in a wide range of cognitive functions, but it is especially detrimental to spatial navigation. In open environments, rodents organize their spatial behaviors around centralized locations, termed home bases, from which they make circuitous and slow locomotor trips (progressions) into the rest of the environment. Open-field behaviors are organized even under darkened test conditions, suggesting a role for self-motion cues (vestibular, motor, etc.). The impact of moderate prenatal alcohol exposure (mPAE) on the organization of spontaneous open-field behaviors under darkened conditions has not been investigated. Here we tested adult female and male rats with mPAE or saccharin control exposure in a circular open field for 30 min in a testing room that was made completely dark. While general locomotion, as measured by reductions in travel distance and increased stop duration, decreased across the test session, the organization of these behaviors, as measured by stop duration, home base establishment, home base stability, progression accuracy, and scaling of peak speeds with progression length, did not differ between mPAE and saccharin control rats. Together, the findings strongly suggest that spontaneous movement organization in relation to self-motion cues remains intact in adult mPAE rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Anatomical Location of the Vesical Branches of the Inferior Hypogastric Plexus in Human Cadavers.

We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder. Forty-four pelvic regions were examined in 30 human cadavers. Gross post-mortem and intra-operative approaches (open anterior abdominal, manual laparoscopic, and robot-assisted) were used. Nerve branch distances and diameters were measured after thorough visual inspection and gentle dissection, so as to not distort tissue. The IHP had between 1 to 4 vesical branches (2.33 ± 0.72, mean ± SD) with average diameters of 0.51 ± 0.06 mm. Vesical branches from the IHP arose from a grossly visible pelvic ganglion in 93% of cases (confirmed histologically). The pelvic ganglion was typically located 7.11 ± 6.11 mm posterolateral to the ureteral orifice in 69% of specimens. With this in-depth characterization, vesical branches from the IHP can be safely located both posterolateral to the ureteral orifice and emanating from a more proximal ganglionic enlargement during surgical procedures.