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1.
J Sleep Res ; : e14330, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39238202

ABSTRACT

People who use substances commonly experience sleep disruptions, affecting the regulation of physical and mental health, and presenting a significant barrier to treatment success. Sleep impairments are noted in all phases of substance use; however, differences between subjective versus objective methods used to measure sleep quality have been reported. While polysomnography is the gold-standard for sleep measurement, recent advances in actigraphy may help address the discordance between subjective and objective sleep reports. This systematic review examined emerging evidence (2016-present) for sleep impairment in people who use substances, with the twofold goal of: (1) identifying whether sleep outcomes vary across substance type (alcohol, nicotine, cannabis, cocaine, methamphetamine and opioids); and (2) contrasting results from subjective and objective measures. While some differences between subjective and objective sleep were noted, there was overwhelming evidence of clinically relevant sleep impairment in people who use alcohol, nicotine, cocaine, methamphetamine and opioids, with less consistent results for cannabis. Gaps in the literature are identified and future recommendations are presented, including utilization of common methodological frameworks, identification of mechanisms, and closer examination of sleep across stages of substance use and the interconnection between sleep and return to use.

3.
JACC Adv ; 3(9): 101207, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39238853

ABSTRACT

Background: Hypertension is an important contributor to cardiovascular disease (CVD) in breast cancer (BC) survivors; however, research on blood pressure (BP) and CVD outcomes in BC survivors is limited. Objectives: The purpose of this study was to better characterize the association between BP and CVD in a large, longitudinal cohort of BC patients. Methods: Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California were matched 1:5 to women without BC. Patient data were obtained from electronic health records. Multivariable Cox regression and penalized spline models were used to explore the linear and nonlinear relationship of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CVD outcomes. Results: BC cases (n = 12,713) and controls (n = 55,886) had median follow-up of 9.6 years (IQR: 5.0-11.9 years). Women with BC had a mean age of 60.6 years; 64.8% were non-Hispanic White. For ischemic heart disease (IHD), every 10 mmHg increase in SBP and DBP was associated with 1.23 (95% CI: 1.14-1.33) and 1.10 (95% CI: 0.98-1.24) risk, respectively, in women with BC. For stroke, every 10 mmHg increase in SBP and DBP was associated with a 1.45 (95% CI: 1.34-1.58) and 1.91 (95% CI: 1.68-2.18) risk, respectively. A U-shaped relationship was observed between heart failure/cardiomyopathy and BP. The associations between BP and risk of IHD, stroke, and any primary CVD were not statistically different comparing women with BC to controls, but risks varied by BC status for heart failure/cardiomyopathy (P for interaction = 0.01). Conclusions: Women with and without BC showed similar risks for IHD, stroke, and any primary CVD suggesting similar BP targets should be pursued regardless of BC survivorship status.

4.
Res Sq ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39108487

ABSTRACT

Background: In the 50 years since public health firearm research began, the decades have witnessed several pioneering investigators, followed by NRA backlash and a CDC funding moratorium, then increasing firearm mortality punctuated by mass shootings, and finally an unprecedented release of funding dedicated for research and to support trainees. Motivated by my own efforts to stay productive in firearm research, by the shirtsleeves-to-shirtsleeves cautionary lesson that wealth - for us this a researcher's funding, infrastructure, and capacity - amassed by one generation will soon diminish, and by my worry that we are not adequately dedicated to growing new investigators, I set out to document researcher lineages in this field. Methods: I created a multigenerational lineage map to find authors using "gun" or "firearm" in the title/abstract as a way to find peer-reviewed publications on firearms as a public health issue. I designated the first author as Gen1 if the manuscript was sole authored or the senior author had never been first author on a firearm publication. I plotted each Gen1 author at the year of their first first-authored publication, and pointed from them to subsequent "first-time first-author investigators" (Gen2) for whom they were senior author, and so on for a Gen2 serving as senior author for a Gen3, and so on in that lineage. Results: Gen1 authors numbered 91 by 2023, the first being Rushforth in 1974.3 Rushforth, 14 years later, produced the first and his only Gen2 author, Paulson,4 who produced no Gen3 authors. The field had produced 6 Gen2 authors when the first Gen3 author appeared in 1993, who produced the first Gen4 author in 1998, 14 years after Kraus5 that initiated that lineage in 1984. To date, only 5 lineages have produced a Gen4 author and among those only one lineage, from Schwab in 2002,6 has produced a Gen5. Twenty-four Gen3 authors have emerged. Only 35% of Gen2 authors produced a Gen3. Conclusion: I hope this motivates years-long strategies to help trainees become established, informed by modeling quantitative and qualitative data to identify characteristics underlying the investigator network related to productivity and shortcomings alike. Without dedication to understand the science of science, shirtsleeves-to-shirtsleeves in three generations may be the fate of firearm research.

5.
J Neural Eng ; 21(4)2024 Aug 22.
Article in English | MEDLINE | ID: mdl-39094627

ABSTRACT

Objective. Phantom limb pain (PLP) is debilitating and affects over 70% of people with lower-limb amputation. Other neuropathic pain conditions correspond with increased spinal excitability, which can be measured using reflexes andF-waves. Spinal cord neuromodulation can be used to reduce neuropathic pain in a variety of conditions and may affect spinal excitability, but has not been extensively used for treating PLP. Here, we propose using a non-invasive neuromodulation method, transcutaneous spinal cord stimulation (tSCS), to reduce PLP and modulate spinal excitability after transtibial amputation.Approach. We recruited three participants, two males (5- and 9-years post-amputation, traumatic and alcohol-induced neuropathy) and one female (3 months post-amputation, diabetic neuropathy) for this 5 d study. We measured pain using the McGill Pain Questionnaire (MPQ), visual analog scale (VAS), and pain pressure threshold (PPT) test. We measured spinal reflex and motoneuron excitability using posterior root-muscle (PRM) reflexes andF-waves, respectively. We delivered tSCS for 30 min d-1for 5 d.Main Results. After 5 d of tSCS, MPQ scores decreased by clinically-meaningful amounts for all participants from 34.0 ± 7.0-18.3 ± 6.8; however, there were no clinically-significant decreases in VAS scores. Two participants had increased PPTs across the residual limb (Day 1: 5.4 ± 1.6 lbf; Day 5: 11.4 ± 1.0 lbf).F-waves had normal latencies but small amplitudes. PRM reflexes had high thresholds (59.5 ± 6.1µC) and low amplitudes, suggesting that in PLP, the spinal cord is hypoexcitable. After 5 d of tSCS, reflex thresholds decreased significantly (38.6 ± 12.2µC;p< 0.001).Significance. These preliminary results in this non-placebo-controlled study suggest that, overall, limb amputation and PLP may be associated with reduced spinal excitability and tSCS can increase spinal excitability and reduce PLP.


Subject(s)
Amputation, Surgical , Phantom Limb , Spinal Cord Stimulation , Humans , Phantom Limb/physiopathology , Male , Female , Spinal Cord Stimulation/methods , Amputation, Surgical/adverse effects , Amputation, Surgical/methods , Middle Aged , Spinal Cord/physiopathology , Spinal Cord/physiology , Adult , Tibia/surgery , Transcutaneous Electric Nerve Stimulation/methods , Pain Measurement/methods , Treatment Outcome
6.
Indian J Orthop ; 58(8): 1109-1117, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39087033

ABSTRACT

Background: The use of robotic-assisted total knee arthroplasty (RA-TKA) is gaining traction. There is evidence to suggest that RA-TKA can help to optimize the precision and accuracy of implant positioning and that there may be protective effects on surrounding bony and soft tissues. Yet, there are important differences between the various RA-TKA systems currently on the market. One such newly introduced RA-TKA system uses imageless technology and performs bony cuts with the use of a burr-based device. The learning curve and complications unique to this system have yet to be assessed. Methods: We evaluated 500 consecutive RA-TKA cases using a newly developed burr-based and imageless system which were done by a single surgeon between the months of October 2021 and February 2023. Operative times were recorded and compared to the previous 150 conventional TKA cases allowing for the learning curve to be calculated using the CUSUM method. Intraoperative and postoperative complications were categorically profiled. Results: The learning curve of this RA-TKA system was found to be 6 cases. Intraoperative complications included unintended bony over resection (n = 3), soft tissue injury (n = 2), and robotic system hardware (n = 2) or software (n = 2) malfunction. Postoperative complications consisted of superficial pin site infection (n = 1) and periprosthetic fracture near the pin sites (n = 1). There were no identified cases of prosthetic joint infection, instability events, or wound complications. Conclusions: The learning curve and the complication profile of a newly introduced imageless and burr-based RA-TKA system were described. This information serves to guide surgeons in adopting this technology and can counsel them regarding the potential pitfalls and challenges associated with its integration into practice. The work sheds light on the complexity and learning curve of the recently released imageless burr-based RA-TKA system. This important information is intended to help surgeons accept this cutting-edge technology by providing advice on any errors and difficulties that can occur when integrating it into clinical practice. This information can help surgeons navigate the complexities of integrating this new burr-based robotic technology into knee replacement procedures, enabling them to make well-informed decisions and receive guidance.

7.
Pain Res Manag ; 2024: 7361038, 2024.
Article in English | MEDLINE | ID: mdl-39104726

ABSTRACT

Background: The Pain Resilience Scale (PRS), which measures behavioral perseverance and the ability to regulate emotions and cognition despite ongoing pain, lacks an Arabic version. Objectives: This study aimed to translate, culturally adapt, and validate an Arabic version of the Pain Resilience Scale (PRS-A) among Lebanese adults. Methods: Phase 1 involved translation and cross-cultural adaptation of the PRS into Arabic. Phase 2 examined the reliability and validity of the PRS-A. A convenience sample of 154 Lebanese adults with chronic musculoskeletal pain completed the PRS-A and self-report measures of pain catastrophizing, pain self-efficacy, pain intensity and interference, depression and anxiety, and quality of life. Results: The PRS-A yielded a two-factor structure with factor 1 representing "cognitive/affective positivity" and factor 2 representing "behavioral perseverance," accounting for 41.93% and 15.15% of the variance in pain resilience, respectively. Total PRS-A score (M = 33.20 and SD = 9.90) showed significant correlations with pain catastrophizing (M = 27.65, SD = 13.03, and r = -0.52), pain self-efficacy (median = 9.00, IQR = 4, and rho = 0.61), pain intensity (M = 4.50, SD = 2.25, and r = -0.28), pain interference (M = 4.30, SD = 2.89, and r = -0.56), physical (M = 34.95, SD = 9.52, and r = 0.34) and mental (M = 40.08, SD = 12.49, and r = 0.58) health functioning, anxiety (median = 7.00, IQR = 7, and rho = -0.57), and depression (median = 4.00, IQR = 6, and rho = -0.58). PRS-A subscale was also significantly related to all measures except pain intensity, which was correlated with cognitive/affective positivity (r = -0.33) but not behavioral perseverance (r = -0.09). Cronbach's alpha for the PRS-A was 0.87. Conclusion: The PRS-A demonstrated validity and acceptable reliability among Arab-speaking individuals with chronic musculoskeletal pain, suggesting its potential utility for assessing pain resilience within this population.


Subject(s)
Catastrophization , Chronic Pain , Musculoskeletal Pain , Pain Measurement , Psychometrics , Resilience, Psychological , Humans , Male , Female , Musculoskeletal Pain/psychology , Adult , Middle Aged , Lebanon , Reproducibility of Results , Catastrophization/psychology , Chronic Pain/psychology , Pain Measurement/methods , Quality of Life , Young Adult , Aged , Surveys and Questionnaires , Depression/psychology , Depression/diagnosis
8.
Lancet Reg Health Am ; 37: 100837, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39105140

ABSTRACT

Background: Most Americans believe that gun-free zones make locations more vulnerable to violent crimes, particularly active shootings. However, there is no empirical evidence regarding the impact of gun-free zones on protecting locations from violence. The objective of this study was to estimate the association between gun-free zones and active shootings. Methods: We used a pair-matched case-control study where cases were all US establishments where active shootings occurred between 2014 and 2020, and controls were randomly selected US establishments where active shootings could have but did not occur, pair-matched by establishment type, year, and county. Gun-free status of included establishments was determined via local laws, company policy, news reporting, Google Maps and posted signage, and calling establishments. Findings: Of 150 active shooting cases, 72 (48.0%) were determined to have occurred in a gun-free zone. Of 150 controls where no active shooting occurred, 92 (61.3%) were determined to be gun-free. After accounting for matched pairs, the conditional odds of an active shooting in gun-free establishments were 0.38 times those in non-gun-free establishments, with a 95% confidence interval of 0.19-0.73 (p-value = 0.0038). Several robustness analyses affirmed these findings. Interpretation: It is unlikely that gun-free zones attract active shooters; gun-free zones may be protective against active shootings. This study challenges the proposition of repealing gun-free zones based on safety concerns. Funding: This work was funded in part by the National Collaborative on Gun Violence Research and the Arnold Foundation.

9.
Rare Tumors ; 16: 20363613241271669, 2024.
Article in English | MEDLINE | ID: mdl-39105190

ABSTRACT

Background: Rhabdomyosarcomas are the most common soft tissue sarcoma in children, and pediatric alveolar rhabdomyosarcoma (ARMS) prognosis has improved based on cooperative studies. However, in adults, ARMS is significantly rarer, has poorer outcomes, and currently lacks optimal treatment strategies. Objective: This study aimed to evaluate the clinical outcome of an adult ARMS population with different front-line systemic chemotherapies and determine if any chemotherapy regimen is associated with improved survival. Materials and methods: This is a retrospective study of histologically confirmed fusion-positive ARMS patients over 18 years of age, who were treated at MD Anderson Cancer Center (MDACC) from 2004 to 2021 and received systemic chemotherapy. Descriptive clinical statistics were performed, including staging, front-line chemotherapy, multimodal therapy usage, response rates, and survival analyses. Results: 49 ARMS patients who received upfront chemotherapy were identified. Locoregional treatments included radiotherapy (RT) alone (29%, n = 14), surgery alone (10%, n = 5), or both (45%, n = 22). Median overall survival (OS) for the entire cohort was 3.6 years, and the overall response rate to systemic therapy was 89%. No chemotherapy regimen showed OS benefit, specifically analyzing the pediatric-based vincristine, actinomycin-D, cyclophosphamide (VAC) or adult-based vincristine, doxorubicin, ifosfamide (VDI) regimens, even when controlled for other clinical risk factors. Conclusion: In this single-center contemporary series, adult ARMS patient outcomes remain poor. There was no statistically significant OS difference in patients who did or did not receive adult or pediatric based ARMS regimens, although a high overall response rate to chemotherapy was seen across the entire cohort. Based on these observations, further randomized prospective studies are necessary to delineate which frontline chemotherapy regimen is most beneficial in this rare adult cancer.

10.
Science ; 385(6708): adl2362, 2024 Aug 02.
Article in English | MEDLINE | ID: mdl-39088608

ABSTRACT

In ecosystems, sharks can be predators, competitors, facilitators, nutrient transporters, and food. However, overfishing and other threats have greatly reduced shark populations, altering their roles and effects on ecosystems. We review these changes and implications for ecosystem function and management. Macropredatory sharks are often disproportionately affected by humans but can influence prey and coastal ecosystems, including facilitating carbon sequestration. Like terrestrial predators, sharks may be crucial to ecosystem functioning under climate change. However, large ecosystem effects of sharks are not ubiquitous. Increasing human uses of oceans are changing shark roles, necessitating management consideration. Rebuilding key populations and incorporating shark ecological roles, including less obvious ones, into management efforts are critical for retaining sharks' functional value. Coupled social-ecological frameworks can facilitate these efforts.


Subject(s)
Anthropogenic Effects , Ecosystem , Oceans and Seas , Sharks , Animals , Humans , Carbon Sequestration , Climate Change , Food Chain , Human Activities , Predatory Behavior , Sharks/physiology
11.
Am J Emerg Med ; 85: 24-28, 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39178628

ABSTRACT

BACKGROUND: As e-scooters have become common modes of transportations in urban environments, riding e-scooters has become a common mechanism of injury. This study examines the relationship between when riders are using these devices (i.e. day of week, and time of the day) and injury incidence based on data from a large U.S. city. METHODS: This study is a retrospective cohort study of patients in the trauma registry at a level one trauma center. Registry data were combined with a publicly available dataset of all e-scooter trips that occurred during the study period. Frequency of injuries and trips were analyzed using ANOVA. Poisson regressions were conducted to calculate incidence rate ratios associated with injury incidence by day of the week and time of day. RESULTS: A total of 194 injured e-scooter patients were admitted to the trauma center during the study period. Patients were injured most often on Fridays (21%) and most often presented between 18:00-23:59 (38%). E-Scooter riders in general, most often rode on Saturdays (20%) and between 12:00-17:59 (44%). There was no significant relationship between day of week and injury. Riders in the early morning (IRR = 16.7, p < .001 95% CI: 10.5, 26.6), afternoon (IRR = 2.0, p = .01 95% CI: 1.2, 3.4), and evening (IRR = 3.7, p < .001 95% CI: 2.3, 6.2) had significant increased injury incidence compared to morning riders. CONCLUSION: E-Scooter injury incidence varies by the time of day. The time of day in which a person rides an e-scooter can have a significant impact on the likelihood that the person will sustain an injury.

12.
Pain ; 2024 Aug 23.
Article in English | MEDLINE | ID: mdl-39190341

ABSTRACT

ABSTRACT: The thalamus plays an important role in sensory and motor information processing by mediating communication between the periphery and the cerebral cortex. Alterations in thalamic development have profound consequences on sensory and motor function. In this study, we investigated a mouse model in which thalamic nuclei formation is disrupted because of the absence of Sonic hedgehog (Shh) expression from 2 key signaling centers that are required for embryonic forebrain development. The resulting defects observed in distinct thalamic sensory nuclei in Shh mutant embryos persisted into adulthood prompting us to examine their effect on behavioral responses to somatosensory stimulation. Our findings reveal a role for first-order posterior medial thalamic neurons and their projections to layer 4 of the secondary somatosensory cortex in the transmission of nociceptive information. Together, these results establish a connection between a neurodevelopmental lesion in the thalamus and a modality-specific disruption in pain perception.

13.
Sci Data ; 11(1): 895, 2024 Aug 17.
Article in English | MEDLINE | ID: mdl-39154067

ABSTRACT

Rapid climatic warming of the Antarctic Peninsula is driving regional population declines and distribution shifts of predators and prey. Affected species include Antarctic ice seals and the southern elephant seal, all of which rely on the peninsula region for critical stages of their life cycle. However, data collection is difficult in this remote region, and therefore long-term time series with which to identify and investigate population trends in these species are rare. We present the Cape Shirreff Phocid Census (CS-PHOC) dataset: weekly counts of phocids (crabeater, leopard, southern elephant, and Weddell seals) hauled out at Cape Shirreff, Livingston Island, during most austral summers since 1997. Data from these censuses were cleaned and aggregated, resulting in robust and comparable count data from 284 censuses across 23 field seasons. The CS-PHOC dataset, which is publicly available through the SCAR Biodiversity Portal, will be updated yearly to provide important information about Southern Ocean phocids in the Antarctic Peninsula.


Subject(s)
Seals, Earless , Antarctic Regions , Animals , Seasons , Islands , Biodiversity , Population Dynamics
14.
Ann Rev Mar Sci ; 2024 Aug 19.
Article in English | MEDLINE | ID: mdl-39159203

ABSTRACT

Advancements in space-based ocean observation and computational data processing techniques have demonstrated transformative value for managing living resources, biodiversity, and ecosystems of the ocean. We synthesize advancements in leveraging satellite-derived insights to better understand and manage fishing, an emerging revolution of marine industrialization, ocean hazards, sea surface dynamics, benthic ecosystems, wildlife via electronic tracking, and direct observations of ocean megafauna. We consider how diverse space-based data sources can be better coupled to modernize and improve ocean management. We also highlight examples of how data from space can be developed into tools that can aid marine decision-makers managing subjects from whales to algae. Thoughtful and prospective engagement with such technologies from those inside and outside the marine remote sensing community is, however, essential to ensure that these tools meet their full potential to strengthen the effectiveness of ocean management.

15.
bioRxiv ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39091828

ABSTRACT

The prolyl isomerase Pin1 catalyzes the cis-trans isomerization of proline peptide bonds, a non-covalent post-translational modification that influences cellular and molecular processes, including protein-protein interactions. Pin1 is a two-domain enzyme containing a WW domain that recognizes phosphorylated serine/threonine-proline (pS/pT-P) canonical motifs and an enzymatic PPIase domain that catalyzes proline cis-trans isomerization of pS/pT-P motifs. Here, we show that Pin1 uses a tethering mechanism to bind and catalyze proline cis-trans isomerization of a noncanonical motif in the disordered N-terminal activation function-1 (AF-1) domain of the human nuclear receptor PPARγ. NMR reveals multiple Pin1 binding regions within the PPARγ AF-1, including a canonical motif that when phosphorylated by the kinase ERK2 (pS112-P113) binds the Pin1 WW domain with high affinity. NMR methods reveal that Pin1 also binds and accelerates cis-trans isomerization of a noncanonical motif containing a tryptophan-proline motif (W39-P40) previously shown to be involved in an interdomain interaction with the C-terminal ligand-binding domain (LBD). Cellular transcription studies combined with mutagenesis and Pin1 inhibitor treatment reveal a functional role for Pin1-mediated acceleration of cis-trans isomerization of the W39-P40 motif. Our data inform a refined model of the Pin1 catalytic mechanism where the WW domain binds a canonical pS/T-P motif and tethers Pin1 to the target, which enables the PPIase domain to exert catalytic cis-trans isomerization at a distal noncanonical site.

16.
Nat Cardiovasc Res ; 3(7): 869-882, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39196175

ABSTRACT

Differentiation of cardiac fibroblasts to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported that mitochondrial calcium signaling drives α-ketoglutarate-dependent histone demethylation, promoting myofibroblast formation. Here we investigate the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast fate and persistence in cardiac fibrosis. We show that inactivation of ACLY prevents myofibroblast differentiation and reverses myofibroblasts towards quiescence. Genetic deletion of Acly in post-activated myofibroblasts prevents fibrosis and preserves cardiac function in pressure-overload heart failure. TGFß stimulation enhances ACLY nuclear localization and ACLY-SMAD2/3 interaction, and increases H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of a dominant-negative ACLY mutant prevents myofibroblast formation and H3K27ac. Our data indicate that nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFß-induced myofibroblast genes. These findings provide targets to prevent and reverse pathological fibrosis.


Subject(s)
ATP Citrate (pro-S)-Lyase , Cell Differentiation , Fibrosis , Histones , Myofibroblasts , Smad2 Protein , Myofibroblasts/metabolism , Myofibroblasts/drug effects , ATP Citrate (pro-S)-Lyase/metabolism , ATP Citrate (pro-S)-Lyase/genetics , Animals , Fibrosis/metabolism , Cell Differentiation/drug effects , Histones/metabolism , Smad2 Protein/metabolism , Smad2 Protein/genetics , Acetylation/drug effects , Cell Nucleus/metabolism , Cell Nucleus/drug effects , Smad3 Protein/metabolism , Smad3 Protein/genetics , Cells, Cultured , Chromatin/metabolism , Mice, Knockout , Transforming Growth Factor beta/metabolism , Disease Models, Animal , Signal Transduction , Mice, Inbred C57BL , Male , Mice , Gene Expression Regulation/drug effects
17.
Mol Pharm ; 21(9): 4747-4753, 2024 Sep 02.
Article in English | MEDLINE | ID: mdl-39145436

ABSTRACT

Ionizable lipid-containing lipid nanoparticles (LNPs) have enabled the delivery of RNA for a range of therapeutic applications. In order to optimize safe, targeted, and effective LNP-based RNA delivery platforms, an understanding of the role of composition and pH in their structural properties and self-assembly is crucial, yet there have been few computational studies of such phenomena. Here we present a coarse-grained model of ionizable lipid and mRNA-containing LNPs. Our model allows access to the large length- and time-scales necessary for LNP self-assembly and is mapped and parametrized with reference to all-atom structures and simulations of the corresponding components at compositions typical of LNPs used for mRNA delivery. Our simulations reveal insights into the dynamics of self-assembly of such mRNA-encapsulating LNPs, as well as the subsequent pH change-driven LNP morphology and release of mRNA.


Subject(s)
Lipids , Nanoparticles , RNA, Messenger , RNA, Messenger/chemistry , RNA, Messenger/genetics , Nanoparticles/chemistry , Lipids/chemistry , Hydrogen-Ion Concentration , Molecular Dynamics Simulation , Liposomes
18.
J Hist Neurosci ; : 1-23, 2024 Aug 26.
Article in English | MEDLINE | ID: mdl-39186639

ABSTRACT

Jean-Martin Charcot, often lauded for his seminal contributions, is seldom critiqued for his blunders. One such blunder was his double-semidecussation scheme for the retinocortical visual pathways, proposed in 1875 to explain, on neuroanatomic grounds, cases of hysteria that manifest hysterical amblyopia accompanied with ipsilateral hemianaesthesia. Charcot's scheme was inconsistent with the older, broadly correct scheme of Prussian ophthalmologist Albrecht von Gräfe. Charcot failed to perform clinicopathologic correlation studies. His analysis relied on a series of mistaken conclusions he made in conjunction with Swiss-French ophthalmologist Edmund Landolt: (1) only an optic tract lesion could produce a homonymous hemianopsia; (2) cerebral lesions, if they ever produced homonymous hemianopsia, did so by secondary effects (e.g. pressure) on the optic tracts; and (3) damage to the cortical projections from the lateral geniculate produces a crossed amblyopia. Challenges to Charcot's theory came from within France by 1880. By 1882, Charcot recognized that his scheme was erroneous, and he approved a thesis by his pupil Charles Féré that reverted to Gräfe's scheme with an ill-conceived modification to accommodate Charcot's concept of hysterical cerebral amblyopia. A critique by American neurologist Moses Starr in 1884 argued for Gräfe's scheme and refuted Charcot's erroneous scheme and its subsequent derivatives.

20.
Nat Commun ; 15(1): 7432, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39198419

ABSTRACT

When wet soil becomes fully saturated by intense rainfall, or is shaken by an earthquake, it may fluidize catastrophically. Sand-rich slurries are treated as granular suspensions, where the failure is related to an unjamming transition, and friction is controlled by particle concentration and pore pressure. Mud flows are modeled as gels, where yielding and shear-thinning behaviors arise from inter-particle attraction and clustering. Here we show that the full range of complex flow behaviors previously reported for natural debris flows can be reproduced with three ingredients: water, silica sand, and kaolin clay. Going from sand-rich to clay-rich suspensions, we observe continuous transition from brittle (Coulomb-like) to ductile (plastic) yielding. We propose a general constitutive relation for soil suspensions, with a particle rearrangement time that is controlled by yield stress and jamming distance. Our experimental results are supported by models for amorphous solids, suggesting that the paradigm of non-equilibrium phase transitions can help us understand and predict the complex behaviors of Soft Earth suspensions.

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