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1.
Article in English | MEDLINE | ID: mdl-39358668

ABSTRACT

This scoping review examined grief related to the incarceration of a family member in order to establish a theoretical framework. A comprehensive search of PubMed, Social Sciences Citation Index, Embase, PsycInfo, Psychology & Behavioral Sciences, CINAHL, Cochrane Central Register of Controlled Trials & Cochrane Database of Systematic Reviews, PILOTS, and Psychiatry Online was conducted. We extracted data on sample characteristics, study design, purpose of the study, grief measure used, grief term and definition used, and key qualitative and quantitative findings. Twenty-five studies met inclusion criteria. Most studies used the terms 'ambiguous loss' (n = 15) and 'disenfranchised grief' (n = 12); however, grief terms and their definitions varied. The review identified 14 unique terms and more than 20 definitions. In several cases, the same term was defined and conceptualized differently between studies. This review also revealed shortcomings in existing theoretical frameworks for grief related to incarceration. Grief related to losing a family member to incarceration involves two distinct constructs: non-traditional losses and cascading losses. Non-traditional losses (measured on a continuum) capture elements of a loss to incarceration that are unique (compared to a loss via death) or may not be socially accepted, whereas cascading losses refers to the ongoing losses that one may experience related to the incarceration (e.g., loss of financial stability). This framework provides the field with consistent constructs and definitions that can be used to further advance research in incarceration-related grief and facilitates an improved ability to replicate findings between laboratories.

2.
Biomechanics (Basel) ; 4(3): 507-519, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39364279

ABSTRACT

This study examined the effect of age and surface on patellofemoral joint (PFJ) stress magnitude and waveform during stair ascent and descent tasks. A total of 12 young and 12 older adults had knee biomechanics quantified while they ascended and descended stairs on normal, slick, and uneven surfaces. The peak of stance (0-100%) PFJ stress and associated components were submitted to a two-way repeated measures ANOVA, while the PFJ stress waveform was submitted to statistical parametric mapping two-way ANOVA. During stair ascent, older adults exhibited greater PFJ stress waveforms, from 55 to 59% and 74 to 84% of stance (p < 0.001) as well as greater PFJ stress-time integral across stance (p = 0.003), and later peak PFJ stress, than young adults (p = 0.002). When ascending on the uneven surface, participants exhibited smaller PFJ stress from 9 to 24% of stance compared to the normal surface, but greater PFJ stress from 75 to 88% and from 63 to 68% of stance (p < 0.001) as well as greater PFJ stress-time integrals compared to normal and slick surfaces (p < 0.032). During stair descent, older adults exhibited a smaller PFJ contact area range (p = 0.034) and peak knee flexion angle (p = 0.022) than young adults. When descending on the slick surface, participants exhibited smaller PFJ stress from 5 to 18% of stance, but greater stress, from 92 to 98% of stance (both: p < 0.001), compared to the normal surface. Negotiating slick and uneven stairs may produce knee biomechanics that increase PFJ stress, and the larger, later PFJ stress exhibited by older adults may further increase their risk of PFJ pain.

3.
Soft Matter ; 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39377100

ABSTRACT

Active nematic fluids exhibit complex dynamics in both bulk and in simple confining geometries. However, complex confining geometries could have substantial impact on active spontaneous flows. Using multiparticle collision dynamics simulations adapted for active nematic particles, we study the dynamic behaviour of an active nematic fluid confined in a corrugated channel. The transition from a quiescent state to a spontaneous flow state occurs from a weak swirling flow to a strong coherent flow due to the presence of curved-wall induced active flows. We show that the active nematic fluid flows in corrugated channels can be understood in two different ways: (i) as the result of an early or delayed flow transition when compared with that in a flat-walled channel of appropriate width and (ii) boundary-induced active flows in the corrugations providing an effective slip velocity to the coherent flows in the bulk. Thus, our work illustrates the crucial role of corrugations of the confining boundary in dictating the flow transition and flow states of active fluids.

4.
J Subst Use Addict Treat ; 167: 209505, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39241929

ABSTRACT

INTRODUCTION: Despite effective medications for opioid use disorder (MOUD), treatment engagement remains low. As the overdose crisis is increasingly characterized by opioids co-used with other substances, it is important to understand whether existing models effectively support treatment for patients who use multiple substances. Hospital-based addiction consultation services (ACS) have shown promise at increasing MOUD initiation and treatment engagement, but the effectiveness for patients with specific co-use patterns remains unknown. METHODS: Using 2016-2023 admissions data from a large safety net hospital, we estimated a random-effects logistic regression model to determine whether specific co-use (methamphetamine, cocaine, alcohol, sedative, and other) moderated the effect of being seen by ACS on the receipt of MOUD. Adjusting for patient sociodemographic, health, and admission characteristics we estimated the proportion of patients who received MOUD across specific co-use groups. RESULTS: Of 7679 total admissions indicating opioid use, of which 5266 (68.6 %) indicated co-use of one or more substances and 2387 (31.1 %) were seen by the ACS. Among admissions not seen by the ACS, a smaller proportion of admissions with any co-use received MOUD (23.5 %; 95 % CI: 21.9-25.1) compared to admissions with opioid use alone (34.0 %; 95 % CI: 31.9-36.1). However, among admissions seen by the ACS a similar proportion of admissions with any co-use received MOUD (57.8 %; 95 % CI: 55.5-60.1) as admissions with opioid use alone (56.2 %; 95 % CI: 52.2-60.2). The increase in proportion of admissions receiving MOUD associated with being seen by the ACS was larger for admissions with methamphetamine (38.6 percentage points; 95 % CI: 34.6-42.6) or cannabis co-use (39.0 percentage points; 95 % CI: 32.9-45.1) compared to admissions without methamphetamine (25.7 percentage points; 95 % CI: 22.2-29.2) or cannabis co-use (29.1 percentage points; 95 % CI: 26.1-32.1). CONCLUSIONS: The ACS is an effective hospital-based treatment model for increasing the proportion of admissions which receive MOUD. This study shows that ACSs are also able to support increased receipt of MOUD for patients who use other substances in addition to opioids. Future research is needed to further understand what transition strategies best support treatment linkage for patients who use multiple substances.

5.
Clin Gerontol ; : 1-17, 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39263858

ABSTRACT

OBJECTIVES: This study aimed to validate a measure of feelings of empowerment among family caregivers of persons with life limiting illnesses. METHODS: Family caregivers (N = 295) completed a survey on their feelings of empowerment and psychosocial constructs. RESULTS: Utilizing exploratory and confirmatory factor analyses, the study validated the Empowerment in the Context of Caregiving scale, revealing a two-factor structure related to influencing the care recipient and controlling personal outcomes, with high reliability and validity. Convergent validity was supported by a strong association with an established measure of power. Discriminant validity was demonstrated through weak associations with theoretically less relevant constructs, confirming the scale's validity. CONCLUSIONS: This scale provides a reliable tool to identify feelings of disempowerment among caregivers, with implications for theory and practice. Future research should explore predictive validity and consider cultural factors to enhance its applicability in diverse caregiving contexts. CLINICAL IMPLICATIONS: This study provides a reliable tool to identify feelings of empowerment among family caregivers of persons with life limiting illnesses for clinicians. It also allows future studies to reliably investigate a theory-driven intervention target, feelings of power, and allows clinicians to tailor this into theory-driven intervention for family caregivers of persons with life limiting illnesses.

6.
Virus Evol ; 10(1): veae067, 2024.
Article in English | MEDLINE | ID: mdl-39310091

ABSTRACT

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements of mutational effects on viral traits, but epistatic shifts in the impacts of mutations can hinder viral forecasting when measurements were made in outdated strain backgrounds. Here, we report measurements of the impact of all single amino acid mutations on ACE2-binding affinity and protein folding and expression in the SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain. As with other SARS-CoV-2 variants, we find a plastic and evolvable basis for receptor binding, with many mutations at the ACE2 interface maintaining or even improving ACE2-binding affinity. Despite its large genetic divergence, mutational effects in BA.2.86 have not diverged greatly from those measured in its Omicron BA.2 ancestor. However, we do identify strong positive epistasis among subsequent mutations that have accrued in BA.2.86 descendants. Specifically, the Q493E mutation that decreased ACE2-binding affinity in all previous SARS-CoV-2 backgrounds is reversed in sign to enhance human ACE2-binding affinity when coupled with L455S and F456L in the currently emerging KP.3 variant. Our results point to a modest degree of epistatic drift in mutational effects during recent SARS-CoV-2 evolution but highlight how these small epistatic shifts can have important consequences for the emergence of new SARS-CoV-2 variants.

7.
bioRxiv ; 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39091888

ABSTRACT

Deep mutational scanning experiments aid in the surveillance and forecasting of viral evolution by providing prospective measurements of mutational effects on viral traits, but epistatic shifts in the impacts of mutations can hinder viral forecasting when measurements were made in outdated strain backgrounds. Here, we report measurements of the impact of all single amino acid mutations on ACE2-binding affinity and protein folding and expression in the SARS-CoV-2 Omicron BA.2.86 spike receptor-binding domain (RBD). As with other SARS-CoV-2 variants, we find a plastic and evolvable basis for receptor binding, with many mutations at the ACE2 interface maintaining or even improving ACE2-binding affinity. Despite its large genetic divergence, mutational effects in BA.2.86 have not diverged greatly from those measured in its Omicron BA.2 ancestor. However, we do identify strong positive epistasis among subsequent mutations that have accrued in BA.2.86 descendants. Specifically, the Q493E mutation that decreased ACE2-binding affinity in all previous SARS-CoV-2 backgrounds is reversed in sign to enhance human ACE2-binding affinity when coupled with L455S and F456L in the currently emerging KP.3 variant. Our results point to a modest degree of epistatic drift in mutational effects during recent SARS-CoV-2 evolution but highlight how these small epistatic shifts can have important consequences for the emergence of new SARS-CoV-2 variants.

8.
Soft Matter ; 20(36): 7157-7173, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39196548

ABSTRACT

Colloids dispersed in nematic liquid crystals form topological composites in which colloid-associated defects mediate interactions while adhering to fundamental topological constraints. Better realising the promise of such materials requires numerical methods that model nematic inclusions in dynamic and complex scenarios. We employ a mesoscale approach for simulating colloids as mobile surfaces embedded in a fluctuating nematohydrodynamic medium to study the kinetics of colloidal entanglement. In addition to reproducing far-field interactions, topological properties of disclination loops are resolved to reveal their metastable states and topological transitions during relaxation towards ground state. The intrinsic hydrodynamic fluctuations distinguish formerly unexplored far-from-equilibrium disclination states, including configurations with localised positive winding profiles. The adaptability and precision of this numerical approach offers promising avenues for studying the dynamics of colloids and topological defects in designed and out-of-equilibrium situations.

9.
J Subst Use Addict Treat ; 166: 209492, 2024 Nov.
Article in English | MEDLINE | ID: mdl-39151797

ABSTRACT

INTRODUCTION: To guide improvements in treatment for pregnant persons with substance use disorders within the criminal legal system, treatment programs must first determine the primary substances of concern for this population. The objective of this study is to compare trends in specific substance use upon admission to treatment in pregnancy, based upon whether referrals originated from the criminal legal system or from another referral source. METHODS: This research accessed data on perinatal substance use (1995-2021) and referral sources from the Treatment Episode Data Set-Admissions (TEDS-A). Analyses use multiple logistic regressions to evaluate trends in primary substance use leading to treatment admission during pregnancy. RESULTS: Approximately 1 % (N = 536,948) of all substance use treatment admissions in TEDS-A were for pregnant people. Between 1995 and 2021, the percentage of treatment admissions increased for primary methamphetamine use (10 % to 27 %), primary opioid use (21 % to 38 %), and primary cannabis use (9 % to 18 %), and decreased for primary cocaine use (32 % to 6 %) and primary alcohol use (26 % to 11 %). By 2021, treatment admissions referred from criminal legal agencies were more likely to primarily be for primary methamphetamine use (33 % vs 25 %) and less likely to be for primary opioid use (22 % vs 42 %) compared to other referral sources. CONCLUSIONS: Trends in substance use treatment during pregnancy have changed substantially over the past few decades and emphasize the unique needs of patients referred to treatment by the criminal legal system. Treatment programs must therefore adapt to fluctuating trends in perinatal substance use. In particular, it is important to expand programs that prioritize treatment of methamphetamine use disorder for pregnant people referred through criminal legal agencies.


Subject(s)
Pregnancy Complications , Referral and Consultation , Substance-Related Disorders , Humans , Female , Pregnancy , Referral and Consultation/legislation & jurisprudence , Referral and Consultation/trends , Substance-Related Disorders/epidemiology , Substance-Related Disorders/therapy , Pregnancy Complications/epidemiology , Adult , Young Adult , Adolescent , Criminal Law/legislation & jurisprudence , Criminal Law/trends , Opioid-Related Disorders/epidemiology , Opioid-Related Disorders/therapy
10.
Clin Biomech (Bristol, Avon) ; 119: 106331, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39173446

ABSTRACT

BACKGROUND: Strength and neuromuscular decrements following knee musculoskeletal injury may accelerate knee osteoarthritis development. This study assessed isometric knee extensor and flexor strength and steadiness between individuals with knee injury, i.e., ligament reconstruction, and knee osteoarthritis to healthy age-matched controls. METHODS: Four cohorts (1: knee injury and 2: age-matched controls, and 3: radiographic knee osteoarthritis and 4: age-matched controls) were recruited. Participants performed maximal voluntary isometric knee extensor and flexor contractions. Then, strength (e.g., peak and rate of torque development) and steadiness (e.g., peak power, mean, and median frequency) were derived from each raw torque-time curve and associated power spectral density. A Kruskal-Wallis H test and Spearman's rho correlation analysis assessed cohort differences and association between knee extensor and flexor strength and steadiness. FINDINGS: The young adult control and knee injury cohorts exhibited greater knee extensor and flexor strength than the older, knee osteoarthritis cohort (p < 0.043). The knee injury cohort, despite being as strong as their healthy counterparts, were significantly less steady with a 92% increase in peak power frequency (p = 0.046). The osteoarthritis cohort exhibited 157% less total power compared to the knee injury and young control cohorts (p < 0.019). Knee extensor and flexor peak torque, rate of torque development, and mean torque exhibit a significant, positive relation with total power (p < 0.018). INTERPRETATION: Individuals with knee injury and disease may exhibit weaker or less steady knee musculature, predisposing them to degenerative joint disease. Clinicians may need to restore knee extensor and flexor steadiness to facilitate better joint neuromuscular control.


Subject(s)
Muscle Strength , Osteoarthritis, Knee , Humans , Osteoarthritis, Knee/physiopathology , Osteoarthritis, Knee/surgery , Male , Female , Adult , Middle Aged , Anterior Cruciate Ligament Reconstruction/methods , Knee Joint/physiopathology , Torque , Muscle, Skeletal/physiopathology , Isometric Contraction , Anterior Cruciate Ligament/physiopathology , Anterior Cruciate Ligament/surgery , Young Adult , Aged , Knee Injuries/physiopathology
11.
Health Psychol ; 2024 Aug 15.
Article in English | MEDLINE | ID: mdl-39146070

ABSTRACT

OBJECTIVE: Differences in automatic cognitive processes exist among individuals with overweight and obesity, thus there is a need to expand our conceptualization of overweight and obesity to emphasize the predictive utility of these automatic processes, rather than focusing solely on behavioral outputs. Implicit association tests (IATs) may afford a noninvasive method of examining automatic preferences that might contribute to overweight and obesity; namely, preferences for unhealthy foods and sedentary behavior versus healthy foods and physical activity. The purpose of the current study was to examine whether implicit attitudes toward foods and physical activity differed based on body mass index (BMI) status. The relationships between implicit attitudes and key psychosocial factors and health behaviors were also examined. METHOD: Participants (N = 127) included undergraduate students with an average age of 19.05 years old (SD = 1.52). Average BMI of the sample was 24.20 (SD = 4.93); 33.8% met criteria for overweight or obesity. Participants completed an IAT and questionnaires. RESULTS: There were no differences in implicit preferences based on BMI or BMI status. Overall, the sample demonstrated implicit preferences for healthy foods and active words, and preferences were not linked to the corresponding behavioral outputs, though preferences were linked to various indices of emotion and emotion regulation. CONCLUSIONS: Future research should explore an extended model to examine how implicit preferences might impact intentions to engage in protective versus risky obesity-related health behaviors, and the various psychosocial factors that might impact the translation of those preferences and intentions in actual behavioral outputs. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

12.
iScience ; 27(7): 110159, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39021792

ABSTRACT

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [11C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [11C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward.

13.
medRxiv ; 2024 May 03.
Article in English | MEDLINE | ID: mdl-39040210

ABSTRACT

Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant comprehension and satisfaction with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy. iConsent development incorporated stakeholder perspectives including researchers, patient advocates, institutional review board members, and genomic data-sharing considerations. The iConsent platform integrated principles derived from prior electronic consenting research and elements of multimedia learning theory. Participant comprehension was assessed in an interactive teachback format. The iConsent application achieved nine of ten proposed desiderata for effective patient-focused electronic consenting for genomic research. Overall, participants demonstrated high comprehension and retention of key human subjects' considerations. Enrollees reported high levels of satisfaction with the iConsent, and we found that participant comprehension, iConsent clarity, privacy protections, and study goal explanations were associated with overall satisfaction. Although opportunities exist to optimize iConsent, we show that such an approach is feasible, can satisfy multiple stakeholder requirements, and can realize high participant satisfaction and comprehension while increasing study reach.

14.
Am J Public Health ; 114(9): 913-922, 2024 09.
Article in English | MEDLINE | ID: mdl-39024534

ABSTRACT

Objectives. To determine mortality risk among those recently released from a Minnesota jail or prison. Methods. Using linked prison, jail, and death records, our retrospective cohort study followed 99 065 people who were released from Minnesota jails and prisons between March 1, 2020, and December 31, 2021. We explored differences between jail and prison exposures regarding mortality using standardized mortality ratios. Results. Adjusting for age and gender, we estimated that the rate of overdose death for people released from jail was 15.5 times that of the Minnesota general population. Overdose death rates for people released from prison were even higher at 28.3 times the rate of the Minnesota general population. Conclusions. Drug overdose was the leading cause of death for people reentering their communities from both jail and prison in Minnesota-with opioids being the leading cause of overdoses. Overdose death relative to the general population was double the estimates from earlier studies among people leaving prison. Providing seamless access to medications for opioid use disorder during and after incarceration is important to lower the risk of death following release. (Am J Public Health. 2024;114(9):913-922. https://doi.org/10.2105/AJPH.2024.307723).


Subject(s)
Cause of Death , Drug Overdose , Prisoners , Humans , Minnesota/epidemiology , Drug Overdose/mortality , Drug Overdose/epidemiology , Male , Female , Adult , Retrospective Studies , Middle Aged , Prisoners/statistics & numerical data , Young Adult , Jails/statistics & numerical data , Adolescent , Prisons/statistics & numerical data , Risk Factors , Aged
15.
Nutrients ; 16(12)2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38931247

ABSTRACT

Guarana (GUA), a Brazilian seed extract, contains caffeine and other bioactive compounds that may have psychoactive effects. To assess the acute effects of GUA compared to a low dose of caffeine (CAF) on cognitive and mood parameters, twenty participants completed a double-blind, crossover experiment where they ingested capsules containing the following: (1) 100 mg CAF, (2) 500 mg GUA containing 130 mg caffeine, or (3) placebo (PLA). Cognitive tests (Simon and 2N-Back Task) were performed at the baseline (pre-ingestion) and 60 min after ingestion. The response time for the cognitive tests and heart rate variability were unaffected (p > 0.05) by treatment, although 2N-Back was overall faster (p = 0.001) across time. The accuracy in the 2N-Back Task showed a significant interaction effect (p = 0.029) due to higher post-ingestion versus pre-ingestion levels (p = 0.033), but only with the PLA. The supplements also had no effect on cognitive measures following physical fatigue (n = 11). There was an interaction effect on perceived mental energy, where the pre-ingestion of GUA had lower mental pep ratings compared to post-ingestion (p = 0.006) and post-exercise (p = 0.018) levels. Neither the acute ingestion of GUA nor low dose of CAF influenced cognitive performance or provided consistent benefit on mood or mental workload through vagal modulation. Additional investigations are beneficial to determining the lowest effective dose for CAF or GUA to influence mood and/or cognitive performance.


Subject(s)
Affect , Caffeine , Cognition , Cross-Over Studies , Heart Rate , Paullinia , Humans , Caffeine/administration & dosage , Caffeine/pharmacology , Paullinia/chemistry , Male , Double-Blind Method , Cognition/drug effects , Adult , Young Adult , Female , Heart Rate/drug effects , Affect/drug effects , Vagus Nerve/physiology , Vagus Nerve/drug effects , Plant Extracts/pharmacology , Plant Extracts/administration & dosage , Dietary Supplements
16.
Aerosp Med Hum Perform ; 95(5): 278-281, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38715272

ABSTRACT

BACKGROUND: This article documents the stability of photorefractive keratectomy (PRK) and laser-assisted in situ keratomileusis (LASIK) in two astronauts during 6-mo missions to the International Space Station.CASE REPORTS: Ocular examinations including visual acuity, cycloplegic refraction, slit lamp examination, corneal topography, central corneal thickness, optical biometry (axial length/keratometry), applanation tonometry, and dilated fundus examination were performed on each astronaut before and after their missions, and in-flight visual acuity testing was done on flight day 30, 90, and R-30 (30 d before return). They were also questioned regarding visual changes during flight.DISCUSSION: We documented stable vision in both PRK and LASIK astronauts during liftoff, entry into microgravity, 6 mo on the International Space Station, descent, and landing. Our results suggest that both PRK and LASIK are stable and well tolerated during long-duration spaceflight.Gibson CR, Mader TH, Lipsky W, Schallhorn SC, Tarver WJ, Suresh R, Hauge TN, Brunstetter TJ. Photorefractive keratectomy and laser-assisted in situ keratomileusis on 6-month space missions. Aerosp Med Hum Perform. 2024; 95(5):278-281.


Subject(s)
Astronauts , Keratomileusis, Laser In Situ , Photorefractive Keratectomy , Space Flight , Visual Acuity , Humans , Aerospace Medicine , Keratomileusis, Laser In Situ/methods , Myopia/surgery , Myopia/physiopathology , Photorefractive Keratectomy/methods , Visual Acuity/physiology
17.
Elife ; 122024 May 20.
Article in English | MEDLINE | ID: mdl-38767330

ABSTRACT

A protein's genetic architecture - the set of causal rules by which its sequence produces its functions - also determines its possible evolutionary trajectories. Prior research has proposed that the genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest - excluding the vast majority of possible genotypes and evolutionary trajectories - and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here, we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor's specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor's capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.


Subject(s)
Epistasis, Genetic , Evolution, Molecular , Transcription Factors/metabolism , Transcription Factors/genetics , DNA/genetics , DNA/metabolism , Mutation , Protein Binding
18.
Gait Posture ; 112: 140-146, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38781789

ABSTRACT

BACKGROUND: Stress fracture is a concern among older adults, as age-related decrements in ankle neuromuscular function may impair their ability to attenuate tibial compressive forces experienced during daily locomotor tasks, such as stair descent. Yet, it is unknown if older adults exhibit greater tibial compression than their younger counterparts when descending stairs. RESEARCH QUESTION: Do older adults exhibit differences in ankle biomechanics that alter their tibial compression during stair descent compared to young adults, and is there a relation between tibial compression and specific changes in ankle biomechanics? METHODS: Thirteen young (18-25 years) and 13 older (> 65 years) adults had ankle joint biomechanics and tibial compression quantified during a stair descent. Discrete ankle biomechanics (peak joint angle and moment, and joint stiffness) and tibial compression (maximum and impulse) measures were submitted to an independent t-test, while ankle joint angle and moment, and tibial compression waveforms were submitted to an independent statistical parametric mapping t-test to determine group differences. Pearson correlation coefficients (r) determined the relation between discrete ankle biomechanics and tibial compression measures for all participants, and each group. RESULTS: Older adults exhibited smaller maximum tibial compression (p = 0.004) from decreases in peak ankle joint angle and moment between 17 % and 34 % (p = 0.035), and 20-31 % of stance (p < 0.001) than young adults. Ankle biomechanics exhibited a negligible to weak correlation with tibial compression for all participants, with peak ankle joint moment and maximum tibial compression (r = -0.48 ±â€¯0.32) relation the strongest. Older adults typically exhibited a stronger relation between ankle biomechanics and tibial compression (e.g., r = -0.48 ±â€¯0.47 vs r = -0.27 ±â€¯0.52 between peak ankle joint moment and maximum tibial compression). SIGNIFICANCE: Older adults altered ankle biomechanics and decreased maximum tibial compression to safely execute the stair descent. Yet, specific alterations in ankle biomechanics could not be identified as a predictor of changes in tibial compression.


Subject(s)
Ankle Joint , Stair Climbing , Tibia , Humans , Biomechanical Phenomena , Ankle Joint/physiology , Ankle Joint/physiopathology , Male , Adult , Aged , Female , Tibia/physiology , Young Adult , Stair Climbing/physiology , Adolescent , Age Factors , Aging/physiology
19.
bioRxiv ; 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38712126

ABSTRACT

The recurring spillover of pathogenic coronaviruses and demonstrated capacity of sarbecoviruses, such SARS-CoV-2, to rapidly evolve in humans underscores the need to better understand immune responses to this virus family. For this purpose, we characterized the functional breadth and potency of antibodies targeting the receptor binding domain (RBD) of the spike glycoprotein that exhibited cross-reactivity against SARS-CoV-2 variants, SARS-CoV-1 and sarbecoviruses from diverse clades and animal origins with spillover potential. One neutralizing antibody, C68.61, showed remarkable neutralization breadth against both SARS-CoV-2 variants and viruses from different sarbecovirus clades. C68.61, which targets a conserved RBD class 5 epitope, did not select for escape variants of SARS-CoV-2 or SARS-CoV-1 in culture nor have predicted escape variants among circulating SARS-CoV-2 strains, suggesting this epitope is functionally constrained. We identified 11 additional SARS-CoV-2/SARS-CoV-1 cross-reactive antibodies that target the more sequence conserved class 4 and class 5 epitopes within RBD that show activity against a subset of diverse sarbecoviruses with one antibody binding every single sarbecovirus RBD tested. A subset of these antibodies exhibited Fc-mediated effector functions as potent as antibodies that impact infection outcome in animal models. Thus, our study identified antibodies targeting conserved regions across SARS-CoV-2 variants and sarbecoviruses that may serve as therapeutics for pandemic preparedness as well as blueprints for the design of immunogens capable of eliciting cross-neutralizing responses.

20.
Phys Rev Lett ; 132(18): 188301, 2024 May 03.
Article in English | MEDLINE | ID: mdl-38759204

ABSTRACT

While bacterial swarms can exhibit active turbulence in vacant spaces, they naturally inhabit crowded environments. We numerically show that driving disorderly active fluids through porous media enhances Darcy's law. While purely active flows average to zero flux, hybrid active/driven flows display greater drift than purely pressure-driven flows. This enhancement is nonmonotonic with activity, leading to an optimal activity to maximize flow rate. We incorporate the active contribution into an active Darcy's law, which may serve to help understand anomalous transport of swarming in porous media.

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