bluuebunny/crossref_metadata_2025 huggingface dataset:
Knowledge and Utilization of Sex-Specific Lead Aprons Among Pediatric Orthopaedic Surgeons
Authors: Mengers Sunita , Emara Ahmed , Maheshwer Bhargavi , Lopresti Julia , Mistovich R. Justin
Published: July 2024

Background:

Orthopaedic surgeons routinely face exposure to ionizing radiation during intraoperative use of fluoroscopy. Lead personal protective equipment reduces occupational radiation exposure. Female-specific lead aprons are designed with expanded lateral coverage to improve protection of breast tissue against radiation beams. The purpose of this study was to identify current trends in knowledge and utilization of female-specific lead aprons as well as any barriers to utilization.

Methods:

An anonymous electronic survey including 20 multiple choice and multiple selection responses was distributed to all members of the Pediatric Orthopaedic Society of North America (POSNA). Respondents who reported the use of intraoperative fluoroscopy in their practice were included in the study.

Results:

Most respondents were attending surgeons (91%) and practiced in an academic setting (85%) in an urban environment (75%). Most respondents reported using a lead apron for every case (76%) and a thyroid shield for every case (75%), while most respondents reported they do not wear lead glasses (73%). Fifty-one percent of respondents were aware of female-specific lead aprons. The majority of respondents reported female-specific lead is unavailable (45%) or available in insufficient quantities (5.5%) at their institution. Ninety percent of females reported they do not wear female-specific lead with the common reasons being lack of availability and discomfort.

Conclusions:

Knowledge of female-specific lead is low with lack of availability as a common barrier to utilization. As female presence in the field of orthopaedic surgery expands, efforts should be made to improve education and availability of sex-specific lead aprons.
Attention-Deficit/Hyperactivity Disorder in Medication Treated Preschool-Age Children Without and With Autism Spectrum Disorder: A Developmental-Behavioral Research Network Study
Authors: Friedman Sandra L. , Shults Justine , Barbaresi William , Bax Ami , Cacia Jaclyn , Deavenport-Saman Alexis , LaRosa Angela , Loe Irene M. , Mittal Shruti , Vanderbilt Douglas L. , Blum Nathan , Harstad Elizabeth
Published: July 2024

Objectives:

The study objective was to compare preschool children with attention-deficit/hyperactivity disorder without autism spectrum disorder (ADHD − ASD) with those with ADHD and ASD (ADHD + ASD), treated with stimulant or alpha-2-agonist (A2A) medications.

Methods:

Retrospective electronic health record review of 497 children from 7 developmental behavioral pediatrics research network sites. Children were younger than 72 months when treated with medication for ADHD from January 1, 2013, to January 7, 2017. We analyzed differences in children with ADHD − ASD versus ADHD + ASD treated with stimulants or A2As, including demographics, coexisting conditions, medication effectiveness, medication, discontinuation factors, and adverse effects.

Results:

Of the 497 preschool-age children with ADHD, 389 had ADHD − ASD and 108 had ADHD + ASD. No statistically significant differences were found in demographics between the groups. At baseline, ADHD + ASD group reported more sleep problems. For the ADHD − ASD group, stimulant medication was significantly more effective than A2As; no significant differences were found in medication effectiveness of stimulants versus A2As for the ADHD + ASD group. Children with ADHD − ASD experienced more appetite suppression and stomachaches on stimulants. No associations were found between ASD status and rates of common adverse effects for children initiated on A2As.

Conclusion:

We found more similarities than differences when comparing ADHD − ASD preschool-age children with those with ADHD + ASD. For children with ADHD − ASD, stimulant medications were significantly more effective than A2As. Overall, there was notable overlap in presentation, response to medication, coexisting conditions, and effectiveness of medication classes.
Closed Incision Negative-Pressure Therapy on Free Flap Donor Sites: A Meta-analysis of Postoperative Outcomes
Authors: Le Paulina B. , Martinez O. Parker , Mujadzic Tarik , Yturralde Kylee , Gilstrap Jarom N.
Published: July 2024

Background:

Closed incision negative-pressure therapy (ciNPT) has become increasingly used on surgical sites to attempt to minimize postoperative complications. The literature describing the benefits of ciNPT in reducing donor site morbidity after free tissue transfer is limited. This review compares the effectiveness of ciNPT and conventional dressings in reducing donor site complications after free tissue transfer.

Methods:

A systematic review of PubMed and Ovid (MEDLINE) utilizing the search terms ((flap) AND (donor)) AND ((negative pressure) OR (vacuum)) was conducted. Bibliographies of selected articles were also searched. Relevant outcomes were collected and analyzed.

Results:

After screening 156 articles, 12 studies were included in the study with a total of 1074 donor sites. The following postoperative complications at the donor site after a free tissue transfer were analyzed: wound dehiscence, infection, seroma, hematoma, and skin necrosis. Use of ciNPT was associated with lower incidence of wound dehiscence compared with conventional dressings (OR: 0.37; 95% CI, 0.23–0.58). The incidence of infection, seroma, hematoma, and skin necrosis were overall lower in the ciNPT group; although, this was not statistically significant.

Conclusions:

Use of ciNPT was associated with a significantly lower incidence of free flap donor site wound dehiscence compared with conventional dressings. The use of ciNPT on free flap donor sites appears to have overall lower rates of other wound complications such as seroma, hematoma, skin necrosis, and infection.
Adult provider role in transition of care for young adult pediatric recipients of liver transplant: An expert position statement
Authors: Vittorio Jennifer , Kosmach-Park Beverly , Wadhwani Sharad , Jackson Whitney , Kerkar Nanda , Corbo Heather , Vekaria Pooja , Gupta Nitika , Yeh Heidi , King Lindsay Y.
Published: July 2024

Health care transition (HCT) is the process of changing from a pediatric to an adult model of care. Young adult pediatric recipients of liver transplant transferring from pediatric to adult health care services are highly vulnerable and subject to poor long-term outcomes. Barriers to successful transition are multifaceted. A comprehensive HCT program should be initiated early in pediatrics and continued throughout young adulthood, even after transfer of care has been completed. It is critical that pediatric and adult liver transplant providers establish a partnership to optimize care for these patients. Adult providers must recognize the importance of HCT and the need to continue the transition process following transfer. While this continued focus on HCT is essential, current literature has primarily offered guidance for pediatric providers. This position paper outlines a framework with a sample set of tools for the implementation of a standardized, multidisciplinary approach to HCT for adult transplant providers utilizing “The Six Core Elements of HCT.” To implement more effective strategies and work to improve long-term outcomes for young adult patients undergoing liver transplant, HCT must be mandated as a routine part of posttransplant care. Increased advocacy efforts with the additional backing and support of governing organizations are required to help facilitate these practices.
Shorter Telomere Length Is Associated With Older Age, Poor Sleep Hygiene, and Orthopedic Injury, but Not Mild Traumatic Brain Injury, in a Cohort of Canadian Children
Authors: Salberg S. , Smith M. J. , Lamont R. , Chen Z. , Beauchamp M. H. , Craig W. , Doan Q. , Gravel J. , Zemek R. , Lannin N.A. , Yeates K. O. , Mychasiuk R.
Published: July 2024

Background:

Predicting recovery following pediatric mild traumatic brain injury (mTBI) remains challenging. The identification of objective biomarkers for prognostic purposes could improve clinical outcomes. Telomere length (TL) has previously been used as a prognostic marker of cellular health in the context of mTBI and other neurobiological conditions. While psychosocial and environmental factors are associated with recovery outcomes following pediatric mTBI, the relationship between these factors and TL has not been investigated. This study sought to examine the relationships between TL and psychosocial and environmental factors, in a cohort of Canadian children with mTBI or orthopedic injury (OI).

Methods:

Saliva was collected at a postacute (median 7 days) timepoint following injury to assess TL from a prospective longitudinal cohort of children aged 8 to 17 years with either mTBI (n = 202) or OI (n = 90), recruited from 3 Canadian sites. Questionnaires regarding psychosocial and environmental factors were obtained at a postacute follow-up visit and injury outcomes were assessed at a 3-month visit. Univariable associations between TL and psychosocial, environmental, and outcome variables were assessed using Spearman’s correlation. Further adjusted analyses of these associations were performed by including injury group, age, sex, and site as covariates in multivariable generalized linear models with a Poisson family, log link function, and robust variance estimates.

Results:

After adjusting for age, sex, and site, TL in participants with OI was 7% shorter than those with mTBI (adjusted mean ratio = 0.93; 95% confidence interval, 0.89-0.98; P = .003). As expected, increasing age was negatively associated with TL (Spearman’s r = −0.14, P = .016). Sleep hygiene at 3 months was positively associated with TL (adjusted mean ratio = 1.010; 95% confidence interval, 1.001-1.020; P = .039).

Conclusion:

The relationships between TL and psychosocial and environmental factors in pediatric mTBI and OI are complex. TL may provide information regarding sleep quality in children recovering from mTBI or OI; however, further investigation into TL biomarker validity should employ a noninjured comparison group.
Characterizing HIV Acquisition Risk, Treatment Gaps, and Populations Reached Through Venue-Based Outreach and Clinical Services in Blantyre, Malawi: Findings From a District-wide CLOVE Study
Authors: Singogo Emmanuel , Weir Sharon S. , Kudowa Evaristar , Chagomerana Maganizo , Chapola John , Edwards Jessie K. , Banda Confidence , Kawalazira Gift , Kamgwira Yohane , Jahn Andreas , Bourdin Sarah , Hartney Thomas , Platt Lucy , Rice Brian , Hargreaves James R. , Hosseinipour Mina C. ,   CLOVE Study Group
Published: July 2024

Background:

In 2017, Blantyre district had the highest adult HIV prevalence in Malawi (17.7%) and lowest viral suppression (60%). In response, the Ministry of Health expanded prevention and treatment services. We assessed whether outreach to social venues could identify individuals with increased HIV acquisition risk or with unsuppressed HIV not currently reached by clinic-based services.

Methods:

We conducted a cross-sectional biobehavioral survey in Blantyre, Malawi, from January to March 2022. We visited social venues where people meet new sexual partners and government clinics providing HIV testing or STI screening. Participants older than 15 years were interviewed and tested for HIV infection if not on ART. HIV recency tests were performed on those testing positive, and dried blood spots (DBS) were collected to quantify viral load and also to identify acute infection in those with HIV- results.

Results:

HIV prevalence (18.5% vs 8.3%) and unsuppressed HIV infection (3.9% vs 1.7%) were higher among venue-recruited (n = 1802) than among clinic-recruited participants (n = 2313). Among PLHIV at both clinics (n = 199) and venues (n = 289), 79% were virally suppressed. Few had acute (n = 1) or recent infection (n = 8). Among women, HIV prevalence was 4 times higher (38.9% venue vs 8.9% clinic). At clinics, PLHIV reporting visiting venues were less likely to be suppressed (54.6 vs 82.6%). More men at venues than at clinics reported paying for sex (49% vs 30%) or having multiple sex partners in the past 4 weeks (32% vs 16%).

Conclusions:

Enhanced venue-based prevention and testing for men and women could reduce treatment lapses, onward transmission, and improve HIV treatment outcomes.
The Value of Magnetic Resonance Imaging in Assessing Immediate Efficacy After Microwave Ablation of Lung Malignancies
Authors: Zhu Fandong , Yang Chen , Wang Jianyun , Zhou Tong , Li Qianling , Wang Subo , Zhao Zhenhua
Published: July 2024

Purpose:

To investigate the imaging performance and parametric analysis of magnetic resonance imaging (MRI) immediately after microwave ablation (MWA) of lung malignancies.

Materials and Methods:

We retrospectively analyzed the MRI performance immediately after MWA of 34 cases of lung malignancies. The ablation zone parameters of lung malignancies were measured, including the long diameter (L), short diameter (S), and safety margin of the ablation zone on plain computed tomography (CT), T1-weighted imaging (T1WI), and T2-weighted imaging (T2WI) after MWA. The study calculated the tumor volume (V0), the ablation zone volume (V1), and the ratio of V0 to V1 (V%). Statistical differences between the parameters were analyzed.

Results:

The ablation area of the lesion exhibited central low signal and peripheral high signal on T2WI, central high signal and peripheral equal or high signal on T1WI, and circumferential enhancement in the periphery. The safety margin measured on T2WI was greater than that measured on plain CT and T1WI. On plain CT, the L, S, and V1 were smaller in the effective treatment group than in the ineffective treatment group (P<0.05). On T1WI, the V% and safety margin were greater in the effective treatment group than in the ineffective treatment group (P=0.009 and P=0.016, respectively).

Conclusions:

MRI may be a new, valuable method to assess immediate efficacy after MWA for lung malignancies using the ablation zone parameters V% on T1WI and safety margin on T2WI.
Early Use of Aspirin for Coronary Allograft Prophylaxis in Heart Transplant Recipients
Authors: Kessler Iglesias Cassia , Bloom Jason E. , Xiao Xiaoman , Moskovitch Jeremy , Eckford Hunter , Offen Sophie , Kotlyar Eugene , Keogh Anne , Jabbour Andrew , Bergin Peter , Leet Angeline , Hare James L. , Taylor Andrew J. , Hayward Christopher S. , Jansz Paul , Kaye David M. , Macdonald Peter S. , Muthiah Kavitha
Published: July 2024

Background.

Coronary allograft vasculopathy (CAV) remains a significant cause of morbidity and mortality after heart transplantation. The use of aspirin for CAV prophylaxis has recently garnered interest as a possible therapeutic adjunct in this setting.

Methods.

This 2-center retrospective cohort study included 372 patients who underwent heart transplantation between January 2009 and March 2018 and were stratified according to the commencement of aspirin during their index transplant admission. The primary outcome was the development of moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) at surveillance coronary angiography. Secondary endpoints included mortality at follow-up.

Results.

There were no differences in age, sex, and cause of heart failure. In the early aspirin group, the preponderant risk factors included use of ventricular assist devices, pretransplant smoking, and mild or moderate rejection. Multivariable analyses to assess for independent predictors of CAV development and mortality demonstrated that aspirin was associated with reduced mortality (adjusted hazard ratio = 0.19; 95% confidence interval, 0.08-0.47, P < 0.01) and a trend toward a protective effect against the development of moderate or severe CAV (adjusted hazard ratio = 0.24; 95% confidence interval, 0.54-1.19; P = 0.08).

Conclusions.

In this retrospective risk-adjusted 2-center cohort study, early aspirin administration was associated with reduced risk of death and a trend toward a protective effect against CAV development. These findings warrant validation in prospective randomized trials.
Body Size Remains the Major Source of Sex Disparity Despite Updated Liver Transplant Allocation Policies
Authors: Tanaka Tomohiro , Ross-Driscoll Katherine , Pancholia Smita , Axelrod David
Published: July 2024

Background.

Efforts to address US liver transplant (LT) access inequities continue, yet disparities linked to candidate traits persist.

Methods.

Analyzing national registry data pre- and post-Acuity Circle (AC) policy, our study assessed the impact of low body surface area (BSA) on LT waitlist mortality. The outcomes of LT candidates listed in the pre-AC era (n = 39 227) and post-AC (n = 38 443) were compared for patients with low BSA (22.9% pre-AC and 23.3% post-AC).

Results.

Fine-Gray competing risk models highlighted that candidates with low BSA had a lower likelihood of LT both pre-AC (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.92-0.95) and post-AC (HR 0.96; 95% CI, 0.94-0.98), with minimal improvement in waitlist mortality/dropout risk from pre-AC (HR 1.15; 95% CI, 1.09-1.21) to post-AC (HR 1.13; 95% CI, 1.06-1.19). Findings were mostly reaffirmed by Cox regression models incorporating the trajectory of Model for End-stage Liver Disease (MELD) scores as time-dependent covariates. Regions 3, 5, and 7 showed notable LT waitlist disparities among low BSA patients post-AC policy. Causal mediation analysis revealed that low BSA and the difference between MELD-sodium and MELD 3.0 (MELD_D, as a proxy for the potential impact of the introduction of MELD 3.0) largely explained the sex disparity in AC allocation (percent mediated 90.4).

Conclusions.

LT waitlist disparities for female candidates persist, largely mediated by small body size. Although MELD 3.0 may reduce some disparities, further body size adjustments for in allocation models are justified.
Comparison of Climate Impact, Clinical Outcomes, and Cost-Efficiency of Pediatric Transumbilical Laparoscopic-Assisted Appendectomy vs Standard 3-Port Laparoscopic Appendectomy
Authors: Fitzpatrick Colleen M , Meinrenken Christoph J , Eimicke William B
Published: July 2024

BACKGROUND:

Healthcare is responsible for 8.5% of US greenhouse gas emissions. This impact must be mitigated while maintaining clinical excellence. This study compares clinical outcomes, cost-efficiency, and climate impact of transumbilical laparoscopic-assisted appendectomy (TULAA) vs 3-port laparoscopic appendectomy (LA).

STUDY DESIGN:

IRB approval was obtained. Appendectomies performed between January 1, 2020, and December 31, 2022, at a tertiary children’s hospital were reviewed. Data abstracted included clinical characteristics, operative approach and findings, supplies and equipment used, and complication. For analysis, TULAA was combined with cases converted to LA (TULAA+C). To determine a surgical site infection increase of ≤2.5%, a minimum sample size of 479 patients per group was needed to achieve a power of 80%. A composite supply list for each approach was determined by averaging supplies from cases reviewed. The composite was used to calculate cost-efficiency and climate impact. Life cycle assessment was used to determine the carbon footprint (according to International Organization for Standardization standard 14067) of supplies and equipment.

RESULTS:

Analysis was performed on 1,611 appendectomies: 497 LA and 1,114 TULAA+C (932 TULAA and 182 converted). Except for BMI, there were no clinically significant differences between groups. Surgical site infection did not increase with TULAA+C (15, 1.3%) vs LA (6, 1.2%), p = 0.81. TULAA+C ($369.21 per case) was more cost-efficient than LA ($879.30 per case) and TULAA+C (24.8 kilograms of carbon dioxide equivalents) produced fewer emissions than LA (27.4 kilograms of carbon dioxide equivalents).

CONCLUSIONS:

Although patient safety and excellent clinical outcomes must remain the top priority in healthcare, the current environmental crisis demands consideration of climate impact. When clinical noninferiority can be demonstrated, treatment options with fewer greenhouse gas emissions should be chosen.
Human Brain Ancestral Barcodes
Authors: Shibata Darryl
Published: July 2024

Dynamic CpG methylation “barcodes” were read from 15,000 to 21,000 single cells from three human male brains. To overcome sparse sequencing coverage, the barcode had ∼31,000 rapidly fluctuating X-chromosome CpG sites (fCpGs), with at least 500 covered sites per cell and at least 30 common sites between cell pairs (average of ∼48). Barcodes appear to start methylated and record mitotic ages because excitatory neurons and glial cells that emerge later in development were less methylated. Barcodes are different between most cells, with average pairwise differences (PWDs) of ∼0.5 between cells. About 10 cell pairs per million were more closely related with PWDs < 0.05. Barcodes appear to record ancestry and reconstruct trees where more related cells had similar phenotypes, albeit some pairs had phenotypic differences. Inhibitory neurons showed more evidence of tangential migration than excitatory neurons, with related cells in different cortical regions. fCpG barcodes become polymorphic during development and can distinguish between thousands of human cells.
Analysis of Ground Reaction Force Impulses During Uneven Walking for Young and Older Adults
Authors: Hosseini Yazdi Seyed Saleh
Published: July 2024

Humans navigate various terrains by exerting forces to direct the Center of Mass (COM) and maintain balance. During walking, humans transition from one stance leg to the next by exerting impulses during the step-to-step transition. Studying these transition impulses may provide insight into how humans traverse uneven terrains. When walking speed increased (constant terrain amplitude), the average braking and propulsive impulses (posterior/anterior) increased comparably (−0.0270 m · s−1· g−1v−1versus 0.0252 m s−1· g−1v−1). In the vertical direction, while the collision impulse remained constant, the push-off impulse declined by -0.0535 m · s−1· g−1· v−1. The interaction of age and speed also increased the collision impulse (0.0202 m · s−1· g−1· v−1). With the rise of terrain amplitude (constant speed), the braking and propulsive impulses rose by -0.0607 m · s−1· g−1· m−1and 0.0701 m · s−1· g−1· m−1, respectively. Thus, we could infer that the propulsive impulse also contributed to the gait mechanical energy. While the collision impulse increased with terrain amplitude (0.1775 m · s−1· g−1· m−1) and the interaction of age and terrain amplitude (0.1058 m · s−1· g−1· m−1), the push-off impulse declined (−0.2700 m · s−1· g−1· m−1and -0.1473 m · s−1· g−1· m−1). We also observed the push-off as a fraction of the total vertical impulse declined. Therefore, we detected a mechanical energy deficit in the step-to-step transition that must have been compensated for during the mid-flight phase. Considering the portion of push-off occurring after the subsequent heel-strike as delayed push-off, while it increased with walking speed, it declined with terrain amplitude. Thus, during uneven walking, the push-off exertion must have been interrupted, indicating the demand for further mechanical energy infusion after the transition.
Dominance hierarchies are linear but shallow in the social amoebaDictyostelium discoideum.
Authors: Broersma Cathleen M.E. , Ostrowski Elizabeth A.
Published: July 2024

Social groups often form dominance hierarchies, and these hierarchies are almost always linear. However, why linear dominance hierarchies emerge is not well-understood. In the social amoebaDictyostelium discoideum, cells form a multicellular fruiting body when starved, which consists of a ball of viable spores held aloft by a stalk of dead cells. In genetically mixed (chimeric) fruiting bodies, conflicts can arise over the equitable sacrifice of cells to the dead stalk, and some strains predictably dominate others in the spores. Using pairwise mixes of strains that co-occurred in small soil samples, we determined the dominance hierarchies in four natural populations ofDictyostelium. These hierarchies were significantly linear in two of four populations, but also extremely shallow, indicating that co-occurring strains are competitively similar. We used quantitative genetic analyses to assess the causes of social dominance. Each strain's solo spore production was a significant predictor of its performance in pairs. However, we detected additional genetic contributions of both the focal and partner strain, indicating additional cryptic traits that mediate social competitiveness. In contrast to earlier studies showing strong fitness differences among strains collected over a larger spatial scale, we show that co-occurring strains are remarkably competitively equivalent, resulting in linear yet shallow hierarchies. Our results underscore the importance of biologically relevant spatial scales in assessing fitness interactions among microbes. They also explain why social trait diversity might be observed despite dominance hierarchies that should eliminate this variation.
An Adipo-Pulmonary Axis Mediated by FABP4 Hormone Defines a Therapeutic Target Against Obesity-Induced Airway Disease
Authors: Burak M. Furkan , Tuncman Gurol , Ayci Ayse Nur , Chetal Kashish , Seropian Grace Yankun Lee , Inouye Karen , Lai Zon Weng , Dagtekin Nurdan , Sadreyev Ruslan I. , Israel Elliot , Hotamışlıgil Gökhan S
Published: July 2024

Obesity-related airway disease is a clinical condition without a clear description and effective treatment. Here, we define this pathology and its unique properties, which differ from classic asthma phenotypes, and identify a novel adipo-pulmonary axis mediated by FABP4 hormone as a critical mediator of obesity-induced airway disease. Through detailed analysis of murine models and human samples, we elucidate the dysregulated lipid metabolism and immunometabolic responses within obese lungs, particularly highlighting the stress response activation and downregulation of surfactant-related genes, notably SftpC. We demonstrate that FABP4 deficiency mitigates these alterations, demonstrating a key role in obesity-induced airway disease pathogenesis. Importantly, we identify adipose tissue as the source of FABP4 hormone in the bronchoalveolar space and describe strong regulation in the context of human obesity, particularly among women. Finally, our exploration of antibody-mediated targeting of circulating FABP4 unveils a novel therapeutic avenue, addressing a pressing unmet need in managing obesity-related airway disease. These findings not only define the presence of a critical adipo-pulmonary endocrine link but also present FABP4 as a therapeutic target for managing this unique airway disease that we refer to as fatty lung disease associated with obesity.

Graphical Abstract

One Sentence Summary

Investigating FABP4’s pivotal role in obesity-driven airway disease, this study unveils an adipo-pulmonary axis with potential therapeutic implications.
Growth of soil ammonia-oxidizing archaea on air-exposed solid surface
Authors: Abiola Christiana , Gwak Joo-Han , Lee Ui-Ju , Awala Samuel Imisi , Jung Man-Young , Park Woojun , Rhee Sung-Keun
Published: July 2024

Soil microorganisms often thrive as microcolonies or biofilms within pores of soil aggregates exposed to the soil atmosphere. However, previous studies on the physiology of soil ammonia-oxidizing microorganisms (AOM), which play a critical role in the nitrogen cycle, were primarily conducted using freely suspended AOM cells (planktonic cells) in liquid media. In this study, we examined the growth of two representative soil ammonia-oxidizing archaea (AOA),Nitrososphaera viennensisEN76 and “Nitrosotenuis chungbukensis” MY2, and an ammonia-oxidizing bacterium,Nitrosomonas europaeaATCC 19718 on polycarbonate membrane filters floated on liquid media to observe their adaptation to air-exposed solid surfaces. Interestingly, ammonia oxidation activities ofN. viennensisEN76 and “N. chungbukensis” MY2 were significantly repressed on floating filters compared to the freely suspended cells in liquid media. Conversely, the ammonia oxidation activity ofN. europaeaATCC 19718 was comparable on floating filters and liquid media.N. viennensisEN76 andN. europaeaATCC 19718 developed microcolonies on floating filters. Transcriptome analysis ofN. viennensisEN76 floating filter-grown cells revealed upregulation of unique sets of genes for cell wall and extracellular polymeric substance biosynthesis, H2O2-induced oxidative stress defense, and ammonia oxidation, including ammonia monooxygenase subunit C (amoC3) and the multicopper oxidases. These genes may play a pivotal role in adapting AOA to air-exposed solid surfaces. Furthermore, the floating filter technique resulted in the enrichment of distinct soil AOA communities dominated by the “Ca. Nitrosocosmicus” clade. Overall, this study sheds light on distinct adaptive mechanisms governing AOA growth on air-exposed solid surfaces.
Heterogeneous Slowdown of Dynamics in the Condensate of an Intrinsically Disordered Protein
Authors: Mukherjee Saumyak , Schäfer Lars V
Published: July 2024

The high concentration of proteins and other biological macromolecules inside biomolecular condensates leads to dense and confined environments, which can affect the dynamic ensembles and the time-scales of the conformational transitions. Here we use atomistic molecular dynamics (MD) simulations of the intrinsically disordered low complexity domain (LCD) of the human fused in sarcoma (FUS) RNA-binding protein to study how self-crowding inside a condensate affects the dynamic motions of the protein. We found a heterogeneous retardation of the protein dynamics in the condensate with respect to the dilute phase, with large-amplitude motions being strongly slowed by up to two orders of magnitude, whereas small-scale motions, such as local backbone fluctuations and side-chain rotations, are less affected. The results support the notion of a liquid-like character of the condensates and show that different protein motions respond differently to the environment.
Mechanism of host cell invasion byLeishmaniathrough KMP-11 mediated cholesterol-transport and membrane phase transition
Authors: Sannigrahi Achinta , Ghosh Souradeepa , Pradhan Supratim , Jana Pulak , Jawed Junaid Jibran , Majumdar Subrata , Roy Syamal , Karmakar Sanat , Mukherjee Budhaditya , Chattopadhyay Krishnananda
Published: July 2024

The first step of successful infection by any intracellular pathogen relies on its ability to invade its host cell membrane. However, the detailed structural and molecular understanding underlying lipid membrane modification during pathogenic invasion remains unclear. In this study, we show that a specificLeishmania donovani(LD) protein, KMP-11, forms oligomers that bridge LD and host macrophage (MΦ) membranes. This KMP-11 induced interaction between LD and MΦ depends on the variations in cholesterol (CHOL) and ergosterol (ERG) contents in their respective membranes. These variations are crucial for the subsequent steps of invasion, including (a) the initial attachment, (b) CHOL transport from MΦ to LD, and (c) detachment of LD from the initial point of contact through a liquid ordered (Lo) to liquid disordered (Ld) membrane-phase transition. To validate the importance of KMP-11, we generated KMP-11 depleted LD, which failed to attach and invade host MΦ. Through tryptophan-scanning mutagenesis and synthesized peptides, we developed a generalized mathematical model, which demonstrates that the hydrophobic moment and the symmetry sequence code at the membrane interacting protein domain are key factors in facilitating the membrane phase transition and, consequently, the host cell infection process by Leishmania parasites.
Stratifying variant deleteriousness and trait-modulating effect under human recent adaptation
Authors: Fan Xutong , Huang Dandan , Dong Xinran , Yi Xianfu , Wang Jianhua , Zhang Shijie , Dong Xiaobao , Gu Xiaoqiong , Li Miaoxin , Sham Pak Chung , Zhou Wenhao , Li Mulin Jun
Published: July 2024

Despite advances in annotating and interpreting human genetic variants, existing methods to distinguish deleterious/pathogenic from neutral variants still inadequately capture the nuanced impact of genetic variants on fitness and disease susceptibility. In this study, we introduced a new deep learning framework, the FIND model, by stratifying genetic variants into refined categories based on selection pressures and derived allele frequency. FIND demonstrated superior performance over existing genome-wide methods, delivering enhanced resolution in differentiating trait-modulating alleles from those that are pathogenic or neutral. Access to base-wise informative annotations has unveiled novel features that significantly enhance the model interpretability, and FIND has adeptly delineated evolutionary trends in human accelerated regions. Furthermore, applying FIND to the interpretation of clinical variants demonstrates its substantial potential in reclassifying variants of unknown significance. This work advances our understanding of the genetic underpinnings of human adaptation and disease, providing a new tool to explore the complexities of genetic contributions to health.
Deep Learning-Driven Discovery of FDA-Approved BCL2 Inhibitors: In Silico Analysis Using a Deep Generative Model NeuralPlexer for Drug Repurposing in Cancer Treatment
Authors: Sayyah Ehsan , Tunç Hüseyin , Durdağı Serdar
Published: July 2024

Finding strong inhibitors of the BCL2 target, which is essential for controlling apoptosis and ensuring the survival of cancer cells, has prompted research into FDA-approved drugs. This study uses an advanced deep generative model called NeuralPlexer to produce protein-ligand complex conformations one-by-one and performin silicoanalysis. This is the first time in the literature using NeuralPlexer in virtual screening, as we comprehensively evaluate the conformations of an FDA-approved drug library to ascertain their potential efficacy in suppressing BCL2 by utilizing NeuralPlexer’s capabilities. Obtained results were re-confirmed by physics-based molecular simulations and neural relational inference (NRI) analysis. Our study reveals several intriguing candidates such as Lathyrol and Fadrozole with potent inhibitory interactions with the BCL2 target, offering important new information for repurposing currently available drugs in cancer treatment. This work highlights the promise of deep learning technology in pharmaceutical research by integrating NeuralPlexer into the process of drug development, while also improving the accuracy of predictions made about protein-ligand interactions.
Modeling the effect of daytime duration on the biosynthesis of terpenoid precursors
Authors: Basallo Oriol , Lucido Abel , Sorribas Albert , Marin-Sanguino Alberto , Vilaprinyo Ester , Martinez Emilce , Eleiwa Abderrahmane , Alves Rui
Published: July 2024

Terpenoids are valued chemicals in the pharmaceutical, biotechnological, cosmetic, and biomedical industries. Biosynthesis of these chemicals relies on polymerization of Isopentenyl di-phosphate (IPP) and/or dimethylallyl diphosphate (DMAPP) monomers, which plants synthesize using a cytosolic mevalonic acid (MVA) pathway and a plastidic methyleritritol-4-phosphate (MEP) pathway. Circadian regulation affects MVA and MEP pathway activity at three levels: substrate availability, gene expression of pathway enzymes, and utilization of IPP and DMAPP for synthesizing complex terpenoids. There is a gap in understanding the interplay between the circadian rhythm and the dynamics and regulation of the two pathways. In this paper we create a mathematical model of the MVA and MEP pathways in plants that incorporates the effects of circadian rhythms. We then used the model to investigate how annual and latitudinal variations in circadian rhythm affect IPP and DMAPP biosynthesis. We found that, despite significant fluctuations in daylight hours, the amplitude of oscillations in IPP and DMAPP concentrations remains stable, highlighting the robustness of the system. We also examined the impact of removing circadian regulation from different parts of the model on its dynamic behavior. We found that regulation of pathway substrate availability alone results in higher sensitivity to daylight changes, while gene expression regulation alone leads to less robust IPP/DMAPP concentration oscillations. Our results suggest that the combined circadian regulation of substrate availability, gene expression, and product utilization, along with MVA- and MEP-specific regulatory loops, create an optimal operating regime. This regime maintains pathway flux closely coupled to demand and stable across a wide range of daylight hours, balancing the dynamic behavior of the pathways and ensuring robustness in response to cellular demand for IPP/DMAPP.
Mistargeted retinal axons induce a synaptically independent subcircuit in the visual thalamus of albino mice
Authors: McCracken Sean , McCoy Liam , Hu Ziyi , Hodges Julie , Valkova Katia , Williams Philip R. , Morgan Josh
Published: July 2024

In albino mice and EphB1 knock out mice, mistargeted retinal ganglion cell (RGC) axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity. We conclude that, when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit within the otherwise fully connected network. The fact that there is a developmental starting condition that can induce a synaptically segregated microcircuit has important implications for our understanding of the organization of visual circuits and for our understanding of the implementation of activity dependent development.
Persistent, Private and Mobile genes: a model for gene dynamics in evolving pangenomes
Authors: Gamblin Jasmine , Lambert Amaury , Blanquart François
Published: July 2024

The pangenome of a species is the set of all genes carried by at least one member of the species. In bacteria, pangenomes can be much larger than the set of genes carried by a single organism. Many questions remain unanswered regarding the evolutionary forces shaping the patterns of presence/absence of genes in pangenomes of a given species. We introduce a new model for bacterial pangenome evolution along a species phylogeny that explicitly describes the timing of appearance of each gene in the species and accounts for three generic types of gene evolutionary dynamics: persistent genes that are present in the ancestral genome, private genes that are specific to a given clade, and mobile genes that are imported once into the gene pool and then undergo frequent horizontal gene transfers. We call this model the Persistent-Private-Mobile (PPM) model. We develop an algorithm fitting the PPM model and apply it to a dataset of 902Salmonella entericagenomes. We show that the best fitting model is able to reproduce the global pattern of some multivariate statistics like the gene frequency spectrum and the parsimony vs. frequency plot. Moreover, the gene classification induced by the PPM model allows us to study the position of accessory genes on the chromosome depending on their category, as well as the gene functions that are most present in each category. This work paves the way for a mechanistic understanding of pangenome evolution, and the PPM model developed here could be used for dynamics-aware gene classification.
Variation in a microbial mutualist has transcriptional and phenotypic consequences for host-parasite interactions
Authors: Buxton-Martin Addison D. , Gluck-Thaler Emile , Yi Eunnuri , Stinchcombe John R. , Wood Corlett W.
Published: July 2024

Strains of microbial symbionts often vary in their effect on their host. However, little is known about how the genetic variation in microbial symbiont populations impacts host interactions with other co-colonizing microbes. Here we investigated how different strains of nitrogen-fixing rhizobial bacteria affect their host plant’s response to parasitic root-knot nematodes in the legumeMedicago truncatula. Using dual RNAseq of the root organs harboring rhizobia or nematodes, we identified genes from plant host, rhizobia, and nematode whose expression differed between parasite-infected and -uninfected plants, and between plants inoculated with different rhizobial strains. At the site of host-parasite interactions (in nematode galls), hundreds of host genes and few nematode genes differed in expression between host plants inoculated with different rhizobia strains. At the site of host-mutualist interactions (in rhizobia nodules), hundreds of host genes and few rhizobial genes responded to parasite infection. The vast majority of parasite-induced changes in host gene expression depended on the resident rhizobia strain. We additionally observed phenotypic differences in the gall and nodule counts on host root systems and in some root architecture traits, showing that genetic variation in a mutualist symbiont impacted parasite colonization rates. The transcriptomic and phenotypic differences we observed suggest that microbial indirect genetic effects play an underappreciated role in structuring their host’s interactions with other co-colonizing microorganisms, which may be mediated by changes in host resource budgets, defense response, or developmental trajectories.
Insights into the role of root exudates in bacteriophage infection dynamics
Authors: Novak Vlastimil , van Winden Michelle C. M. , Harwood Thomas V. , Neurath Rachel , Kosina Suzanne M. , Louie Katherine B. , Sullivan Matthew B. , Roux Simon , Zengler Karsten , Mutalik Vivek K. , Northen Trent R.
Published: July 2024

Bacteriophages impact soil bacteria through lysis, altering the availability of organic carbon and plant nutrients. However, the magnitude of nutrient uptake by plants from lysed bacteria remains unknown, partly because this process is challenging to investigate in the field. In this study, we extend ecosystem fabrication (EcoFAB 2.0) approaches to study plant-bacteria-phage interactions by comparing the impact of phage-lysed and uninfected15N-labeled bacterial necromass on plant nitrogen acquisition and rhizosphere exometabolites composition. We show that grassBrachypodium distachyonderives some nitrogen from amino acids in uninfectedPseudomonas putidanecromass but not from virocell necromass. Additionally, the bacterial necromass elicits the formation of rhizosphere exometabolites, some of which (guanosine), alongside tested aromatic acids (p-coumaric and benzoic acid), show distinct effects on bacteriophage-induced lysis when testedin vitro. The study highlights the dynamic feedback between bacterial necromass and plants and suggests that root exudate metabolites can impact bacteriophage infection dynamics.
Psychometric Properties of the Spanish Simultaneous Alcohol and Cannabis Motives Measure (S-SACM) among Young Adults
Authors: Pérez Lucía Vélez , Márquez José Carmona , Ponce Bella M. González , Calderón Fermín Fernández
Published: July 2024

Background

Simultaneous Alcohol and Cannabis (SAC) use is associated with greater negative consequences than individual use. Motives to use are robust predictors of alcohol and cannabis consumption, both separately and simultaneously. While instruments such as the SAC Motives Scale and its short form have recently been developed, no Spanish adaptation is currently available.

Aims

To provide a Spanish adaptation of both versions of the simultaneous alcohol and cannabis motives measure and to examine its psychometric properties in a sample of young adults who simultaneously consume both substances.

Method

A targeted sampling procedure was used to recruit 612 young cannabis users, of whom 479 reported SAC use (18-25 years old [M= 21.01,SD =2.14]; 36% female). Following adaptation and translation, participants completed the scale, along with measures of alcohol, cannabis, and simultaneous use, cannabis motives, and alcohol- and cannabis- related negative consequences.

Results

Confirmatory factor analyses showed a four-factor structure (conformity, positive effects, calm/coping, and social). Moreover, the results indicated acceptable internal consistency (.70 - .88), providing evidence of convergent, discriminant, and predictive validity for most dimensions.

Conclusions

The results suggest that both versions of the scale are valuable tools for assessing motives for SAC consumption among young adults. These scales could aid in investigating motives for SAC use and informing interventions to mitigate associated harms.

Public Significance Statement

This study provides the first Spanish adapted-version measure to assess motives for Simultaneous Alcohol and Cannabis (SAC) consumption. Our findings support the use of this measure for assessing these motives and guiding interventions aimed at preventing or reducing SAC use and its negative consequences among Spanish-speaking young adults who use alcohol and cannabis simultaneously.
Low muscle strength is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes
Authors: Jung Chan-Hee , Cho Yoon Young , Choi Dug-Hyun , Kim Bo-Yeon , Jung Sang-Hee , Kim Chul-Hee , Mok Ji-Oh
Published: July 2024

Background

Several studies have investigated whether sarcopenia is associated with diabetic microvascular complications, but very few have examined associations between sarcopenia and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM). Therefore, we investigated associations of muscle strength (handgrip strength [HGS]) and mass (appendicular skeletal muscle mass index [ASMI]) and CAN in patients with T2DM.

Methods

We enrolled 342 T2DM patients (mean age 56.1±11.5 years; 58.2% male) in this retrospective, cross-sectional study. Cardiovascular reflex tests were used to assess CAN according to Ewing’s protocol. Relative HGS was determined after normalizing absolute HGS to body weight (HGS/body weight [kg]). We defined low HGS and low ASMI according to a consensus report of the Asian Group for Sarcopenia. Logistic regression analyses were carried out to assess the associations between relative HGS or ASMI quartiles and the presence of CAN in patients with T2DM.

Results

The prevalence rates of CAN, low HGS, and low ASMI in the study subjects were 34.8%, 17.3%, and 18.7%, respectively. Low HGS was significantly more prevalent in patients with CAN than those without CAN (23.5% vs. 13.9%, p=0.025). The CAN scores were significantly and negatively correlated with relative HGS but not with ASMI. Relative HGS was negative correlated with age, glycated hemoglobin, fasting plasma glucose, hsCRP, body mass index, and HOMA-IR and positively correlated with ASMI. The prevalence of CAN gradually increased with decreasing quartile of relative HGS (28.4% in Q4, 31.8% in Q3, 34.2% in Q2, and 45.3% in Q1, p=0.02 for trend). Multivariable-adjusted prevalence ratios (PRs) for CAN, determined by comparing the first, second, and third quartiles with the fourth quartile of relative HGS, were 4.4 with a 95% confidence interval (95% CI) of [1.1 to 17.3]), 2.3 (95% CI [0.8 to 6.9]), and 1.2 (95% CI [0.4 to 3.7]), respectively. The prevalence of CAN and the PRs (95% [CI]) for CAN based on ASMI were not statistically significant.

Conclusions

Our findings suggest that low muscle strength rather than low muscle mass was significantly associated with the presence of CAN. Therefore, HGS testing could help identify patients who would benefit from screening for earlier diagnosis of CAN.