bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer
Authors: Liu Richard F. , Ferrario Cristiano , Fallah Parvaneh , Rose April A.N. , Labidi Soumaya , Mamo Aline , Probst Stephan M.
Published: May 2024

Background

Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment.

Methods

We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed.

Results

Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia.

Conclusion

131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.
Platelet lipidomics and de novo lipogenesis: impact on health and disease
Authors: Pirotton Laurence , de Cartier d’Yves Emma , Bertrand Luc , Beauloye Christophe , Horman Sandrine
Published: May 2024

Purpose of review

Lipids play vital roles in platelet structure, signaling, and metabolism. In addition to capturing exogenous lipids, platelets possess the capacity for de novo lipogenesis, regulated by acetyl-coA carboxylase 1 (ACC1). This review aims to cover the critical roles of platelet de novo lipogenesis and lipidome in platelet production, function, and diseases.

Recent findings

Upon platelet activation, approximately 20% of the platelet lipidome undergoes significant modifications, primarily affecting arachidonic acid-containing species. Multiple studies emphasize the impact of de novo lipogenesis, with ACC1 as key player, on platelet functions. Mouse models suggest the importance of the AMPK-ACC1 axis in regulating platelet membrane arachidonic acid content, associated with TXA2 secretion, and thrombus formation. In human platelets, ACC1 inhibition leads to reduced platelet reactivity. Remodeling of the platelet lipidome, alongside with de novo lipogenesis, is also crucial for platelet biogenesis. Disruptions in the platelet lipidome are observed in various pathological conditions, including cardiovascular and inflammatory diseases, with associations between these alterations and shifts in platelet reactivity highlighted.

The platelet lipidome, partially regulated by ACC-driven de novo lipogenesis, is indispensable for platelet production and function. It is implicated in various pathological conditions involving platelets.
Histologic Features of Mycobacterial Spindle Cell Pseudotumors
Authors: Szczepanski Julianne M. , Lieberman Joshua A. , Lamps Laura W. , Gonzalez Raul S. , Xue Yue , Zhang Xuchen , Yilmaz Osman H. , Hart John , Krausz Thomas , Mantilla Jose G. , McHugh Jonathan B. , Westerhoff Maria
Published: May 2024

Mycobacterial spindle cell pseudotumors (MSPs) are a rare and diagnostically challenging manifestation of non-tuberculous mycobacterial (NTM) infections. Proper recognition of these pseudotumors is important because they are treatable and benign. In this study, we evaluated the morphologic patterns of MSPs to improve their pathologic identification. Clinical and morphologic features of 14 MSPs were analyzed. Histologic factors evaluated included the architectural growth pattern of spindled or epithelioid macrophages, granulomas and their location within the lesion, neutrophilic microabscesses, multinucleated giant cells, necrosis, and effacement of background tissue. The composition of inflammatory infiltrates, organism density by acid-fast staining, and stromal changes were also assessed. In addition, 8 of 14 cases underwent molecular microbiology identification by a clinical amplicon-sequencing assay for non-tuberculous mycobacteria. MSP sites included 2 bowel, 10 lymph nodes, 1 liver, and 1 extremity. Cases with available clinical history (n=10) all occurred in immunocompromised patients. All demonstrated effacement of normal structures with spindled cells arranged in a storiform or fascicular architectural pattern. In addition, all cases showed lymphocytic inflammation, with prominent concurrent neutrophilic inflammation in 50% (7/14) of cases. Other morphologic findings included foamy histiocytes (64%, 9/14), peripherally situated granulomas (21%, 3/14), and neutrophilic microabscesses (21%, 3/14). All tested cases were positive for NTM by PCR methods. Mycobacterium avium was the most commonly isolated pathogen (6/8). Mycobacterial spindle cell pseudotumors show predominantly spindled morphology that may be mistaken as a neoplasm. Surgical pathologists who evaluate lymph nodes, soft tissue, and gastrointestinal tissues should be aware of this spindled tumefactive phenomenon in the setting of immunocompromised patients. Recognition of key morphologic features of neutrophilic inflammation, peripheral granulomas, or foamy histiocytes within a spindled lesion can help guide the pathologist to a correct diagnosis of an inflammatory process secondary to infection rather than a spindle cell neoplasm. Accurate diagnosis to facilitate appropriate antimicrobial and/or surgical therapy requires a comprehensive evaluation combining clinical, histopathologic, and microbiological findings.
Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America
Authors: Bauer Anna H. , Alkhateeb Khaled J. , Agoston Agoston T. , Odze Robert D. , Joshi Megha G. , Huffman Brandon M. , Enzinger Peter , Perez Kimberly , Deshpande Vikram , Cleary James M. , Wee Jon O. , Dong Fei , Zhao Lei
Published: May 2024

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.
Prevalence and Clinical Implications of Osteosarcopenia in Patients With Acute Stroke
Authors: Kim Kyoung Tae , Lee Soyoung , Cho Jang Hyuk , Choi Yongmin
Published: May 2024

Objective

The aim of the study is to investigate the prevalence and risk factors of osteosarcopenia in patients with acute stroke.

Design

Overall, 224 patients within 2 wks of having a stroke were enrolled. Demographic characteristics, National Institutes of Health Stroke Scale, modified Rankin Scale, modified Barthel Index, Functional Ambulation Category, Berg Balance Scale, and handgrip strength were recorded. Body composition was evaluated using dual-energy x-ray absorptiometry. Patients who met the diagnostic criteria for osteoporosis and sarcopenia were defined as having osteosarcopenia.

Results

The overall prevalence of osteoporosis and sarcopenia was 46.9% and 50.9%, respectively. The prevalence of osteoporosis without sarcopenia, sarcopenia without osteoporosis, and osteosarcopenia was 18.3%, 22.3%, and 28.6%, respectively. The proportion of female sex (71.9%), median age, and National Institutes of Health Stroke Scale score were significantly higher, and modified Rankin Scale, Berg Balance Scale, modified Barthel Index, Functional Ambulation Category, and grip strength were significantly lower in patients with osteosarcopenia. Older age (≥65 yrs) (odds ratio, 15.4), female sex (odds ratio, 6.23), and lower body mass index (<25 kg/m2) (odds ratio, 43.13) were independently associated with the likelihood of osteosarcopenia.

Conclusions

Osteosarcopenia may occur in acute stroke survivors. Patients with osteosarcopenia have a significantly higher stroke severity and disability. A comprehensive diagnostic approach is imperative for osteosarcopenia, thereby facilitating implementation of optimal rehabilitative strategies.
The Association of Multidimensional Sleep Health With HbA1c and Depressive Symptoms in African American Adults With Type 2 Diabetes
Authors: Woo Jihun , Lehrer H. Matthew , Tabibi Doonya , Cebulske Lauren , Tanaka Hirofumi , Steinhardt Mary
Published: May 2024

Objective

Sleep is important for diabetes-related health outcomes. Using a multidimensional sleep health framework, we examined the association of individual sleep health dimensions and a composite sleep health score with hemoglobin A1c (HbA1c) and depressive symptoms among African American adults with type 2 diabetes.

Methods

Participants (N = 257; mean age = 62.5 years) were recruited through local churches. Wrist-worn actigraphy and sleep questionnaire data assessed multidimensional sleep health using the RuSATED framework (regularity, satisfaction, alertness, timing, efficiency, duration). Individual sleep dimensions were dichotomized into poor or good sleep health and summed into a composite score. HbA1c was assessed using the DCA Vantage™ Analyzer or A1CNow® Self Check. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Regression models examined the association of individual sleep dimensions and composite sleep health with HbA1c and depressive symptoms.

Results

Higher composite sleep health scores were associated with a lower likelihood of having greater than minimal depressive symptoms (PHQ-9 ≥ 5) (odds ratio [OR] = 0.578, 95% confidence interval [CI] = 0.461–0.725). Several individual sleep dimensions, including irregularity (OR = 1.013, CI = 1.005–1.021), poor satisfaction (OR = 3.130, CI = 2.095–4.678), and lower alertness (OR = 1.866, CI = 1.230–2.833) were associated with a greater likelihood of having depressive symptoms. Neither composite sleep health scores nor individual sleep dimensions were associated with HbA1c.

Conclusions

Better multidimensional sleep health is associated with lower depressive symptoms among African American adults with type 2 diabetes. Longitudinal research is needed to determine the causal association between multidimensional sleep health and depressive symptoms in this population.

Trial Registry

ClinicalTrials.gov identifier NCT04282395.
Pre-exposure Prophylaxis Awareness and Use Among Transgender and Nonbinary Individuals in Canada
Authors: Hallarn Jason , Scheim Ayden I. , Bauer Greta R.
Published: May 2024

Background:

Transgender and nonbinary populations are disproportionately affected by HIV and face barriers to accessing HIV-related services. Pre-exposure prophylaxis (PrEP) may benefit those at risk of HIV acquisition. However, PrEP awareness and uptake, along with potential barriers and facilitators, have not been investigated among transgender and nonbinary individuals living in Canada.

Setting:

This study analyzed data from 1965 participants of the 2019 Trans PULSE Canada survey, a national convenience sampling survey of transgender and nonbinary individuals in Canada.

Methods:

Data were analyzed to estimate levels of PrEP awareness and uptake and to identify predictors of PrEP awareness among the study population. Prevalence ratios estimated from block-wise modified Poisson regression models were used to assess predictors of PrEP awareness.

Results:

PrEP awareness, lifetime PrEP use, and current PrEP use were estimated to be 71.0%, 2.2%, and 0.9%, respectively, among the full sample, and 82.3%, 7.3%, and 3.8% among those with indications for PrEP use. Respondents who were aged 45 years or older, transfeminine, Indigenous, living in Atlantic Canada or Quebec, and had high school education or less were significantly less likely to be aware of PrEP. Lifetime sex work, past-year HIV/STI testing, being single or in a nonmonogamous relationship, and higher levels of emotional social support were positively associated with PrEP awareness.

Conclusions:

There is a need to improve PrEP awareness and particularly uptake among transgender and nonbinary individuals in Canada. This study revealed inequities in PrEP awareness within this population, which may serve as targets for future public health initiatives.
Brief Report: Youth Who Acquired HIV Perinatally Have Poorer Viral Suppression Than Those Who Acquired HIV Later in Life: Findings From a Population Survey in Zimbabwe
Authors: Simms Victoria , Kranzer Katharina , Dziva Chikwari Chido , Dauya Ethel , Bandason Tsitsi , Dzavakwa Nyasha , Ferrand Rashida A.
Published: May 2024

Background:

Perinatally acquired HIV may lead to worse health outcomes than later acquisition. We compared the demographic and clinical characteristics of youth diagnosed with HIV in childhood and adulthood, as a proxy for acquisition route (perinatal vs. horizontal).

Setting:

Youth aged 18–24 years in 3 provinces in Zimbabwe were included.

Methods:

In a representative population-based survey, participants were asked their HIV status, date of HIV diagnosis if positive, and whether they were diagnosed in childhood. A dried blood spot was taken to measure viral load. Multilevel mixed-effects generalized linear modelling was used to estimate the association between HIV acquisition time and viral nonsuppression (≥1000 copies/mL).

Results:

A total of 17,682 participants (60.8% female) were enrolled, 17,553 (99.3%) gave a dried blood spot sample, 1200 (6.8%) tested HIV antibody–positive (7 indeterminate results), and 26 reported being HIV-positive without confirmation. Of the 1226 participants living with HIV, 435 (35.5%) self-reported that they were HIV-positive, of whom 196 (45.1%) were diagnosed in childhood (median age 7 years). A higher proportion of adult-diagnosed than child-diagnosed participants were female (91.2% vs. 76.5%), had ever had sex (93.3% vs. 61.5%), had been married/cohabiting (59.4% vs. 19.4%), and had been pregnant (78.9% of women vs. 40.0%). A lower proportion had viral suppression (39.3% vs. 52.5%). Adjusting for sex, age, marital status, and education, those diagnosed in childhood had higher odds of viral nonsuppression (adjusted odds ratio = 1.83, 95% confidence interval: 1.17 to 2.85, P = 0.008).

Conclusions:

Youth who acquired HIV perinatally have differentiated care needs and greater risk of viral nonsuppression compared with those who acquired HIV later.
Outcomes and Complications of Sole Reconstruction Using Lateral Thoracic Free Tissue Transfer
Authors: Zhang Ran , Wang Hyung Woo , Kim Youn Hwan , Park Seong Oh
Published: May 2024

Background

The complex structure of the sole of the foot makes the repair of extensive defects challenging. The present study, therefore, aimed to address a gap in current research by evaluating the potential of the lateral thoracic free flap, including perforator options and chimeric configurations, to be used as an advanced solution for comprehensive sole reconstruction.

Patients and Methods

We retrospectively collected the following data from the charts of patients with sole defects, due to various causes, who underwent lateral thoracic free tissue transfers: patient demographics; etiologies; comorbidities; flap types and dimensions; pedicle length; operative time; follow-up period; complications; and management.

Results

The present study included 54 patients who underwent lateral thoracic free tissue transfer, citing infection, trauma, tumor, and posttraumatic sequelae as the major etiologies. We used the following techniques for the reconstruction of sole defects: thoracodorsal artery perforator free flap (83.3%); latissimus dorsi musculocutaneous free flap (1.9%); and various chimeric pattern flaps (14.8%). Free tissue transfer in the lateral thoracic region offers versatility for reconstruction, as well as low donor site morbidity. Complications observed in the present study included wound dehiscence (9.3%), partial necrosis (9.3%), and pressure ulcers (22.2%), although most patients healed favorably without flap loss.

Conclusions

The lateral thoracic free flap is a viable option for the reconstruction of the sole of the foot and allows for the effective reconstruction of complex defects. It contains a sustainable skin paddle, and multiple components can be easily included as a chimeric type. Further studies should seek to identify ways to prevent pressure ulcers, which was the only known long-term complication in the present study.
Comparative Analysis of Silicone Tube Intubation Versus Probing and Balloon Dilation for Congenital Nasolacrimal Duct Obstruction: A Systematic Review and Meta-Analysis
Authors: Alruwaili Rahaf , Alanazi Farhan , Alrashidi Ali , Hazazi Mohammed , Alenezi Mazyad
Published: May 2024

Objective:

Congenital nasolacrimal duct obstruction (CNLDO) is a pediatric disorder with a wide range of pathology. If untreated, the condition may end up with serious complications. Multiple treatment options for CNLDO exist throughout the literature, and there is an ongoing debate on the best intervention for each disease subgroup and the best timing of such interventions. This study compares the success and failure rates of silicone tube intubation (STI) against probing and balloon dilation (BD).

Methods:

The authors searched the literature for relevant articles using PubMed, Scopus, web of Science, and Cochrane Library until January 2024. Using RevMan 5.4, the authors compared STI’s success and failure rates to probing and BD using risk ratios (RRs) and a random-effect model. In addition, the complication rate of monocanalicular intubation (MCI) versus bicanalicular intubation (BCI) was investigated. The authors used the leave-one-out method to check for influential studies and to resolve heterogeneity.

Results:

The screening process resulted in 23 eligible articles for inclusion in the authors’ review. Silicone tube intubation had a higher chance of resolving the symptoms of CNLDO than probing (RR = 1.11; 95% CI: 1.04, 1.20; P = 0.004) while having less risk of surgical failure (RR = 0.48; 95% CI: 0.30, 0.76; P = 0.002]. Monocanalicular intubation showed no statistically significant difference when compared with BCI in terms of surgical success and failure; however, MCI had a lower risk of complications (RR = 0.68; 95% CI: 0.48, 0.97; P = 0.04). In addition, STI did not demonstrate any significant difference from BD.

Conclusion:

There was no significant difference in success/failure between MCI and BCI; monocanalicular had fewer complications. Silicone tube intubation did better in terms of surgical success than probing, especially in children over 12 months, suggesting that it is the preferred intervention for older patients with CNLDO.
Outcomes from 871,441 Consecutive Surgical Procedures without Overlap or with Maximally Permissible Non-Concurrent Overlap
Authors: Borja Austin J. , Karsalia Ritesh , Gallagher Ryan S. , Strouz Krista , Na Jianbo , McClintock Scott D. , DeMatteo Ronald P. , Malhotra Neil R.
Published: May 2024

Objective:

To isolate the impact of subsumed surgery (a shorter procedure completed entirely during overlapping non-critical portions of a longer antecedent procedure) on patient outcomes.

Summary Background Data:

The American College of Surgeons recently recommended the elimination of “concurrent surgery” with overlap during a procedure’s critical portions. Guidelines for non-concurrent overlap have been established, but the safety of subsumed surgery remains to be examined.

Methods:

All consecutive procedures from 2013 to 2021 within a multihospital academic medical center were included (n=871,441). Simple logistic regression was performed to compare postoperative events between patients undergoing non-overlap surgery (n=533,032) and completely subsumed surgery (n=11,319). Thereafter, coarsened exact matching was used to match patients with non-overlap and subsumed surgery 1:1 on CPT code, 18 demographic features, baseline health characteristics, and procedural variables (n=7,146). Exact-matched cases were subsequently limited to pairs performed by the same surgeon (n=5,028). Primary outcomes included 30-day readmission, ED visits, and reoperations.

Results:

Univariate analysis suggested that subsumed surgery had a higher 30-day risk of readmission (OR 1.55, P<0.0001), ED evaluation (OR 1.19, P<0.0001), and reoperation (OR 1.98, P<0.0001). When comparison was limited to the exact same procedure and patients were matched on demographics and health characteristics, there were no outcome differences between patients with subsumed surgery and non-overlapping surgery, even when limiting analyses to the same surgeon.

Conclusions:

Similar surgeries for similar patients result in similar outcomes whether there is completely subsumed or no overlap. Individual surgeons performing a specific procedure have no outcome differences with subsumed and non-overlapping cases.
Value in acute care surgery, part 3: Defining value in acute surgical care—It depends on the perspective
Authors: Ayoung-Chee Patricia R. , Gore Amy V. , Bruns Brandon , Knowlton Lisa M. , Nahmias Jeffry , Davis Kimberly A. , Leichtle Stefan , Ross Samuel W. , Scherer L. R. , Velopulos Catherine , Martin R. Shayn , Staudenmayer Kristan L. ,   the AAST Health Economics Committee
Published: May 2024

The prior articles in this series have focused on measuring cost and quality in acute care surgery. This third article in the series explains the current ways of defining value in acute care surgery, based on different stakeholders in the health care system—the patient, the health care organization, the payer and society. The heterogenous valuations of the different stakeholders require that the framework for determining high-value care in acute care surgery incorporates all viewpoints.

LEVEL OF EVIDENCE

Expert Opinion; Level V.
The nature and characteristics of problem gaming, with a focus on ICD-11 diagnoses
Authors: Saunders John B. , Chan Gary , Leung Janni , Stjepanović Daniel , Connor Jason P.
Published: May 2024

Purpose of review

This review describes the diagnoses related to problem gaming that are included in ICD-11, published by the WHO in 2022. It summarizes the recent literature on the prevalence of Gaming Disorder, its structure, antecedents and comorbidities, and explores whether the range of diagnoses currently available adequately covers the range of experiences seen with problem gaming.

Recent findings

Overall, between 3 and 6% of the population worldwide are reported to have a gaming disorder as defined by ICD-11 or DSM-5. However, most studies are constrained by methodological issues such as nonrepresentative samples and the use of brief questionnaires to determine prevalence. ICD-11 Gaming Disorder is a psychometrically sound diagnosis. There is no diagnosis that currently captures the experience of harm from gaming, where the requirements for the diagnosis of Gaming Disorder are not reached.

There is evidence in support of the proposed new entity of ‘Harmful Gaming’, which encompasses mental and physical harm/impairment due to a repeated pattern of gaming, but where requirements for the diagnosis of Gaming Disorder are not met. Such a diagnosis would complete the spectrum of diagnoses available for problem or unhealthy gaming, similar to those for unhealthy substance use, and would provide a framework for a public health approach to reducing the overall harm from unhealthy gaming.
Anti-tetanus vaccination is associated with reduced occurrence and slower progression of Parkinson’s disease
Authors: Israel Ariel , Magen Eli , Merzon Eugene , Ruppin Eytan , Vinker Shlomo , Giladi Nir
Published: May 2024

Parkinson’s disease (PD) is characterized by progressive neurodegeneration in the autonomic and central nervous systems, manifesting with hallmark symptoms of resting tremor, bradykinesia and rigidity. The etiology of PD remains elusive, and currently available treatments do not halt disease progression.

In this study, conducted within a national health provider, we examined the impact of vaccination and medication purchase on PD occurrence and severity, using an innovative machine learning algorithm to track disease progression.

Our findings reveal a significant reduction in PD occurrence following anti-tetanus vaccination, with a time-dependent association between the elapsed time since vaccination and both the rate and progression of PD. These results are supported by evidence that antimicrobial treatments significantly alter disease severity, suggesting the actual involvement ofClostridium Tetaniin PD pathology.

Thus, tetanus vaccination andC. tetanieradication could be promising strategies for preventing PD and slowing its progression, pending controlled clinical trials.
Kinetics and optimality of influenza A virus locomotion
Authors: Agarwal Siddhansh , Veytsman Boris , Fletcher Daniel A. , Huber Greg
Published: May 2024

Influenza A viruses (IAVs) must navigate through a dense extracellular mucus to infect airway epithelial cells. The mucous layer, composed of glycosylated biopolymers (mucins), presents sialic acid that binds to ligands on the viral envelope and can be irreversibly cleaved by viral enzymes. It was recently discovered that filamentous IAVs exhibit directed persistent motion along their long axis on sialic acid-coated surfaces. This study demonstrates through stochastic simulations and mean-field theory, how IAVs harness a ‘burnt-bridge’ Brownian ratchet mechanism for directed persistent translational motion. Importantly, our analysis reveals that equilibrium features of the system primarily control the dynamics, even out-of-equilibrium, and that ligand asymmetry allows for more robust directed transport. We show viruses occupy the optimal parameter range (‘Goldilocks zone’) for efficient mucous transport, possibly due to the evolutionary adaptation of enzyme kinetics. Our findings suggest novel therapeutic targets and provide insight into possible mechanisms of zoonotic transmission.
Exonic splice variant discovery using in vitro models of inherited retinal disease
Authors: Mullin Nathaniel Kevin , Bohrer Laura R. , Anfinson Kristin R. , Andorf Jeaneen L. , Mullins Robert F. , Tucker Budd A. , Stone Edwin M.
Published: May 2024

Correct identification of the molecular consequences of pathogenic genetic variants is essential to the development of allele-specific therapies. However, in some cases, such molecular effects may be ambiguous following genetic sequence analysis alone. One such case is exonic, codon-altering variants that are also predicted to disrupt normal RNA splicing. Here, we identify such cases in the context of inherited retinal disease.NR2E3c.932G>A (p.Arg311Gln) is a variant commonly associated with Enhanced S Cone Syndrome (ESCS). Previous studies using mutagenized cDNA constructs have shown that the arginine to glutamine substitution at position 311 of NR2E3 does not meaningfully diminish function of the rod-specific transcription factor. Using retinal organoids, we explored the molecular consequences ofNR2E3c.932G>A when expressed endogenously during human rod photoreceptor cell development. Retinal organoids carrying theNR2E3c.932G>A allele expressed a transcript containing a 186-nucleotide deletion of exon 6 within the ligand binding domain. This short transcript was not detected in control organoids or control human donor retina samples. A minigene containing exons 5 and 6 ofNR2E3showed sufficiency of the c.932G>A variant to cause the observed splicing defect. These results support the hypothesis that the pathogenicNR2E3c.932G>A variant leads to photoreceptor disease by causing a splice defect and not through an amino acid substitution as previously supposed. They also explain the relatively mild effect of Arg311Gln on NR2E3 functionin vitro. We also usedin silicoprediction tools to show that similar changes are likely to affect other inherited retinal disease variants in genes such asCEP290, ABCA4, andBEST1.
Gelatinous fibers develop asymmetrically for posture support of bends and coils in common bean vine
Authors: Onyenedum Joyce G. , Sousa-Baena Mariane S. , Acevedo Angelique A. , Hunt Lena , Glos Rosemary A.E. , Anderson Charles T.
Published: May 2024

Gelatinous (G)-fibers are common in the stems of twining vines (twiners), but their role remain unclear given the lack of developmental insights. Here, we characterize the developmental anatomy of G-fiber formation in common bean stems (Phaseolus vulgarisL., Fabaceae). G-fibers in common bean exhibit cell wall organization comparable to other species, consisting of cellulose and Rhamnogalacturonan-I pectins, with possible traces of lignin. We show that G-fibers are absent in the actively circumnutating stems, thus these tensile fibers are not associated with the dynamic searching movements characteristics of twiners. Instead, we found that after a subtle bend or dramatic coil is formed, G-fibers form asymmetrically on the concave side of the stem for posture maintenance. Therefore, G-fibers do not drive movement, but provide support for existing bends, thus stabilizing the helical conformation of twiners around its host to avoid slippage. Finally, we present common bean as an emergent system to study twiners and growth form diversity given its easy cultivation, self-pollination, fast growth, and habit diversity arising from plant breeding, and the ability to induce habit shifts through simple modifications to light conditions.
The vulnerability of overwintering insects to loss of the subnivium
Authors: Thompson Kimberly L. , Pauli Jonathan N. , Zuckerberg Benjamin
Published: May 2024

Winter climate change threatens the subnivium (i.e., the microhabitat that exists between the snowpack and the ground), and the community of species that depends on it for overwintering survival. One group of species that will likely exhibit an array of responses to subnivium loss are overwintering insects because they vary in their cold tolerance strategies and lower thermal limits. For an assemblage of eight insect species that range in their cold tolerance strategies and include both pollinators and pests, we investigated species-specific vulnerabilities to shifting subnivium conditions by applying information on each species’ supercooling point to spatially- and temporally-explicit models of minimum subnivium temperatures for three warming scenarios in the Great Lakes region in the United States: current conditions (i.e., control), +3°C, and +5°C. Although species varied in their vulnerabilities, our predictions indicated that exposure to lethal temperatures generally decreased under warming of 3°C, but increased under warming of 5°C, indicating that once enough warming happens, a tipping point is reached. We also found that freeze-tolerant species (i.e., species that can survive at temperatures below their supercooling point) possess a more cryptic vulnerability to winter climate change because sustained below-freezing temperatures were sufficient to induce vulnerability (i.e., predicted mortality), even when temperatures were above the supercooling point. This work provides a better understanding of the vulnerability of different insect species to winter climate change, which is critical because overwintering survival and the fitness consequences incurred during overwintering likely represent important bottlenecks for the population dynamics of subnivium-dependent species.
Evaluating the feasibility of medium chain oleochemical synthesis using microbial chain elongation
Authors: Agena Ethan , Gois Ian M. , Bowers Connor M. , Mahadevan Radhakrishnan , Scarborough Matthew J. , Lawson Christopher E.
Published: May 2024

Chain elongating bacteria are a unique guild of strictly anaerobic bacteria that have garnered interest for sustainable chemical manufacturing from carbon-rich wet and gaseous waste streams. They produce C6-C8medium-chain fatty acids which are valuable platform chemicals that can be used directly, or derivatized to service a wide range of chemical industries. However, the application of chain elongating bacteria for synthesizing products beyond C6-C8medium-chain fatty acids has not been evaluated. In this study, we assess the feasibility of expanding the product spectrum of chain elongating bacteria to C9-C12fatty acids, along with the synthesis of C6fatty alcohols, dicarboxylic acids, diols, and methyl ketones. We propose several metabolic engineering strategies to accomplish these conversions in chain elongating bacteria and utilize constraint-based metabolic modelling to predict pathway stoichiometries, assess thermodynamic feasibility, and estimate ATP and product yields. We also evaluate how producing alternative products impacts the growth rate of chain elongating bacteria via resource allocation modelling, revealing a trade-off between product carbon length and class versus cell growth rate. Together, these results highlight the potential for using chain elongating bacteria as a platform for diverse oleochemical biomanufacturing and offer a starting point for guiding future metabolic engineering efforts aimed at expanding their product range.

Graphical Abstract

In this work, the authors use constraint-based metabolic modelling and enzyme cost minimization to assess the feasibility of using metabolic engineering to expand the product spectrum of anaerobic chain elongating bacteria.

One Sentence Summary

In this work, the authors use constraint-based metabolic modelling and enzyme cost minimization to assess the feasibility of using metabolic engineering to expand the product spectrum of anaerobic chain elongating bacteria.
Machine learning models of human tissue microbiomes for tissue-of-origin prediction
Authors: Mahmoudabadi Gita , Quake Stephen R.
Published: May 2024

There is increasing interest in using microbial data diagnostically for tissue health monitoring such as in early cancer detection. To build such models, we need to understand whether normal tissue microbiomes can also be predictive of tissue of origin, and importantly ask how contaminants may contribute to model performance. In this study, using the Tabula Sapiens Microbiome dataset, we built machine learning models of human tissue microbiomes that can predict tissue of origin. This may in part explain how tumor types can be predicted based on the tumor microbiomes. We also demonstrate that machine learning models built using contaminants alone, though not as powerful as those built on true signal, can still predict tissue of origin. Reassuringly, the addition of contaminants to true signal does not increase the performance over models built on true signal. Overall, our findings raise the burden of proof for predictive models of the human tissue and tumor microbiomes. Without addressing the magnitude of contribution from contaminants to model performance, a model’s reproducibility and its clinical value becomes questionable. We also discuss the optimal microbial taxonomic resolution for building these models.
Predicting locus phylogenetic utility using machine learning
Authors: Knyshov Alexander , Walling Alexandra , Guccione Caitlin , Schwartz Rachel
Published: May 2024

Disentangling evolutionary signal from noise in genomic datasets is essential to building phylogenies. The efficiency of current sequencing platforms and workflows has resulted in a plethora of large-scale phylogenomic datasets where, if signal is weak, it can be easily overwhelmed with non-phylogenetic signal and noise. However, the nature of the latter is not well understood. Although certain factors have been investigated and verified as impacting the accuracy of phylogenetic reconstructions, many others (as well as interactions among different factors) remain understudied. Here we use a large simulation-based dataset and machine learning to better understand the factors, and their interactions, that contribute to species tree error. We trained Random Forest regression models on the features extracted from simulated alignments under known phylogenies to predict the phylogenetic utility of the loci. Loci with the worst utility were then filtered out, resulting in an improved signal-to-noise ratio across the dataset. We investigated the relative importance of different features used by the model, as well as how they correspond to the originally simulated properties. We further used the model on several diverse empirical datasets to predict and subset the least reliable loci and re-infer the phylogenies. We measure the impacts of the subsetting on the overall topologies, difficult nodes identified in the original studies, as well as branch length distribution. Our results suggest that subsetting based on the utility predicted by the model can improve the topological accuracy of the trees and their average statistical support, and limits paralogy and its effects. Although the topology generated from the filtered datasets may not always be dramatically different from that generated from unfiltered data, the worst loci consistently yielded different topologies and worst statistical support, indicating that our protocol identified phylogenetic noise in the empirical data.
Protocols for circulating neutrophil depletion in neonatal C57Bl/6 mice
Authors: Mukherjee Devashis , Satyavolu Sriram , Cioffi Sarah , Thomas Asha , Li Yuexin , Nayak Lalitha
Published: May 2024

Murine neonatal neutrophil depletion strategies have problems achieving deep neutrophil clearance and accurate residual neutrophil fraction detection. An isotype switch method can achieve profound neutrophil clearance using a combination of anti-Ly6G and anti-rat κ Ig light chain antibodies in adult C57Bl/6 mice, proven by extra- and intracellular Ly6G detection by flow cytometry. We adapted this technique to neonatal mice, testing four neutrophil depletion strategies in the peripheral circulation, bone marrow, and spleen. Four protocols were tested: P3 Ly6G and P1-3 Ly6G (anti-Ly6G on postnatal days (P) 3 and 1-3 respectively), and P3 Dual and P1-3 Dual (anti-Ly6G and anti-rat κ Ig light chain on P3 and P1-3 respectively). Intracellular and extracellular Ly6G presence was detected using flow cytometry. Isotype control antibodies were used as controls. P1-3 Dual protocol achieved significantly better neutrophil depletion than the P1-3 Ly6G or P3 Ly6G protocols (97% vs. 74% and 97% vs. 50%, respectively) in the peripheral circulation. The P3 Dual protocol alone was enough to achieve significantly better neutrophil clearance (93%) than any of the Ly6G alone protocols. The Ly6G alone protocols led to near-total elimination of extracellular Ly6G. However, there was a significant presence of intracellular Ly6G in the CD45+ cell population, evading detection by extracellular Ly6G antibody-based detection methods. P3 protocols perform better than P1-3 protocols for bone marrow and splenic neutrophil clearance. Thus, the P3 Dual protocol might be the most effective and ethical protocol to induce profound neutrophil depletion in neonatal mice, an alternative to daily anti-Ly6G injections.

Summary Sentence

Dual antibody-based neutrophil depletion effectively induces circulating neutrophil clearance in neonatal mice.
Utilizing transcriptomics and metabolomics reveal drought tolerance mechanism inNicotiana tabacum
Authors: Yin Quanyu , Feng Zhao , Ren Zhichao , Wang Hui , Wu Dongling , Jaisi Amit , Yang Mengquan
Published: May 2024

The development and growth of plants are significantly impacted by adverse surroundings, particularly drought conditions. The yield and quality of plants, in particular, are heavily reliant on the presence of favorable growth conditions. Here, we performed comprehensive research to investigate phenotype, physiological characteristics, transcriptomic and metabolomic changes inNicotiana tabacum(N. tabacum) in responses to drought stress (DS). This work aimed to investigate the detailed responses ofN. tabacumto DS under different drought conditions (CK, well-watered; LD, light drought; MD, moderate drought and SD, severe drought).N. tabacumgrew normally under CK but was inhibited under LD, MD and SD stress; the relative water content, transpiration rate and protective enzyme activity significantly influenced under DS. In the LD/CK, MD/CK and SD/CK comparison groups, there were 7483, 15558 and 16876 differentially expressed genes (DEGs), respectively, and 410, 485 and 523 differentially accumulated metabolites (DAMs), respectively. The combined analysis of transcriptomic and metabolomic data unveiled the significant involvement of phenylpropanoid biosynthesis in theN. tabacum’s response to drought stress. These findings characterized the key metabolites and genes in responses to drought stress inN. tabacum, hence offering valuable insights into the underlying mechanisms driving these responses to DS and maintaining plant health under climate change.
Depicting the regulatory role of JZOL on TRP channels in the treatment of Acute Bronchitis based on the combination of clinical trials, computational analysis and in vivo experiments
Authors: Fan Qinhua , Wu Chongming , Du Yawei , Wang Boyang , Xie Yanming , Zhang Zeling , Su Wenquan , Wang Zizhuo , Xu Changchang , Li Xueke , Ding Ying , An Xinjiang , Chen Jing , Xiao Yunying , Yu Rong , Li Nan , Wang Juan , Teng Yiqun , Lv Hongfen , Yang Nian , Wen Yuling , Huang Xiaoli , Pan Wei , Liu Yufeng , Xi Xueqin , Zhao Qianye , Liu Changshan , Xu Jian , Zhang Haitao , Zhuo Lie , Rong Qiangquan , Xia Yu , Shen Qin , Li Shao , Wang Junhong , Wu Shengxian
Published: May 2024

The comparison between traditional Chinese medicine Jinzhen Oral Liquid (JZOL) and western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or Ambroxol Hydrochloride and Clenbuterol Hydrochloride Oral Solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This head to head randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1β/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1 and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels was the key mechanism of action.
Trophic adaptation of large terrestrial omnivores to global change
Authors: Albrecht Jörg , Bocherens Hervé , Hobson Keith A , Drucker Dorotheé G , Sergiel Agnieszka , Swenson Jon E , Zedrosser Andreas , Marciszak Adrian , Iregren Elisabeth , Drenzel Leena , Kyselý René , Lipecki Grzegorz , Makowiecki Daniel , Wagner Jan , Zwijacz-Kozica Tomasz , Fritz Susanne A , Revilla Eloy , Selva Nuria
Published: May 2024

Large omnivores at the top of food webs play a key role in ecosystems, as their ability to feed on multiple trophic levels stabilizes food-web dynamics and impacts ecosystem functioning. However, it is largely unexplored how large omnivores adapt their trophic interactions to altered resource availability under global change, particularly in terrestrial ecosystems. Here, we combine macroecological and paleoecological approaches and reveal that extant bears, the largest terrestrial omnivores, adapt their trophic position in food webs dynamically to net primary productivity and growing season length. Throughout their geographic ranges, extant bears occupy higher trophic positions in unproductive ecosystems with short growing seasons than in productive ecosystems with long growing seasons. Consistent with this geographic pattern, the trophic position of the brown bear sharply decreased at the transition from the Late Pleistocene to the Holocene, coinciding with an increase in net primary productivity and growing season length. These findings demonstrate that trophic interactions of omnivores are not static but change dynamically in response to environmental change. Our findings suggest that global change impacts on primary production and vegetation seasonality may trigger shifts in the functional role of omnivores, with consequences for food webs and ecosystem functions.
Early precursor-derived pituitary gland tissue-resident macrophages play a pivotal role in modulating hormonal balance
Authors: Lehtonen Henna , Jokela Heli , Hofmann Julian , Tola Lauriina , Mehmood Arfa , Ginhoux Florent , Becher Burkhard , Greter Melanie , Salmi Marko , Gerke Heidi , Rantakari Pia
Published: May 2024

The pituitary gland is the central endocrine regulatory organ underneath the brain, producing and releasing a variety of hormones that coordinate major body functions. The physical location of the pituitary gland underneath the brain, though outside the protective blood-brain barrier, leads to a unique immune environment of the pituitary that has not been studied. Here, we defined the development, diversity, spatial niche, and origin of the pituitary gland macrophage subsets using single cell transcriptomics, fate mapping, and imaging. We identified early yolk sac precursors solely seeding pituitary gland macrophages which are maintained by proliferation. Macrophage depletion experiments unveiled the essential contribution of early macrophages in the pituitary gland’s hormonal production and in modulating the post-pubertal expression of genes related to the sexually dimorphic processes regulated by the pituitary gland. Altogether, these findings provide novel information on pituitary gland macrophages and advance our understanding of immune-endocrine system crosstalk.