bluuebunny/crossref_metadata_2025 huggingface dataset:
Polysaccharide Peptide Treatment Eliminates Strawberry Viruses and Promotes Strawberry Plant Growth and Rooting in Tissue Culture Media
Authors: Li Danyang , Sujata Shrestha , Kang Kun , Pang Hanyu , Li Yin , Hou Caiting , Jelkmann Wilhelm , Wu Yunfeng , Zhao Lei
Published: February 2024

Based on our previous finding that polysaccharide peptide (PSP) has substantial antiviral activity, we cultured strawberry plants infected with strawberry mild yellow edge virus (SMYEV) or strawberry vein banding virus (SVBV) in Murashige and Skoog (MS) media supplemented with PSP to test its ability to eliminate these viruses. PSP not only improved the elimination of SMYEV and SVBV but also promoted the growth and rooting of strawberry plants in tissue culture. On the 45th day, the average height of the ‘Ningyu’ strawberry plants in the 1-mg/ml PSP treatment group was 1.91 cm, whereas that of the plants in the control group was 1.51 cm. After the same time point, the number of new leaves on the tissue culture media supplemented with 1 mg/ml and 500 μg/ml of PSP and without PSP were 4.92, 4.41, and 3.53, respectively. PSP also promoted strawberry rooting and significantly increased both the length and number of roots. In addition, after treatment with the 1-mg/ml PSP treatment in tissue culture for 45 days followed by meristem-shoot-tip culture, the elimination rates of SMYEV and SVBV in regenerated ‘Ningyu’ strawberry plants ranged from 60 to 100%. This study investigated the use of the antiviral agent PSP for virus elimination. PSP has a low production cost and thus has great application potential for virus elimination in crop plants.
Seed Priming for Defense Priming: An Innovative Approach to Enhance the Resilience of Crop Plants to Biotic and Abiotic Stresses
Authors: Bruno Jobelle , Ham Jong Hyun
Published: February 2024

Seed priming (a.k.a. seed treatment) is an excellent cost-effective practice to improve the growth and health of crop plants. Defense priming is a plant defense mechanism gained through the exposure to primary stimuli, which sets the plant up for more rapid and robust defense responses against severe biotic and abiotic challenges. Here, we discuss how the defense-priming mechanism could be implemented efficiently through the seed-priming technology and introduce previous related studies as the theoretical basis for this strategy to augment crop resistance.
The Significance of the Redox Gene in the Prognosis and Therapeutic Response of Glioma
Authors: Niu Huatao , Cao Honghua , Liu Xin , Chen Yanbei , Cheng Zhaojin , Long Jinyong , Li Fuhua , Sun Chaoyan , Zuo Pin
Published: February 2024

Objective:

Glioblastoma (GBM) is a fatal adult central nervous system tumor. Due to its high heterogeneity, the survival rate and prognosis of patients are poor. Thousands of people die of this disease every year all over the world. At present, the treatment of GBM is mainly through surgical resection and the combination of later drugs, radiotherapy, and chemotherapy. An abnormal redox system is involved in the malignant progression and treatment tolerance of glioma, which is the main reason for poor survival and prognosis. The construction of a GBM redox-related prognostic model may be helpful in improving the redox immunotherapy and prognosis of GBM.

Methods:

Based on glioma transcriptome data and clinical data from The Cancer Genome Atlas, databases, a risk model of redox genes was constructed by univariate and multivariate Cox analysis. The good prediction performance of the model was verified by the internal validation set of The Cancer Genome Atlas, and the external data of Chinese Glioma Genome Atlas.

Results:

The results confirmed that the higher the risk score, the worse the survival of patients. Age and isocitrate dehydrogenase status were significantly correlated with risk scores. The analysis of immune infiltration and immunotherapy found that there were significant differences in the immune score, matrix score, and ESTIMATE score between high and low-risk groups. reverse transcription polymerase chain reaction and immunohistochemical staining of glioma samples confirmed the expression of the hub gene.

Conclusion:

Our study suggests that the 5 oxidative-related genes nitricoxidesynthase3, NCF2, VASN, FKBP1B, and TXNDC2 are hub genes, which may provide a reliable prognostic tool for glioma clinical treatment.
Predicting Colonic Neoplasia Surgical Complications: A Machine Learning Approach
Authors: Nwaiwu Chibueze A. , Perla Krissia Rivera , Abel Logan B. , Sears Isaac J , Barton Andrew T. , Peterson Race C. , Liu Yao Z. , Khatri Ishaani S , Sarkar Indra N. , Shah Nishit
Published: February 2024

BACKGROUND:

A range of statistical approaches have been used to help predict outcomes associated with colectomy. The multifactorial nature of complications suggest that machine learning algorithms may be more accurate in determining postoperative outcomes by detecting nonlinear associations, which are not readily measured by traditional statistics.

OBJECTIVE:

The aim of this study was to investigate the utility of machine learning algorithms to predict complications in patients undergoing colectomy for colonic neoplasia.

DESIGN:

Retrospective analysis using decision tree, random forest, and artificial neural network classifiers to predict postoperative outcomes.

SETTINGS:

National Inpatient Sample database (2003-2017).

PATIENTS:

Adult patients who underwent elective colectomy with anastomosis for neoplasia.

INTERVENTIONS(S) IF ANY:

N/A.

MAIN OUTCOME MEASURES:

Performance was quantified using sensitivity, specificity, accuracy, and area-under-the-curve-receiver-operator-characteristic to predict the incidence of anastomotic leak, prolonged length of stay, and inpatient mortality.

RESULTS:

A total of 14,935 patients (4,731 laparoscopic, 10,204 open) were included. They had an average age of 67±12.2 years and 53% were female. The three machine learning models successfully identified patients who developed the measured complications. Although differences between model performance were largely insignificant, the neural network scored highest for most outcomes: predicting anastomotic leak, area-under-the-curve-receiver-operator-characteristic 0.88/0.93 (open/laparoscopic, 95% CI, 0.73-0.92/0.80-0.96); prolonged length of stay, area-under-the-curve-receiver-operator-characteristic 0.84/0.88 (open/laparoscopic, 95% CI, 0.82-0.85/0.85-0.91); and inpatient mortality, area-under-the-curve-receiver-operator-characteristic 0.90/0.92 (open/laparoscopic, 95% CI, 0.85-0.96/0.86-0.98).

LIMITATIONS:

The patients from the National Inpatient Sample database may not be an accurate sample of the population of all patients undergoing colectomy for colonic neoplasia and does not account for specific institutional and patient factors.

CONCLUSIONS:

Machine learning predicted postoperative complications in patients with colonic neoplasia undergoing colectomy with good performance. Though validation using external data and optimization of data quality will be required, these machine learning tools show great promise in assisting surgeons with risk-stratification of perioperative care to improve postoperative outcomes. See Video Abstract.
Association of Perioperative Antibiotics with the Prevention of Postoperative Fistula after Cleft Palate Repair
Authors: Davies Alex , Davies Amy , Main Barry , Wren Yvonne , Deacon Scott , Cobb Alistair , McLean Neil , David David , Chummun Shaheel
Published: February 2024

Background:

There is debate amongst surgeons regarding the use of antibiotics to prevent fistulae after palatoplasty. Prescribing should be evidence based, as antibiotic stewardship is integral to reducing antibiotic resistance. Our aim was to determine whether differing perioperative regimens affect the prevalence of postoperative fistulae.

Methods:

The sample comprised participants from the Cleft Collective who had undergone palatoplasty. Participants were recruited across all 16 UK cleft centers between 2013 and 2021. The exposure was perioperative antibiotic regimen prescribed at the time of palatoplasty. The primary outcome was the presence of palatal fistula.

Results:

Fistula data were available for 167 participants when exploring antibiotic regimen and for 159 when exploring antibiotic agent. There was no evidence to suggest a difference in fistula rate between those receiving antibiotics on induction only versus as an inpatient or up to 7 days postoperatively (χ2 = 4.57; P = 0.10). There was no evidence to suggest a difference in fistula rate between those who received co-amoxiclav and those who had an alternative antibiotic (χ2 = 0.16; P = 0.69). Postoperative fistulae increased with the extent of the cleft (χ2 = 20.39; P < 0.001). When adjusting for cleft type, no evidence of an association between antibiotic regimen and fistulae was found (inpatient antibiotics: OR 1.36; 95% confidence interval, 0.53–3.51; antibiotics up to 7 days postoperatively: OR 0.68; 95% confidence interval, 0.26–1.80).

Conclusions:

The choice of antibiotic and dosing regimen does not influence the formation of postoperative fistulae. These results should be supported by interventional trials.
Histopathologic Analysis of a Recalcitrant Calcaneal Wound Treated Using a Synthetic Hybrid-scale Fiber Matrix
Authors: Harder Justin G. , Hernandez Evan J. , MacEwan Matthew M. , Sallade Emily R. , Warraich Irfan , Gaschen Paul , MacKay Brendan J.
Published: February 2024

Traditionally, full-thickness wounds with exposed structures are treated with flap coverage or dermal regenerative templates. Most dermal regenerative templates are biologic in origin, but recently synthetic options have become available. One such product is a synthetic hybrid-scale fiber matrix (SHSFM). In this case, SHSFM was used to treat a recalcitrant calcaneal wound. After the wound granulated, it was biopsied, and histopathologic analysis was conducted. A 16-year-old woman involved in a motor vehicle collision sustained multiple traumatic injuries which were stabilized. Postoperatively, she developed a calcaneal infection and associated wound, which developed into a chronic, nonhealing wound. Failed treatments included removal of hardware, multiple debridements, and advanced wound therapies. An SHSFM was then trialed, which led to granulation of the wound without infection. Despite wound healing, the patient subsequently elected to undergo a below-the-knee amputation due to pain and functional disability from posttraumatic ankle arthritis. The heel was biopsied at the time of amputation for analysis. Pathologists noted excellent granulation tissue formation and complete coverage of the wound surface area and 75% of the wound depth, which included epithelialization and decreasing inflammation at wound edges. Collagen deposition and numerous interspersed blood vessels were present. Foreign material and bacteria were absent. No osteomyelitis was observed. This analysis provided the opportunity to investigate the in vivo regenerate from a novel synthetic SHSFM. Given the uniqueness and challenges presented in this case, the usage of this relatively new product warrants further investigation with larger populations and assorted wound etiologies.
Early Results on the Efficacy of Demineralized Bone Matrix, Bone Morphogenic Protein, and Freeze-dried Bone Chips in Alveolar Cleft Repair
Authors: Marquez Jessica L. , Sudduth Jack , DeMay Henning , Kuo Keith , Battistini Andrea , Yamashiro Duane K. , Siddiqi Faizi A. , Gociman Barbu
Published: February 2024

Background:

Conventional treatment for alveolar cleft repair is done using autologous iliac crest alveolar bone graft (ABG). However, this method may not be ideal in all patients. Analysis of the efficacy of a mixture of demineralized bone matrix (DBX), bone morphogenic protein (rhBMP-2), and freeze-dried bone chips (FDBC) as an alternative for alveolar cleft repair was performed.

Methods:

Consecutive patients from August 2019 to June 2022 undergoing early alveolar cleft repair, concomitant hard palate and alveolar cleft repair, secondary alveolar cleft repair, and regrafting from a previously failed ABG were analyzed. Computed tomography scans were performed to evaluate graft take at least 6 months postoperatively. Images were reviewed and scored. Alveolar graft height and graft thickness were recorded. A standardized scoring system was developed, with a score of 0 representing no graft take and 3 representing best possible graft take.

Results:

Fifty-five consecutive alveolar clefts (43 patients) were identified as having undergone ABG and satisfied all the other inclusion criteria. Of these, 29 underwent first time ABG and 26 underwent redo ABG. The mean graft height and graft thickness recorded for all clefts was 2.2 and 2.0, respectively.

Conclusions:

Early results evaluating the efficacy of ABG using DBX, rhBMP-2, and FDBC show feasibility in regard to both graft height and thickness when using a maxillary computed tomography scan to measure the bone graft take. These results suggest that DBX, rhBMP-2, and FDBC may act as a versatile bone graft material in cleft care, although further studies are needed to determine long-term outcomes.
Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment
Authors: Zhu Yu-Xin , Tang Zi-Ling , Lu Lu , Qiu Zuo-Cheng , Pan Dabo , Yu Yang , Xiao Hui-Hui , Wong Man-Sau
Published: February 2024

Objective:

Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast proliferation. Our previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance, a folk herbal medicine used to treat bone fractures and joint diseases in China, exerted bone-protective effects, and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1 (TPH-1). However, there is no direct evidence for the action of lignans on TPH-1. This study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone properties.

Methods:

Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to TPH-1. The cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 cells. The serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were determined.

Result:

The lignans showed high binding scores and binding affinities to TPH-1, inhibited the activity and protein expression of TPH-1, suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral density.

Conclusion:

This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases, including osteoporosis.
Lacrimal Gland Adenocarcinoma Clinicopathologic Features and Outcomes Compared With Those of Lacrimal Gland Adenoid Cystic Carcinoma
Authors: Goldberg Hila , Jiang Xinyang , Fan Janet , Zhao Jiawei , Ning Jing , Williams Michelle , Frank Steven , Moreno Amy , Gunn Brandon , Ferrarotto Renata , Esmaeli Bita
Published: February 2024

Purpose:

Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC).

Methods:

The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed.

Results:

The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All groups had male predominance. The initial T category was T2 in 50% (5/10) of de-novo ACs; 60% (6/10) of ex-pleomorphic ACs; and 59% (30/51) of ACCs. Perineural invasion was present in 33% (5/15) of ACs and 90% (45/50) of ACCs (p < 0.001). Of the 20 AC patients, 14 had eye-sparing surgery; 4 had orbital exenteration; and 2 had unresectable disease. All AC patients received postoperative radiotherapy and 15 (75%) received concurrent chemotherapy. Fourteen AC patients were tested for human growth factor receptor 2 expression, and 10 (71%) were human growth factor receptor 2 positive; 5 received human growth factor receptor 2-targeted therapy. AC and ACC had similar 5-year recurrence rates (20% and 33%, respectively, p = 0.31) and metastasis rates (20% and 34%, respectively, p = 0.30). de-novo AC, ex-pleomorphic AC, and ACC had similar 5-year disease-specific survival rates (80%, 79%, and 81%, respectively, p > 0.99).

Conclusions:

LG AC and ACC have similar baseline clinicopathologic features, except that perineural invasion is more common in ACC, and similar recurrence, metastasis, and survival rates. Human growth factor receptor 2-targeted therapy may be appropriate in some patients with LG AC.
A Simple Procedure of Fascia-Fat Grafting and Blepharoplasty as a Single-Stage Procedure for the Correction of Sunken Eyelids in Vietnamese Population
Authors: Hoang Thanh Tuan , Nguyen Kim Thanh
Published: February 2024

Purposes:

Upper sunken eyelids, which are characterized by the hollowness of the upper eyelids, often cause a poor aesthetic appearance. Herein, we present a simplified technique using fascia-fat grafts for volume augmentation combined with blepharoplasty as a single-stage procedure.

Methods:

From January 2021 to December 2021, 30 patients with sunken eyelids visiting our clinic for hollow eyelid treatment underwent a fascia-fat grafting derived from the inguinal crease combined with simultaneous eyelid reconstruction. A modified classification of sunken eyelids that was more suitable for the Asian population was proposed.

Results:

Postoperatively, edema and ptosis were transient and addressed thanks to proper massage and compresses. Two cases had scar fibers leading to a slight tension of upper eyelids at 6-month follow-up. This event was addressed by triamcinolone acetonide injections at 4–6-week intervals with satisfactory results. The orbital volume of all patients was satisfying and stable up to 12 months after the surgery. The satisfaction rate was 100% and 88.8% in group 1 and group 2, respectively, at 12-month follow-up.

Conclusions:

Fascia-fat grafting combined with blepharoplasty as a single-stage procedure was a simplified method that did not require varied types of surgical tools but brought satisfactory results. This method facilitated the routine procedure and eased surgeons in the clinical practices.
Body mass index and the risk of abdominal aortic aneurysm presence and post-operative mortality: a systematic review and dose-response meta-analysis
Authors: Wu Yihao , Zhang Hao , Jiang Deying , Yin Fanxing , Guo Panpan , Zhang Xiaoxu , Zhang Jian , Han Yanshuo
Published: February 2024

Background:

The clinical data regarding the relationships between body mass index (BMI) and abdominal aortic aneurysm (AAA) are inconsistent, especially for the obese and overweight patients. The aims of this study were to determine whether obesity is associated with the presence of AAA and to investigate the quantitative relationship between BMI and the risk of AAA presence and post-operative mortality.

Materials and Methods:

PubMed, Web of Science and Embase databases were used to search for pertinent studies updated to December 2023. The pooled relative risk (RR) with 95% confidence interval (CI) was estimated by conventional meta-analysis based on random effects model. Dose-response meta-analyses using robust-error meta-regression (REMR) model were conducted to quantify the associations between BMI and AAA outcome variables. Subgroup analysis, sensitivity analysis and publication bias analysis were performed according to the characteristics of participants.

Results:

18 studies were included in our study. The meta-analysis showed a higher prevalence of AAA with a RR of 1.07 in patients with obesity. The dose-response meta-analysis revealed a non-linear relationship between BMI and the risk of AAA presence. A “U” shape curve reflecting the correlation between BMI and the risk of post-operative mortality in AAA patients was also uncovered, suggesting the “safest” BMI interval [28.55, 31.05] with the minimal RR.

Conclusions:

Obesity is positively but nonlinearly correlated with the increased risk of AAA presence. BMI is related to AAA post-operative mortality in a “U” shaped curve, with the lowest RR observed among patients suffering from overweight and obesity. These findings offer a preventive strategy for AAA morbidity and provide guidance for improving the prognosis in patients undergone AAA surgical repair.
Central Nervous System Metastases in Pediatric Patients With Ewing Sarcoma
Authors: Slatnick Leonora R. , Cost Carrye , Garrington Timothy , Donaldson Nathan , Macy Margaret E.
Published: February 2024

Metastatic central nervous system (CNS) involvement is rare in pediatric primary extracranial Ewing sarcoma (ES). We describe the incidence and course of 6 patients with extracranial ES who developed metastatic CNS lesions treated at a single institution. The median time to CNS disease detection was 16.3 months (10.0-28.3 months). Event-free and overall survival after CNS disease detection were 1.9 months (0.4 to 10.3 months) and 4.6 months (1.1 to 50.9 months), respectively. One patient was alive at the time of analysis. Clinical status and ability to obtain disease control should be considered when making decisions regarding aggressive interventions in these patients with poor prognosis.
Modified Mustardé and Superolateral Periosteal Flaps for Full-Thickness Defects of Medial and Central Lower Eyelid
Authors: Ongkasuwan Pattana
Published: February 2024

Background

Reconstructing full-thickness defects involving 50% to 75% of the horizontal length of the lower eyelid after medial and central full-thickness block resection can be challenging. As a disadvanatge, 1-stage reconstructions may require a free graft reconstruction of the posterior lamella. In addition, 2-stage reconstructions are associated with several complications, including erythema, and the eye must be temporarily closed after surgery.

Methods

The present study describes a single-surgeon retrospective case series. Five patients diagnosed with basal cell carcinoma underwent wide full-thickness block resection with optimal excision margins (3–5 mm). Subsequently, 1-stage reconstruction was performed using the modified Mustardé flap, incised using the transconjunctival approach. This flap comprised the skin, muscle, tarsus, and conjunctival flap raised from the lateral canthus through a lateral cantholysis procedure, and then extended to the lateral cheek. The flap was medially transposed to cover the medial and central lower eyelid defect. The superolateral periosteal flap was harvested from the superolateral orbital rim attached to the lateral border of the tarsus of the modified Mustardé flap. The lateral forniceal conjunctiva was released from the retractor and advanced superiorly to cover the inner surface.

Results

The study included 3 men and 2 women, with a mean age of 71 years (range, 62–90 years). Histological evaluations confirmed tumor-free margins in all cases. The average follow-up duration was 20 months (6–60 months), with no tumor recurrence. None of the patients developed long-term complications, such as ectropion, entropion, lagophthalmos, trichiasis, symblepharon, erythema, wound dehiscence, or flap necrosis. All patients had minimal scarring, and no secondary surgical interventions were necessary.

Conclusions

This case series demonstrates the efficacy of the combined modified Mustardé and superolateral periosteal flaps in 1-stage reconstruction of full-thickness defects involving 50% to 75% of the horizontal length of the medial and central lower eyelid without compromising functional and aesthetic outcomes.
Quantifying Perioperative Risks for Antireflux and Hiatus Hernia Surgery
Authors: Liu David S. , Wong Darren J. , Goh Su Kah , Fayed Aly , Stevens Sean , Aly Ahmad , Bright Tim , Weinberg Laurence , Watson David I. ,   on behalf of the PROTECTinG Antireflux Surgery study group
Published: February 2024

Objective:

Using a comprehensive Australian cohort, we quantified the incidence and determined the independent predictors of intraoperative and postoperative complications associated with antireflux and hiatus hernia surgeries. Additionally, we performed an in-depth analysis to understand the complication profiles associated with each independent risk factor.

Background:

Predicting perioperative risks for fundoplication and hiatus hernia repair will inform treatment decision-making, hospital resource allocation, and benchmarking. However, available risk calculators do not account for hernia anatomy or technical aspects of surgery in estimating perioperative risk.

Methods:

Retrospective analysis of all elective antireflux and hiatus hernia surgeries in 36 Australian hospitals over 10 years. Hierarchical multivariate logistic regression analyses were performed to determine the independent predictors of intraoperative and postoperative complications accounting for patient, surgical, anatomical, and perioperative factors.

Results:

A total of 4301 surgeries were analyzed. Of these, 1569 (36.5%) were large/giant hernias and 292 (6.8%) were revisional procedures. The incidence rates of intra- and postoperative complications were 12.6% and 13.3%, respectively. The Charlson Comorbidity Index, hernia size, revisional surgery, and baseline anticoagulant usage independently predicted both intraoperative and postoperative complications. These risk factors were associated with their own complication profiles. Finally, using risk matrices, we visualized the cumulative impact of these four risk factors have on the development of intraoperative, overall postoperative, and major postoperative complications.

Conclusions:

This study has improved our understanding of perioperative morbidity associated with antireflux and hiatus hernia surgery. Our findings group patients along a spectrum of perioperative risks that informs care at an individual and institutional level.
Leveraging uncertainty quantification to optimise CRISPR guide RNA selection
Authors: Schmitz Carl , Bradford Jacob , Salomone Robert , Perrin Dimitri
Published: February 2024

CRISPR-based genome editing relies on guide RNA sequences to target specific regions of interest. A large number of methods have been developed to predict how efficient different guides are at inducing indels. As more experimental data becomes available, methods based on machine learning have become more prominent. Here, we explore whether quantifying the uncertainty around these predictions can be used to design better guide selection strategies. We demonstrate how using a deep ensemble approach achieves better performance than utilising a single model. This approach can also provide uncertainty quantification. This allows to design, for the first time, strategies that consider uncertainty in guide RNA selection. These strategies achieve precision over 91% and can identify suitable guides for more than 93% of genes in the mouse genome. Our deep ensemble model is available athttps://github.com/bmdslab/CRISPR_DeepEnsemble.
Cumulus: A federated EHR-based learning system powered by FHIR and AI
Authors: McMurry Andrew J. , Gottlieb Daniel I. , Miller Timothy A. , Jones James R. , Atreja Ashish , Crago Jennifer , Desai Pankaja M. , Dixon Brian E. , Garber Matthew , Ignatov Vladimir , Kirchner Lyndsey A. , Payne Philip R. O. , Saldanha Anil J. , Shankar Prabhu R. V. , Solad Yauheni V. , Sprouse Elizabeth A. , Terry Michael , Wilcox Adam B. , Mandl Kenneth D.
Published: February 2024

Objective

To address challenges in large-scale electronic health record (EHR) data exchange, we sought to develop, deploy, and test an open source, cloud-hosted app ‘listener’ that accesses standardized data across the SMART/HL7 Bulk FHIR Access application programming interface (API).

Methods

We advance a model for scalable, federated, data sharing and learning. Cumulus software is designed to address key technology and policy desiderata including local utility, control, and administrative simplicity as well as privacy preservation during robust data sharing, and AI for processing unstructured text.

Results

Cumulus relies on containerized, cloud-hosted software, installed within a healthcare organization’s security envelope. Cumulus accesses EHR data via the Bulk FHIR interface and streamlines automated processing and sharing. The modular design enables use of the latest AI and natural language processing tools and supports provider autonomy and administrative simplicity. In an initial test, Cumulus was deployed across five healthcare systems each partnered with public health. Cumulus output is patient counts which were aggregated into a table stratifying variables of interest to enable population health studies. All code is available open source. A policy stipulating that only aggregate data leave the institution greatly facilitated data sharing agreements.

Discussion and Conclusion

Cumulus addresses barriers to data sharing based on (1) federally required support for standard APIs (2), increasing use of cloud computing, and (3) advances in AI. There is potential for scalability to support learning across myriad network configurations and use cases.
Microbes as manipulators of developmental life-history
Authors: Kustra Matthew C. , Carrier Tyler J.
Published: February 2024

Marine invertebrates mainly reproduce by energy-poor eggs that develop into feeding larvae or energy-rich eggs that develop into non-feeding larvae1–4. Transitions between these reproductive strategies have been studied in detail5–7, yet the evolutionary factor(s) responsible for these switches remains elusive. Here, we use theoretical models to show that microbes with the capacity to manipulate host reproduction are one possible factor. We report that microbial manipulators create a sperm-limited environment that selects for larger eggs by shifting the host’s sex ratio towards female dominance and, as a result, serve as the evolutionary driver of transitions in the developmental life-history for marine invertebrates. Loss of a microbial manipulator can then recover the ancestral developmental life-history. We also document more than a dozen genera of marine invertebrates from throughout the world’s oceans that fit the framework of a microbe-induced switch between these predominate reproductive strategies. We anticipate that microbial manipulators have a yet-to-be appreciated influence on the life-history strategies of marine invertebrates. We find it paramount to understand if transitions in developmental life-history also occur without microbial manipulators as well as if the underlying mechanisms of these manipulations are convergent with terrestrial systems.
Directing Cell Delivery to Murine Atherosclerotic Aortic Lesions via Targeting Inflamed Circulatory Interface using Nanocarriers
Authors: Huerta Carlos Theodore , Zhang Leiming , Ortiz Yulexi Y. , Li Yan , Zeynaloo Elnaz , Dikici Emre , Siahaan Teruna J. , Deo Sapna K. , Daunert Sylvia , Liu Zhao-Jun , Velazquez Omaida C.
Published: February 2024

Stem cell therapy holds significant potential for many inflammatory diseases and regenerative medicine applications. However, delivery of therapeutic cells to specific disease sites after systemic administration without indiscriminate trafficking to other non-target tissues is a major limitation of current cell therapies. Here, we describe a novel nanocarrier-directed targeted cell delivery system that enables cell surface coating with dendrimer nanocarriers containing adhesion moieties to serve as a global positioning system “GPS” to guide circulating cells to targeted lesions and mediate the anchoring of cells at the inflammation site. By exploiting cell surface ligands/receptors selectively and/or molecular moieties that are highly expressed on activated endothelium in pathologic disease states, nanocarrier-coated cells containing the counterpart binding receptors/ligands can be enabled to specifically traffic to and dock at vasculature within target lesions. We demonstrate the efficacy of the I-domain fragment of LFA-1 (idLFA-1) complexed to modified nanocarriers to facilitate homing of mesenchymal stem cells (MSCs) to inflamed luminal endothelial cells on which ICAM-1 is highly expressed in a murine model of aortic atherosclerosis. Our method can overcome challenges imposed by the high velocity and dynamic circulatory flow of the aorta to successfully deliver MSCs to atherosclerotic regions and allow for docking of the potentially therapeutic and immunomodulating cells. This targeted cell-delivery platform can be tailored for selective systemic delivery of various types of therapeutic cells to different disease areas.
BiaPy: Accessible deep learning on bioimages
Authors: Franco-Barranco Daniel , Andrés-San Román Jesús A. , Hidalgo-Cenalmor Ivan , Backová Lenka , González-Marfil Aitor , Caporal Clément , Chessel Anatole , Gómez-Gálvez Pedro , Escudero Luis M. , Wei Donglai , Muñoz-Barrutia Arrate , Arganda-Carreras Ignacio
Published: February 2024

BiaPy is an open-source library and application that streamlines the use of common deep learning approaches for bioimage analysis. Designed to simplify technical complexities, it offers an intuitive interface, zero-code notebooks, and Docker integration, catering to both users and developers. While focused on deep learning workflows for 2D and 3D image data, it enhances performance with multi-GPU capabilities, memory optimization, and scalability for large datasets. Although BiaPy does not encompass all aspects of bioimage analysis, such as visualization and manual annotation tools, it empowers researchers by providing a ready-to-use environment with customizable templates that facilitate sophisticated bioimage analysis workflows.
Enzyme Bioink for the 3D Printing of Biocatalytic Materials
Authors: Altevogt Luca A. , Sheikh Rakib H. , Molley Thomas G. , Yong Joel , Liang Kang , Spicer Patrick , Kilian Kristopher A. , Wich Peter R.
Published: February 2024

The field of 3D biofabrication faces major challenges on the road to printing fully functional tissues and organs. One of them is adding functionality to the newly formed tissue for replicating an active biochemical environment. Native extracellular matrices sequester numerous bioactive species, making the microenvironment biochemically active. On the other hand, most 3D-printed constructs have limited activity, serving merely as mechanical scaffolding. Here we demonstrate active scaffolding through the integration of biocatalytic enzymes within the bioink. Enzymes are an attractive class of biocompatible and substrate-specific bioactive agents that can improve tissue regeneration outcomes. However, the difficulty in the application remains in providing enzymes at the targeted site in adequate amounts over an extended time.

In this work, a durable biocatalytic active enzyme bioink for 3D extrusion-based bioprinting is developed by covalently attaching the globular enzyme horseradish peroxidase (HRP) to a gelatin methacrylate (Gel-MA) biopolymer scaffold. Upon introducing methacrylate groups on the surface of the enzyme, it undergoes photo-crosslinking in a post-printing step with the methacrylate groups of Gel-MA without compromising its activity. As a result, HRP becomes a fixed part of the hydrogel network and achieves higher stability inside the gel which results in a higher concentration and catalytic activity for a longer time than solely entrapping the protein inside the hydrogel. We also demonstrate the cytocompatibility of this enzyme bioink and show its printing capabilities for precise applications in the field of tissue engineering. Our approach offers a promising solution to enhance the bioactive properties of 3D-printed constructs, representing a critical step towards achieving functional biofabricated tissues.
Multi-class Modeling Identifies Shared Genetic Risk for Late-onset Epilepsy and Alzheimer’s Disease
Authors: Fu Mingzhou , Tran Thai , Eskin Eleazar , Lajonchere Clara , Pasaniuc Bogdan , Geschwind Daniel H. , Vossel Keith , Chang Timothy S
Published: February 2024

Background

Previous studies have established a strong link between late-onset epilepsy (LOE) and Alzheimer’s disease (AD). However, their shared genetic risk beyond theAPOEgene remains unclear. Our study sought to examine the shared genetic factors of AD and LOE, interpret the biological pathways involved, and evaluate how AD onset may be mediated by LOE and shared genetic risks.

Methods

We defined phenotypes using phecodes mapped from diagnosis codes, with patients’ records aged 60-90. A two-step Least Absolute Shrinkage and Selection Operator (LASSO) workflow was used to identify shared genetic variants based on prior AD GWAS integrated with functional genomic data. We calculated an AD-LOE shared risk score and used it as a proxy in a causal mediation analysis. We used electronic health records from an academic health center (UCLA Health) for discovery analyses and validated our findings in a multi-institutional EHR database (All of Us).

Results

The two-step LASSO method identified 34 shared genetic loci between AD and LOE, including theAPOEregion. These loci were mapped to 65 genes, which showed enrichment in molecular functions and pathways such as tau protein binding and lipoprotein metabolism. Individuals with high predicted shared risk scores have a higher risk of developing AD, LOE, or both in their later life compared to those with low-risk scores. LOE partially mediates the effect of AD-LOE shared genetic risk on AD (15% proportion mediated on average). Validation results from All of Us were consistent with findings from the UCLA sample.

Conclusions

We employed a machine learning approach to identify shared genetic risks of AD and LOE. In addition to providing substantial evidence for the significant contribution of theAPOE-TOMM40-APOC1gene cluster to shared risk, we uncovered novel genes that may contribute. Our study is one of the first to utilize All of Us genetic data to investigate AD, and provides valuable insights into the potential common and disease-specific mechanisms underlying AD and LOE, which could have profound implications for the future of disease prevention and the development of targeted treatment strategies to combat the co-occurrence of these two diseases.
Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study
Authors: Barad Alexa , Clark Andrew G. , O’Brien Kimberly O. , Pressman Eva K.
Published: February 2024

Background

Mendelian randomization (MR) studies suggest a causal effect of iron (Fe) status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on CVD risk factors. We aimed to investigate the effect of Fe status on CVD risk controlling for CVD risk factors.

Methods

Fe biomarker IVs (total Fe binding capacity (TIBC,n=208,422), transferrin saturation (TSAT,n=198,516), serum Fe (SI,n=236,612), ferritin (n=257,953)) were selected from a European GWAS meta-analysis. We performed two-sample univariate (UV) MR of each Fe trait on CVD outcomes (all-cause ischemic stroke (IS), cardioembolic IS (CES), large artery IS (LAS), small vessel IS (SVS), and coronary heart disease (CHD)) from MEGASTROKE (n=440,328) and CARDIoGRAMplusC4D (n=183,305). We then implemented multivariate (MV) MR conditioning on six CVD risk factors from independent European samples to evaluate their potential confounding and/or mediating effects on the observed Fe-CVD associations.

Results

With UVMR analyses, we found higher genetically predicted Fe status to be associated with a greater risk of CES (TSAT: OR 1.17 [95%CI 1.03, 1.33], SI: OR 1.21 [ 95%CI 1.02, 1.44]; TIBC: OR 0.81 [95%CI 0.69, 0.94]). The detrimental effects of Fe status on CES risk remained unaffected when adjusting for CVD risk factors (allP<0.05). Additionally, we found diastolic blood pressure (DBP) to mediate between 7.1-8.8% of the total effect of Fe status on CES incidence. While UVMR initially suggested a protective effect of Fe status on LAS and CHD, MVMR analyses factoring CVD risk factors revealed a complete annulment of this perceived protective effect (allP>0.05).

Discussion

Higher Fe status was associated with a greater risk of CES independent of CVD risk factors, and this effect was partly mediated by DBP. These findings support a role of Fe status as a modifiable risk factor for CES.
Quantifying internal conflicts and their threats to organismal form and fitness
Authors: Schenkel Martijn A. , Patten Manus M. , Ågren J. Arvid
Published: February 2024

Evolutionary biologists often treat organisms as both fitness-maximizing agents and as the primary level at which adaptation manifests. Yet, genes and cells may also seek to optimize their fitness by distorting the Mendelian rules of transmission or by influencing organismal traits for their own benefit. Organismal form and fitness are therefore threatened from within by selfish genes and cells. However, to what extent such internal conflicts actually harm individual organisms and threaten our concept of the organism as the sole bearer of adaptation remains unclear. We introduce a mathematical framework to capture the threat posed by internal conflicts and develop two metrics to measure their various forms of harm. We name these metrics fitness unity and trait unity, and use them to refer to the threats posed by internal conflicts to an organism’s role as the optimizing agent and the strategy wielded to achieve that optimization, respectively. We apply our framework to two examples of internal conflicts, genomic imprinting and sex ratio distortion, to illustrate how such harms from internal conflict may be quantified. We conclude by discussing the conditions under which internal conflict becomes sufficiently disruptive to organisms that it no longer makes sense to think of them as unified fitness-maximizing agents, but instead as adaptive compromises of multiple competing sub-agents.
TAF2 condensation in nuclear speckles links basal transcription factor TFIID to RNA splicing
Authors: Bhuiyan Tanja , Mendoza Sanchez Paulina K. , Arecco Niccolò , Kim Juhyeong , Nizamuddin Sheikh , Prunotto Andrea , Tekman Mehmet , Biniossek Martin L. , Koidl Stefanie , Hugel Thorsten , Arnold Sebastian J.
Published: February 2024

TFIID is an essential basal transcription factor, crucial for RNA polymerase II (pol II) promoter recognition and transcription initiation. The TFIID complex consists of the TATA-binding protein (TBP) and 13 TBP-associated factors (TAFs) that contain intrinsically disordered regions (IDRs) with currently unknown functions. Here, we show that a conserved IDR drives TAF2 condensation in nuclear speckles, independently of other TFIID subunits. Quantitative mass spectrometry analyses reveal that the TAF2 IDR specifically interacts with the nuclear speckle and spliceosome-associated protein SRRM2. Consequently, TAF2 recruits SRRM2 to TFIID to form non-canonical TFIID-SRRM2 complexes. Reduced SRRM2 recruitment elicits alternative splicing events in RNAs coding for proteins involved in transcription and transmembrane transport. Further, genome-wide binding analyses suggest TAF2 shuttling between nuclear speckles and pol II promoters. This study identifies an IDR of the basal transcription machinery as a molecular guide for protein partitioning into nuclear compartments, controlling protein complex composition and pre-mRNA splicing.
Examining the relationship between psychosocial adversity and inhibitory control: an fMRI study of children growing up in extreme poverty
Authors: Surani Zoya , Turesky Ted K , Sullivan Eileen , Shama Talat , Haque Rashidul , Islam Nazrul , Kakon Shahria Hafiz , Yu Xi , Petri William A , Nelson Charles , Gaab Nadine
Published: February 2024

Exposure to psychosocial adversity (PA) is associated with poor behavioral, physical, and mental health outcomes in adulthood. As these outcomes are related to alterations in developmental processes, growing evidence suggests that deficits in executive functions–inhibitory control in particular–may, in part, explain this relationship. However, literature examining the development of inhibitory control has been based on children in higher resource environments, and little is known how low resource settings might exacerbate the link between inhibitory control and health outcomes. In this context, we collected fMRI data during a Go/No-Go inhibitory control task and PA variables for 68 children 5 to 7 years of age living in Dhaka, Bangladesh, an area with a high prevalence of PA. The children’s mothers completed behavioral questionnaires to assess the child’s PA and their own PA. Whole-brain activation underlying inhibitory control was examined using the No-Go versus Go contrast, and associations with PA variables were assessed using whole-brain regressions. Childhood neglect was associated with weaker activation in the right posterior cingulate, whereas greater family conflict, economic stress, and maternal PA factors were associated with greater activation in the left medial frontal gyrus, right superior and middle frontal gyri, and left cingulate gyrus. These data suggest that neural networks supporting inhibitory control processes may vary as a function of exposure to different types of PA, particularly between those related to threat and deprivation. Furthermore, increased activation in children with greater PA may serve as a compensatory mechanism, allowing them to maintain similar behavioral task performance.
The role of prospective contingency in the control of behavior and dopamine signals during associative learning
Authors: Qian Lechen , Burrell Mark , Hennig Jay A. , Matias Sara , Murthy Venkatesh. N. , Gershman Samuel J. , Uchida Naoshige
Published: February 2024

Associative learning depends on contingency, the degree to which a stimulus predicts an outcome. Despite its importance, the neural mechanisms linking contingency to behavior remain elusive. Here we examined the dopamine activity in the ventral striatum – a signal implicated in associative learning – in a Pavlovian contingency degradation task in mice. We show that both anticipatory licking and dopamine responses to a conditioned stimulus decreased when additional rewards were delivered uncued, but remained unchanged if additional rewards were cued. These results conflict with contingency-based accounts using a traditional definition of contingency or a novel causal learning model (ANCCR), but can be explained by temporal difference (TD) learning models equipped with an appropriate inter-trial-interval (ITI) state representation. Recurrent neural networks trained within a TD framework develop state representations like our best ‘handcrafted’ model. Our findings suggest that the TD error can be a measure that describes both contingency and dopaminergic activity.