bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifications to the WHISTLE Flap Procedure for Correction of Secondary Cleft Lip Deformities
Authors: Collar Yagas Lucia , Bautista Catherine H. , Chen Joanna , Tausinga Telisha L. , Kim Erinn N. , Johns Dana N. , Gociman Barbu R.
Published: June 2024

Background:

The whistle deformity, a deficiency of tissue in the central upper lip, is a consequential outcome of primary cleft lip repair. Among multiple described reconstructive options, the wide-hinged island swing transposition labial enhancement (WHISTLE) flap procedure by Grewal et al has been shown to be a reliable technique that restores the continuity of the orbicularis oris muscle and creates a more natural appearing tubercle and central lip element. This article aims to refine the WHISTLE flap procedure with the addition of tailored mucomuscular flaps and an upper lip-lengthening mucosal Z-plasty.

Methods:

A total of 11 patients with a whistle deformity were examined. All underwent the WHISTLE flap procedure with tailored mucomuscular flaps and a mucosal Z-plasty. The patients were followed for a period of from 6 to 51.5 months. Pre- and postoperative photographs were used for objective outcome comparison.

Results:

From 2018 to 2023, a total of 11 patients with a whistle deformity were included in the final cohort, comprised four bilateral and seven unilateral cleft lips. Ten cases (90.1%) resulted in satisfactory postoperative cosmetic appearance and did not require further interventions. A single patient with a significant preoperative discrepancy between the upper and lower lip volumes had a postoperative residual deformity. None of the patients demonstrated any functional deficits associated with the procedure.

Conclusions:

The WHISTLE flap procedure with the proposed individual tailoring of the mucomuscular flap and Z-plasty for mucosal scar lengthening has excellent cosmetic outcomes and can be considered as the primary treatment modality in most patients with a whistle deformity.
Longitudinal Speech and Fistula Outcomes Following Primary Cleft Palate Repair at a Single Institution
Authors: Phillips John B. , Galarza Laura I. , Sink Matthew C. , Goza Shelby D. , Brown Madyson I. , Hopper Samuel J. , Brown Kathryn W. , Fernstrum Colton J. , Hoppe Ian C. , Humphries Laura S.
Published: June 2024

Introduction

Fistula formation and velopharyngeal insufficiency (VPI) are complications of cleft palate repair that often require surgical correction. The goal of the present study was to examine a single institution's experience with cleft palate repair with respect to fistula formation and need for surgery to correct velopharyngeal dysfunction.

Methods

Institutional review board approval was obtained. Patient demographics and operative details over a 10-year period were collected. Primary outcomes measured were development of fistula and need for surgery to correct VPI. Chi-square tests and independent t tests were utilized to determine significance (0.05).

Results

Following exclusion of patients without enough information for analysis, 242 patients were included in the study. Fistulas were reported in 21.5% of patients, and surgery to correct velopharyngeal dysfunction was needed in 10.7% of patients. Two-stage palate repair was associated with need for surgery to correct VPI (P = 0.014). Furlow palatoplasty was associated with decreased rate of fistula formation (P = 0.002) and decreased need for surgery to correct VPI (P = 0.014).

Conclusion

This study reiterates much of the literature regarding differing cleft palate repair techniques. A 2-stage palate repair is often touted as having less growth restriction, but the present study suggests this may yield an increased need for surgery to correct VPI. Prior studies of Furlow palatoplasty have demonstrated an association with higher rates of fistula formation. The present study demonstrated a decreased rate of fistula formation with the Furlow technique, which may be due to the use of the Children's Hospital of Philadelphia modification. This study suggests clinically superior outcomes of the Furlow palatoplasty over other techniques.
Characterization of group A streptococci causing invasive diseases in Sri Lanka
Authors: Weerasekara Madumali , Vidanapathirana Gihani , Li Carmen , Tennegedara Asanka , Dissanayake Rasadanie , Ekanayake Asela , Abeykoon Muditha , Kothalawala Mahen , Liyanapathirana Veranja , Ip Margaret
Published: June 2024

Group A β haemolytic streptococcus (GAS) or Streptococcus pyogenes is a human pathogen that causes an array of infections, including pharyngitis, cellulitis, impetigo, scarlet fever, toxic shock syndrome, and necrotizing fasciitis. The present study characterizes 51 GAS isolates from invasive infections in Sri Lanka, focusing on resistance profiles, genetic determinants of resistance, and virulence markers. Isolates were tested for sensitivity to penicillin, erythromycin, clindamycin, and tetracycline. The presence of erm(A), erm(B), and mef(A) was detected in erythromycin-resistant isolates, while tet(M) was detected in the tetracycline-resistant isolates. PCR was used to identify SpeA, SpeB, SpeC, SpeF, SpeG, smez, and ssa as virulence markers. Selected GAS isolates were emm-typed using the updated CDC protocol. All 51 isolates were susceptible to penicillin. The number of isolates non-susceptible to erythromycin was 16. The commonest resistance determinant identified was erm(B) (11/16). Tetracycline non-susceptibility was found in 36 (70.6 %) isolates and 26 of them contained the tet(M) gene. Thirteen (25.5 %) isolates were resistant to both tetracycline and erythromycin, while 12 (23.5 %) isolates were sensitive to both antibiotics. The commonest virulence markers detected among the isolates were SpeB (44, 86.3 %), SpeG (36, 70.6 %), and SpeF (35, 68.6 %), while SpeJ (15, 29.4 %), SpeA (10, 19.6 %), and ssa (5,9.8 %) were less common. The emm types were diverse. In conclusion, the GAS isolates studied showed resistance to erythromycin and tetracycline, while retaining universal susceptibility to penicillin. Additionally, these isolates exhibited diverse genetic backgrounds, displaying varying patterns of virulence genes and emm types.
Comparison of the virulence of community and hospital isolated Acinetobacter baumannii in HeLa cell line and insect model, Galleria mellonella
Authors: Muzahid Nazmul Hasan , Ramesh Aarthi , Siew Tan Hock , Hasan Md Zobaer , Narayanan Kumaran , Rahman Sadequr
Published: June 2024

Acinetobacter baumannii is an important nosocomial pathogen causing high infections and morbidity among affected individuals and most studies focus on nosocomial strains. However, A. baumannii can also be isolated from community healthy individuals. This study compared the pathogenicity of hospital and community A. baumannii isolates using Galleria mellonella and human cell cultures. The insect model, G. mellonella and in vitro HeLa cell line were used with ten A. baumannii isolates (six community and four hospital isolates from Segamat, Malaysia). G. mellonella killing assays and HeLa cell adherence, invasion, and cytotoxicity assays were performed to investigate the virulence and invasion potential of the isolates. Out of the ten isolates investigated, three community and two hospital isolates were found to be highly virulent in G. mellonella infection model, killing 100 % larvae within 96 hours. These strains were also found to be invasive and have significant cytotoxicity in HeLa cells. Our study revealed that community and hospital isolated A. baumannii could be equally virulent judged by both model systems. Undoubtedly, besides hospital settings, the presence of highly virulent A. baumannii in community reservoirs poses a significant public health risk and requires additional investigation.
Elevated CO2alters soybean physiology and defense responses, and has disparate effects on susceptibility to diverse microbial pathogens
Authors: Bredow Melissa , Khwanbua Ekkachai , Chicowski Aline Sartor , Breitzman Matthew W. , Qi Yunhui , Holan Katerina L. , Liu Peng , Graham Michelle A. , Whitham Steven A.
Published: June 2024

Increasing atmospheric CO2levels have a variety of effects that can influence plant responses to microbial pathogens. However, these responses are varied, and it is challenging to predict how elevated CO2(eCO2) will affect a particular plant-pathogen interaction. We investigated howeCO2may influence disease development and responses to diverse pathogens in the major oilseed crop, soybean (Glycine max[L.] Merr.).

Soybeans grown in ambient CO2(aCO2, 419 parts per million (ppm)) or ineCO2(550 ppm) were challenged with bacterial, viral, fungal, and oomycete pathogens, and disease, pathogen growth, gene expression and molecular plant defense responses were quantified.

IneCO2, plants were less susceptible toPseudomonas syringaepv.glycinea(Psg) but more susceptible to bean pod mottle virus, soybean mosaic virus, andFusarium virguliforme. Susceptibility toPythium sylvaticumwas unchanged, although a greater loss in biomass occurred ineCO2. Reduced susceptibility toPsgwas associated with enhanced defense responses. Increased susceptibility to the viruses was associated with reduced expression of antiviral defenses.

This work provides a foundation for understanding of how futureeCO2levels may impact molecular responses to pathogen challenge in soybean and demonstrates that agents infecting both shoots and roots are of potential concern in future climatic conditions.
A paradoxical misperception of relative motion
Authors: D’Angelo Josephine C. , Tiruveedhula Pavan , Weber Raymond J. , Arathorn David W. , Roorda Austin
Published: June 2024

Motion perception is considered a hyperacuity. The presence of a visual frame of reference to compute relative motion is necessary to achieve this sensitivity [Legge, Gordon E., and F. W. Campbell. “Displacement detection in human vision.”Vision Research21.2 (1981): 205-213.]. However, there is a special condition where humans are unable to accurately detect relative motion: images moving in a direction consistent with retinal slip where the motion is unnaturally amplified can, under some conditions, appear stable [Arathorn, David W., et al. “How the unstable eye sees a stable and moving world.”Journal of Vision13.10.22 (2013)]. In this study, we asked: Is world-fixed retinal image background content necessary for the visual system to compute the direction of eye motion to render in the percept images moving with amplified slip as stable? Or, are non-visual cues sufficient? Subjects adjusted the parameters of a stimulus moving in a random trajectory to match the perceived motion of images moving contingent to the retina. Experiments were done with and without retinal image background content. The perceived motion of stimuli moving with amplified retinal slip was suppressed in the presence of visual content; however, higher magnitudes of motion were perceived under conditions with no visual cues. Our results demonstrate that the presence of retinal image background content is essential for the visual system to compute its direction of motion. The visual content that might be thought to provide a strong frame of reference to detect amplified retinal slips, instead paradoxically drives the misperception of relative motion.
Cancer radiomic feature variations due to reconstruction kernel choice and integral tube current.
Authors: Salanon Elfried M.B. , Fu Anqi , Apte Aditya P. , Mahmood Usman , Belkhatir Zehor , Shukla-Dave Amita , Deasy Joseph O.
Published: June 2024

Purpose: Radiological cancer imaging features, or radiomics features, can be derived to diagnose disease or predict treatment response. However, variability between vendors, scanners, protocols, and even reconstruction software versions is an obstacle to the clinical use of radiomics features. This study aimed to characterize the impact of kernel reconstruction differences and integral tube current settings on radiomic features extracted from computed tomography (CT) scans. Methods: Radiomic features were extracted from CT scans of a 3D-printed phantom with five imprinted tumors using the CERR software system, resulting in 282 features. Batch effects were assessed via principal component analysis (PCA) and correlation measures. Robustness was measured using the concordance correlation coefficient (CCC) and Pearson correlation coefficient. Statistical analysis was performed using R software. Results: PCA identified two clusters comprised of Standard, ASIRs, ASIRV, and soft kernels in one, and Lung and Bone Kernels in the other. Features displayed a gradient from ASIR10 to ASIR50 and ASIRV1 to ASIRV5 in terms of nearness to Standard Kernel feature values. Feature correlation matrices revealed little change in ASIRs, ASIRVs, and the Standard Kernel, but showed significant changes in Bone and Lung Kernel results. Combat-algorithm correction improved robustness, particularly in first-order statistic features, and mitigated batch effects due to the ASIRs and the standard kernel. Forty (40) out of 282 features were identified as robust. However, Combat-based correction performed poorly in harmonizing Bone and Lung reconstruction kernels. Conclusions: The robustness of means and median radiomic features across kernel reconstruction choices, in contrast to the lack of robustness in many other radiomic features, suggests that kernel reconstruction effects are not well-addressed by current harmonization methods.
Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair
Authors: Peabody Lever Jacelyn E. , Li Qian , Pavelkova Nikoleta , Hussain Shah S. , Bakshi Sayan , Ren Janna Q. , Jones Luke I. , Kennemur Jared , Weupe Mason , Campos-Gomez Javier , Tang Liping , Lever Jeremie M.P. , Wang Dezhi , Stanford Denise D. , Foote Jeremy , Harrod Kevin S. , Kim Harrison , Phillips Scott E. , Rowe Steven M.
Published: June 2024

Rationale

The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF.

Methods

Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence.

Results

Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant ‘proximalization’ repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level.

Conclusions

Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.
Neural Networks model biological evolution of faithful epigenetic inheritance
Authors: Prabhu B. N. Balakrishna , Pillai Sibi Raj B. , Ramakrishnan Nithya
Published: June 2024

The layer of histone Post-Translational Modification (PTM) patterns, present above the DNA strand, forms an important epigenetic marker sequence which regulates gene expression. The specific pattern of histone PTMs in the region of chromatin housing the gene is critical for turning on/off the expression of the corresponding gene. During DNA replication in mitotic cells, the available evidence suggests that the histone PTMs from the mother chromatid are transferred uniformly at random among the two daughter chromatids. Parental epigenetic memory as well as interactions among multiple PTMs at the same histone facilitates the reconstruction of the PTM sequence at the daughter chromatids. We show that this biological marvel aided by the epigenetic memory has evolutionary analogs in the sense that it can be learnt by an appropriate extended neural network. We show through simulations that high fidelity reconstruction of the mother chromatin’s patterns for certain PTMs can be achieved by our network. This model can be enhanced to include several more interacting histone PTMs, elucidating the role of each. The proposed neural network can possibly be used in a multitude of biological applications related to gene expression regulation.
Gap-App: A sex-distinct AI-based predictor for pancreatic ductal adenocarcinoma survival as a web application open to patients and physicians
Authors: Ojha Anuj , Zhao Shu-Jun , Akpunonu Basil , Zhang Jian-Ting , Simo Kerri A. , Liu Jing-Yuan
Published: June 2024

In this study, using RNA-Seq gene expression data and advanced machine learning techniques, we identified distinct gene expression profiles between male and female pancreatic ductal adenocarcinoma (PDAC) patients. Building upon this insight, we developed sex-specific 3-year survival predictive models along with a single comprehensive model. These sex-specific models outperformed the single general model despite the smaller sample sizes. We further refined our models by using the most important features extracted from these initial models. The refined sex-specific predictive models achieved improved accuracies of 92.62% for males and 91.96% for females, respectively, versus an accuracy of 87.84% from the refined comprehensive model, further highlighting the value of sex-specific analysis. Based on these findings, we created Gap-App, a web application that enables the use of individual gene expression profiles combined with sex information for personalized survival predictions. Gap-App, the first online tool aiming to bridge the gap between complex genomic data and clinical application and facilitating more precise and individualized cancer care, marks a significant advancement in personalized prognosis. The study not only underscores the importance of acknowledging sex differences in personalized prognosis, but also sets the stage for the shift from traditional one-size-fits-all to more personalized and targeted medicine. The GAP-App service is freely available atwww.gap-app.org.
Modeling nascent transcription from chromatin landscape and structure
Authors: Pielies Avelli Marc , Sigurdsson Arnor Ingi , Narita Takeo , Choudhary Chunaram , Rasmussen Simon
Published: June 2024

Different cell types and their associated functionalities emerge from a single genomic sequence when certain regions are expressed while others remain silenced. Modeling gene expression and its potential malfunctioning in different cellular contexts is hence pivotal to understand both development and disease. We present the Chromatin Landscape and Structure to Expression Regressor (CLASTER), an epigenetic-based deep neural network that can integrate different data modalities describing the chromatin landscape and its 3D structure. CLASTER effectively translates them into nascent transcription levels measured by EU-seq at a kilobasepair resolution. Our predictions reached a Pearson correlation with targets above r=0.86 at both bin and gene levels, without relying on DNA sequence nor explicitly extracted chromatin features. The model mostly used the information found within 10 kbp of the predicted locus, even when a wide genomic region of 1 Mbp was available. Explicit modeling of long-range interactions using multi-headed attention and high-resolution chromatin contact maps had little impact on model performance, despite the model correctly identifying elements in these inputs influencing nascent transcription. The trained model served then as a platform to predict the transcriptional impact of simulated epigenetic silencing perturbations. Our results point towards a rather local, integrative and combinatorial paradigm of gene regulation, where changes in the chromatin environment surrounding a gene shape its context-specific transcription. We conclude that the predominant locality and limitations of current machine learning approaches might emerge as a genuine signature of genomic organization, having broad implications for future modeling approaches.
A mathematical model for ketosis-prone diabetes suggests the existence of multiple pancreatic β-cell inactivation mechanisms
Authors: Ridout Sean A. , Vellanki Priyathama , Nemenman Ilya
Published: June 2024

Ketosis-prone diabetes mellitus (KPD) is a subtype of type 2 diabetes, which presents much like type 1 diabetes, with dramatic hyperglycemia and ketoacidosis. Although KPD patients are initially insulin-dependent, after a few months of insulin treatment, ∼ 70% undergo near-normoglycemia remission and can maintain blood glucose without insulin, as in early type 2 diabetes or prediabetes. Here, we propose that these phenomena can be explained by the existence of a fast, reversible glucotoxicity process, which may exist in all people but be more pronounced in those susceptible to KPD. We develop a simple mathematical model of the pathogenesis of KPD, which incorporates this assumption, and show that it reproduces the phenomenology of KPD, including variations in the ability for patients to achieve and sustain remission. These results suggest that a variation of our model may be able to quantitatively describe variations in the course of remission among individuals with KPD.
Dynamin-1 is a potential mediator in Cancer-Related Cognitive Impairment
Authors: Ng Ding Quan , Hudson Casey , Nguyen Tracy , Gupta Sukesh Kumar , Koh Yong Qin , Acharya Munjal M. , Chan Alexandre
Published: June 2024

Dynamin-1 (DNM1) consolidates memory through synaptic transmission and modulation and has been explored as a therapeutic target in Alzheimer’s disease. Through a two-prong approach, this study examined its role in cancer-related cognitive impairment (CRCI) pathogenesis using human and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Concurrently, a syngeneic young-adult WT (C57BL/6 female) mouse model of breast cancer was developed to study DNM1 expression in the brain. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were significantly lower among cancer participants compared to non-cancer prior to treatment. While receiving cancer treatment, cognitively impaired patients were found with a significant downregulation of DNM1, but not among those without impairment. In murine breast cancer-bearing mice receiving chemotherapy, we consistently found a significant decline in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions. Observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. Future research should explore the potential of DNM1 in CRCI pathogenesis and therapeutics development.
Cell-Graph Compass: Modeling Single Cells with Graph Structure Foundation Model
Authors: Fang Chen , Hu Zhilong , Chang Shaole , Long Qingqing , Cui Wentao , Liu Wenhao , Li Cong , Liu Yana , Wang Pengfei , Meng Zhen , Pan Jia , Zhou Yuanchun , Feng Guihai , Chen Linghui , Li Xin
Published: June 2024

Inspired by the advancements in pre-trained Large Language Models, there has been a surge of studies in the Life Sciences focusing on constructing foundation models with large scale single-cell RNA-seq data. These studies typically involve pre-training a transformer model on large-scale single-cell sequencing data, followed by fine-tuning for a variety of downstream tasks, achieving notable performance. However, these models all share a common short-coming: to utilize the transformer architecture, originally designed for textual data, they artificially impose a sequential structure on genes within cells, simplifying the complex interactions between genes. Furthermore, they focus solely on transcriptomic data, neglecting other relevant biological information. To address these issues, here we introduce Cell-Graph Compass (CGC), the first foundational model that leverages graph structures to model single cells and describes cells from multiple perspectives, including transcriptional profiles, gene text summaries, transcription factor regulatory networks, gene co-expression patterns, and gene positional relationships. By incorporating self-attention mechanisms, we pretrained the model on 50 million human single-cell sequencing data, resulting in a robust digital representation of cells. Extensive downstream experiments demonstrate that our approach can capture meaningful biological knowledge and achieve superior results in various problem scenarios, achieving the state-of-the-art (SOTA).
Expression of a single inhibitory member of the Ly49 receptor family is sufficient to license NK cells for effector functions
Authors: Piersma Sytse J. , Li Shasha , Wong Pamela , Bern Michael D. , Poursine-Laurent Jennifer , Yang Liping , Beckman Diana L. , Parikh Bijal A. , Yokoyama Wayne M.
Published: June 2024

Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of MHC class I and related molecules. Functionally, these receptor families are involved in licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cellsin vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on a H-2Ddbackground restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-selfin vivo.
Bbl1 Allele of the Receptor Kinase Subfamily VII PBL38 Is Required for Elongated Root Hairs in Arabidopsis
Authors: Kohorn Bruce D.
Published: June 2024

In a screen for mutations that alter cell morphology and adhesion as a marker for cell wall composition alterations, an Arabidopsis seedling with root hairs that fail to elongate was identified. Root hairs are rounded and bubble-like, and the mutation was named Bubbles or bbl1. No other visible whole plant phenotypes were observed. Using backcrosses with wild type, and genomic sequencing of pooled F2 individuals with the Bubbles phenotype, 14 candidates for the mutant allele were identified. T-DNA alleles of one of these candidates showed a similar but partial phenotype to bbl1, and indicate that bbl1 is an allele of AT2G39110 previously identified as PBL38 (AvrPphB SUSCEPTIBLE1-LIKE38), a member of receptor kinase subfamily VII. PBL38 has been associated with the response to pathogens. bbl1 is a point mutation that causes a Glutamic acid to Lysine change at position 140, and is complimented by a C-terminal GFP fusion to the coding region of AT2G39110, indicating that the BBL1 gene (PBL38) is involved in correct root hair formation. AT2G39110 is expressed only in roots early in seedling maturation, and the GFP fusion protein localizes to the cell surface, consistent with the prediction that the gene encodes a receptor-like protein kinase. In bbl1 root hairs, the actin cytoskeleton does not form, while in bbl1 roots and other tissues normal actin cytoskeleton is observed.
Robust parameter estimation and identifiability analysis with Hybrid Neural Ordinary Differential Equations in Computational Biology
Authors: Giampiccolo Stefano , Reali Federico , Fochesato Anna , Iacca Giovanni , Marchetti Luca
Published: June 2024

Parameter estimation is one of the central problems in computational modeling of biological systems. Typically, scientists must fully specify the mathematical structure of the model, often expressed as a system of ordinary differential equations, to estimate the parameters. This process poses significant challenges due to the necessity for a detailed understanding of the underlying biological mechanisms. In this paper, we present an approach for estimating model parameters and assessing their identifiability in situations where only partial knowledge of the system structure is available. The partially known model is extended into a system of Hybrid Neural Ordinary Differential Equations, which captures the unknown portions of the system using neural networks.

Integrating neural networks into the model structure introduces two primary challenges for parameter estimation: the need to globally explore the search space while employing gradient-based optimization, and the assessment of parameter identifiability, which may be hindered by the expressive nature of neural networks. To overcome the first issue, we treat biological parameters as hyperparameters in the extended model, exploring the parameter search space during hyperparameter tuning. The second issue is then addressed by ana posteriorianalysis of parameter identifiability, computed by introducing a variant of a well-established approach for mechanistic models. These two components are integrated into an end-to-end pipeline that is thoroughly described in the paper. We assess the effectiveness of the proposed workflow on test cases derived from three different benchmark models. These test cases have been designed to mimic real-world conditions, including the presence of noise in the training data and various levels of data availability for the system variables.

Author summary

Parameter estimation is a central challenge in modeling biological systems. Typically, scientists calibrate the parameters by aligning model predictions with measured data once the model structure is defined. Our paper introduces a workflow that leverages the integration between mechanistic modeling and machine learning to estimate model parameters when the model structure is not fully known. We focus mainly on analyzing the identifiability of the model parameters, which measures how confident we can be in the parameter estimates given the available experimental data and partial mechanistic understanding of the system. We assessed the effectiveness of our approach in variousin silicoscenarios. Our workflow represents a first step to adapting traditional methods used in fully mechanistic models to the scenario of hybrid modeling.
Practical considerations regarding estimatingNewhen generations overlap
Authors: Waples Robin S.
Published: June 2024

Researchers studying species in nature often find it challenging to apply methods based on simplistic models of reality. Here I consider how some real-world complications influence demographic estimates of effective population size (Ne) when generations overlap. The most widely-used model (by Hill) expressesNeas a function of variance in lifetime reproductive output (LRO) of theN1members of a newborn cohort. Hill’s model assumes stable age structure and constant population size, in which case mean. In real-world applications, researchers often ask whether unbiased estimates can be obtained under the following conditions: (1) Whenfor empirical data; (2) If cohorts are defined at a later age than newborns; (3) If survival to age at sexual maturity (α) is not random; (4) When some or all null parents (those withLRO=0) are not sampled. Using analytical methods and computer simulations, I show that: (1) Because variance in offspring number is positively correlated with the mean,will be biased using raw data when, but this bias can be overcome by rescaling var(LRO) to its expected value when. (2) The cohort can be defined at any age ≤α, provided that (a)LROdata cover the full lifespan (e.g., production of newborns by newborns, or production of adults by adults), and (b) survival to age α is random. (3) If juvenile survival is family-correlated, defining cohorts at age α avoids upward bias inthat occurs if newborn cohorts are used. (4) Missing some or all null parents has no effect on, provided that data are rescaled to.
Developing epidemiological preparedness for a plant disease invasion: modelling citrus huánglóngbìng in the European Union
Authors: Ellis John , Lázaro Elena , Duarte Beatriz , Magalhães Tomás , Duarte Amílcar , Benhadi-Marín Jacinto , Pereira José Alberto , Vicent Antonio , Parnell Stephen , Cunniffe Nik J.
Published: June 2024

Huánglóngbíng (HLB; citrus greening) is the most damaging disease of citrus worldwide. While citrus production in the USA and Brazil have been affected for decades, HLB has not been detected in the European Union (EU). However, psyllid vectors have already invaded and spread in Portugal and Spain, and in 2023 the psyllid species known to vector HLB in the Americas was first reported within the EU. We develop a landscape-scale, epidemiological model, accounting for heterogeneous citrus cultivation and vector dispersal, as well as climate and disease management. We use our model to predict HLB dynamics following introduction into high-density citrus areas in Spain, assessing detection and control strategies. Even with significant visual surveillance, we predict any epidemic will be widespread on first detection, with eradication unlikely. Introducing increased inspection and roguing following first detection, particularly if coupled with intensive insecticide use, could potentially sustain citrus production for some time. However, this may require chemical application rates that are not permissible in the EU. Disease management strategies targeting asymptomatic infection will likely lead to more successful outcomes. Our work highlights modelling as a key component of developing epidemiological preparedness for a pathogen invasion that is, at least somewhat, predictable in advance.
Development of highly multiplex targeted proteomics assays in biofluids using the Stellar mass spectrometer
Authors: Plubell Deanna L , Remes Philip M. , Wu Christine C. , Jacob Cristina C. , Merrihew Gennifer E. , Hsu Chris , Shulman Nick , MacLean Brendan X. , Heil Lilian , Poston Kathleen , Montine Tom , MacCoss Michael J.
Published: June 2024

The development of targeted assays that monitor biomedically relevant proteins is an important step in bridging discovery experiments to large scale clinical studies. Targeted assays are currently unable to scale to hundreds or thousands of targets. We demonstrate the generation of large-scale assays using a novel hybrid nominal mass instrument. The scale of these assays is achievable with the StellarTMmass spectrometer through the accommodation of shifting retention times by real-time alignment, while being sensitive and fast enough to handle many concurrent targets. Assays were constructed using precursor information from gas-phase fractionated (GPF) data-independent acquisition (DIA). We demonstrate the ability to schedule methods from an orbitrap and linear ion trap acquired GPF DIA library and compare the quantification of a matrix-matched calibration curve from orbitrap DIA and linear ion trap parallel reaction monitoring (PRM). Two applications of these proposed workflows are shown with a cerebrospinal fluid (CSF) neurodegenerative disease protein PRM assay and with a Mag-Net enriched plasma extracellular vesicle (EV) protein survey PRM assay.
Overdriveis essential for targeted sperm elimination bySegregation Distorter
Authors: Ridges Jackson T. , Bladen Jackson , King Thomas D. , Brown Nora C. , Large Christopher R. L. , Cooper Jacob C. , Jones Amanda J. , Loppin Benjamin , Dubruille Raphaëlle , Phadnis Nitin
Published: June 2024

Intra-genomic conflict driven by selfish chromosomes is a powerful force that shapes the evolution of genomes and species. In the male germline, many selfish chromosomes bias transmission in their own favor by eliminating spermatids bearing the competing homologous chromosomes. However, the mechanisms of targeted gamete elimination remain mysterious. Here, we show thatOverdrive (Ovd), a gene required for both segregation distortion and male sterility inDrosophila pseudoobscurahybrids, is broadly conserved in Dipteran insects but dispensable for viability and fertility. InD. melanogaster, Ovdis required for targetedResponderspermatid elimination after the histone-to-protamine transition in the classicalSegregation Distortersystem. We propose thatOvdfunctions as a general spermatid quality checkpoint that is hijacked by independent selfish chromosomes to eliminate competing gametes.
Metabolic activities are selective modulators for individual segmentation clock processes
Authors: Matsuda Mitsuhiro , Lázaro Jorge , Ebisuya Miki
Published: June 2024

A sequence of cellular and molecular processes unfolding during embryonic development prompts fundamental questions of how the tempo of multiple processes is coordinated and whether a common global modulator exists. The oscillation of the segmentation clock is a well-studied model of developmental tempo. While the clock period is known to scale with the kinetics of gene expression and degradation processes of the core clock gene Hes7 across mammalian species, how these key molecular processes are coordinated remains unclear. In this study, we investigated if metabolic activities act as a global modulator for the segmentation clock, finding that they are rather selective modulators. While several metabolic inhibitions extended the clock period, their effects on the key processes varied. Inhibition of glycolysis decelerated the protein degradation of Hes7 and extended the production delay but did not influence the intron delay. Electron transport chain inhibition extended Hes7 intron delay without influencing the other two processes. Combinations of distinct metabolic inhibitions exhibited synergistic effects. By contrast, temperature changes affected the clock period and all three key processes simultaneously. These results highlight the selective effects of metabolic activities on segmentation clock processes, hinting that their scaled kinetics across species may be achieved through combinations of multiple modulators.
Structural polymorphism and diversity of human segmental duplications
Authors: Jeong Hyeonsoo , Dishuck Philip C , Yoo DongAhn , Harvey William T , Munson Katherine M , Lewis Alexandra P , Kordosky Jennifer , Garcia Gage H ,   Human Genome Structural Variation Consortium (HGSVC), Yilmaz Feyza , Hallast Pille , Lee Charles , Pastinen Tomi , Eichler Evan E
Published: June 2024

Segmental duplications (SDs) contribute significantly to human disease, evolution, and diversity yet have been difficult to resolve at the sequence level. We present a population genetics survey of SDs by analyzing 170 human genome assemblies where the majority of SDs are fully resolved using long-read sequence assembly. Excluding the acrocentric short arms, we identify 173.2 Mbp of duplicated sequence (47.4 Mbp not present in the telomere-to-telomere reference) distinguishing fixed from structurally polymorphic events. We find that intrachromosomal SDs are among the most variable with rare events mapping near their progenitor sequences. African genomes harbor significantly more intrachromosomal SDs and are more likely to have recently duplicated gene families with higher copy number when compared to non-African samples. A comparison to a resource of 563 million full-length Iso-Seq reads identifies 201 novel, potentially protein-coding genes corresponding to these copy number polymorphic SDs.
A chemically defined oviposition attractant and repellent of Black Soldier Flies (Hermetia illucens)
Authors: Thomas Nyasha KT , Karpati Zsolt , Schmitt Thomas , Riabinina Olena
Published: June 2024

Black Soldier Flies (BSF),Hermetia illucens, are industrially important species. They can consume large amounts of spoilt organic material as larvae and bio-convert it to more useful biomass. Female BSF lay eggs in crevices adjacent to spoilt organic materials that serve as an oviposition attractant. These kairomones are central to maximising rearing efforts, yet the composition and origin of oviposition cues remain undefined, and no synthetic oviposition attractants are currently available. This work aimed to identify key components of naturally occurring oviposition attractants and to formulate an effective synthetic alternative for BSF. We have developed a novel oviposition assay and found larval food- and frass-based attractants to be the most effective at centralizing egg laying. We have identified the volatile compounds in the headspaces of putative attractants and established that the antennae of the female flies respond to some of these compounds. Behavioural validation using synthetic compounds allowed us to generate a mixture of 5 compounds (p-cresol, decanal, sulcatone, pentanoic acid, acetophenone) that cues oviposition as efficiently as currently used natural oviposition attractants. We also identified a synthetic mixture that deters oviposition in BSF. The synthetic attractant and repellent we generated are likely to simplify BSF rearing in research and industrial settings.
Models trained to predict differential expression across plant organs identify distal and proximal regulatory regions
Authors: Tross Michael C. , Duggan Gavin , Shrestha Nikee , Schnable James C.
Published: June 2024

Abstract

A large proportion of standing phenotypic variation is explained by genetic variation in noncoding regulatory regions. However, tools for the automated identification and characterization of noncoding regulatory sequences in genomes have lagged far behind those employed to annotate and predict the functions of protein coding sequences. We developed a modified transformer model and trained it to predict relative patterns of expression across a diverse set of tissues given a large sequence window for each gene of interest in the maize (Zea mays) genome. Nucleotides in the input DNA sequence with high saliency in gene expression pattern prediction overlapped with regions identified via comparative genomic or chromatin-based approaches as potential regulatory sequences. High saliency regions identified in a second species, sorghum (Sorghum bicolor), without species-specific training were also associated with potential regulatory sequences in noncoding regions upstream and downstream of each gene of interest. The potential impact of a scaleable and transferable approach to identifying regulatory sequences using saliency calculated from large context window models spans multiple applications. Specific use cases could include genome annotation, interpretation of natural genetic variation, and targeted editing in noncoding regions to alter patterns of levels of gene expression.
The disease-causing tau V337M mutation induces tau hypophosphorylation and perturbs axon morphology pathways
Authors: Mohl Gregory A. , Dixon Gary , Marzette Emily , McKetney Justin , Samelson Avi J. , Pereda Serras Carlota , Jin Julianne , Li Andrew , Boggess Steven C. , Swaney Danielle L. , Kampmann Martin
Published: June 2024

Tau aggregation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. There are disease-causing variants of the tau-encoding gene,MAPT, and the presence of tau aggregates is highly correlated with disease progression. However, the molecular mechanisms linking pathological tau to neuronal dysfunction are not well understood due to our incomplete understanding of the normal functions of tau in development and aging and how these processes change in the context of causal disease variants of tau. To address these questions in an unbiased manner, we conducted multi-omic characterization of iPSC-derived neurons harboring theMAPTV337M mutation. RNA-seq and phosphoproteomics revealed that both V337M tau and tau knockdown consistently perturbed levels of transcripts and phosphorylation of proteins related to axonogenesis or axon morphology. Surprisingly, we found that neurons with V337M tau had much lower tau phosphorylation than neurons with WT tau. We conducted functional genomics screens to uncover regulators of tau phosphorylation in neurons and found that factors involved in axonogenesis modified tau phosphorylation in bothMAPTWT andMAPTV337M neurons. Intriguingly, the p38 MAPK pathway specifically modified tau phosphorylation inMAPTV337M neurons. We propose that V337M tau might perturb axon morphology pathways and tau hypophosphorylation via a “loss of function” mechanism, which could contribute to previously reported cognitive changes in preclinicalMAPTgene carriers.
DNA barcode developement based on chloroplast and ITS genes for species identification of endangered and threated species of Western Ghats, India
Authors: Fatima Tanzeem , Srividya MN , Singh Raj Kishore
Published: June 2024

Accurate identification is crucial for conserving species, especially in regions such as the Western Ghats, where trade poses a significant threat to endangered and threatened forest species. Traditional morphology-based identification can be challenging and time-consuming, leading to inaccuracies, especially with similar-looking species or dried specimens. Therefore, DNA barcoding offers a potent solution for precise species identification to address illicit trade and address impactful conservation measures. DNA barcoding is a taxonomic technique that uses standardized short DNA sequences to differentiate and classify species. This approach is especially valuable when morphological characteristics alone are insufficient for accurate species identification. In this study, we focused on the development of a DNA barcoding system for the efficient and accurate identification of threatened and endangered important forest species of Western Ghats Karnataka. To develop the DNA barcoding system, a multilocus approach utilizing sixteen standard DNA barcoding markers was used. A total of 47 threatened and endangered forest species from the Western Ghats were selected for this study. Using a larger number of markers to develop DNA barcodes led to the most precise species identification rates. Moreover, the wide availability of DNA barcode databases allows for quick and accurate species identification. In our study, we observed the highest amplification rates for rbcL1 (40 species), psbtrnH2 (36 species), and PsbA-trnH1 (33 species). DNA amplification varied from 11.76% to 94.11%. Notably, the highest DNA amplification rates were detected forA. wightii(94.11%) andA. hondala (92.34%), both of which belong to the Arecaceae and Passifloraceae families, respectively. Sequencing success rates ranged from 37.5% to 100%. This study will aid in the development of a database of available threatened forest species in western Ghats Karnataka and other regions.