bluuebunny/crossref_metadata_2025 huggingface dataset:
The timing of surgical interventions following the implantation of coronary drug-eluting stents in patients undergoing gastrointestinal cancer surgery: a multicenter retrospective cohort study
Authors: Xu Ziyao , Lai Yingying , Zhou Yan , Qin Lipeng , Hao Xinyu , Li Tian , Gao Lei , Wang Xinxin
Published: December 2024

Aim:

We aim to investigate the optimal timing for surgical interventions to maximize patient benefit.

Background:

The guidelines recommending a minimum deferral of 6 months for non-cardiac surgeries following drug-eluting stent percutaneous coronary intervention (DES-PCI) do not adequately address the requirements for individuals undergoing gastrointestinal cancer surgery (GCS).

Methods:

The study encompassed 2501 patients treated from January 2017 to December 2021, all of whom underwent GCS within 1 year after DES-PCI. We conducted an analysis by comparing the occurrence of major adverse cardiovascular events (MACEs) within 30 days post-surgery at different time points.

Results:

This study enrolled a total of 2501 participants with meticulously recorded data who underwent DES-PCI and subsequently underwent GCS within 1 year post-implantation. The incidence rate of MACEs is 14.2%, including MI (5.1%), HF (5.8%), IS (3.2%), and cardiac death (0.2%), across all patients in this study. The threshold probability was determined using the Youden Index, resulting in a value of 0.320, corresponding to a “time-to-surgery value” of 87. Significant statistical differences were observed in the occurrence rates of MACEs for adjacent time intervals at 30 days (P < 0.001), 90 days (P < 0.009), and 180 days (P < 0.001).

Conclusions:

The timing of surgical intervention following DES-PCI significantly influences the occurrence of MACEs at 1, 3, and 6 months. GCS may be appropriately advanced within the 6-month timeframe, but with the exception of emergency, efforts should be made to defer them beyond the initial month.
Rare Inherited Coagulation Deficiencies: A Single-center Study
Authors: Terzi Özlem , Hatipoğlu Sadik Sami
Published: December 2024

Background:

Rare factor deficiency (RFD) is characterized by a deficiency of factor (F)I, FII, FV, FVII, FX, FXI, FXII, FXIII, or a combined deficiency of FV+FVIII or vitamin K-dependent factors. The prevalence of RFD ranges from 1/1,000,000 to 3,000,000. Combined deficiencies of vitamin K-related factors have been described in 30 families worldwide, and these patients can present with a wide range of clinical symptoms, from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding.

Objective:

This study aimed to contribute to the literature on RFD.

Material and Methods:

This retrospective study analyzed data from 43 children with RFD.

Results:

The most common factor deficiencies were FVII (n=13); whereas the other deficiencies were FI (n=1), FV (n=2), FV+FVIII (n=2), FX (n=6), FXI (n=5), FXII (n=9), FXIII (n=3), and vitamin K-dependent combined factor deficiency (n=2). Acute and severe bleeding was controlled by treatment in 6 patients, and 12 patients with recurrent bleeding symptoms received prophylaxis. RFDs were more common in regions with high rates of consanguineous marriage, and in our study, 16 (16/43) of the cases were found to have consanguineous marriages between parents.

Conclusions:

It is important to improve genetic counseling and access to testing for family members with RFD due to autosomal recessive inheritance. Delays in diagnosis and treatment and lack of adequate prevention are important risk factors for life-threatening bleeding.
The Application of the NOSES System to Treat Cheek Squamous Cell Carcinoma
Authors: Wang Wei-Qi , Mu Si-Qi , Na Si-Jia , Ding Ming-Chao , Chen Jie , Zhang Xi , Wei Jian-Hua
Published: December 2024

Purpose:

Oral squamous cell carcinoma is one of the most common types of cancer in the head and neck. Squamous cell carcinoma of the buccal mucosa is an important part of it. The traditional surgical method leads to great injury and is accompanied by unacceptable scars. Previous improvements have been carried out in a single part. Natural orifice specimen extraction surgery (NOSES) system could perform “scarless surgery” and reduce complications. This technique was usually used for transvaginal or transanal specimen retrieval. There is great potential for oral and maxillofacial applications, especially in the field of oral and maxillofacial surgery. We combine the 2 to achieve better surgical results.

Methods:

The authors applied the NOSES system in the radical operation of buccal mucosa squamous cell carcinoma. Through FACE-LIFT incision, with the help of indocyanine green (ICG) and microscope, they successfully cured buccal mucosa squamous cell carcinoma.

Results:

The patient was cured, and there was no recurrence after 1 year of follow-up. The incision is hidden, and the damage is small. The number of harvested lymph nodes in the pathologic examination was 1/18.

Conclusions:

The application of the NOSES system in maxillofacial surgery has very obvious advantages. The surgical procedures follow the principles of aseptic and tumor-free techniques, making the tumor en-block dissection. For stage 1 patients, this scheme not only ensures the radical cure of the tumor but also improves the detection rate of lymph nodes and ensures the patients' appearance. For doctors, this program is easy to operate and learn and can reduce the peer gap.
Profileplasty: Comprehensive Facial Profile Management Algorithm Based on 426 Patients
Authors: Reategui Alvaro , Jazayeri Hossein , Mier Alexa , Peck Connor J. , Phillips Sarah , Lopez Joseph , Steinbacher Derek
Published: December 2024

Objective:

Profileplasty traditionally involves improving a nasal hump or an underprojected chin. However, this procedure can correct other facial defects like saddle nose or prognathism. To establish the best overall profile, the nose, the midface, and the chin should be considered altogether. This study aimed to describe typical facial profiles and propose an algorithm for targeted correction.

Methods:

Patients who underwent rhinoplasty, with or without other facial procedures performed by the senior author were reviewed. Patients with pre and postoperative photographs and clinical follow-up were included. Images were analyzed using Goode and Steiner analyses and E and S lines to assess and categorize nasal and facial profiles. A treatment algorithm for each sub-group was proposed based on expert opinion. Adherence to the algorithm was validated by reviewing patients’ charts.

Results:

A total of 426 rhinoplasty patients were included, with 72 also undergoing orthognathic surgery, including genioplasty. There were 2 general groups of patients: (1) poor nasal profile with a balanced facial profile and (2) poor nasal profile with an unbalanced facial profile. Group 1 included (1a) prominent (n = 298) or (1b) flat (n = 56) nasal dorsum. Group 2 included (2a) convex profile (n = 38), (2b) concave profile (n = 32), and (2c) “pseudo-dorsum” (n = 2). Proposed treatments for group 1 involved balancing the nasal dorsum and nasofrontal angle, whereas group 2 involved modifying the nasal dorsum and repositioning the maxilla/mandible. Of patients, 98.6% followed the proposed treatment algorithm.

Conclusion:

This study describes common profile patterns and highlights a profileplasty algorithm that offers systematic treatment planning for most patients.
Fitness drivers of division of labor in vertebrates
Authors: García-Ruiz Irene , Rubenstein Dustin
Published: December 2024

Although division of labor as a means to increase productivity is a common feature in animal social groups, most previous studies have focused almost exclusively on eusocial insects with extreme task partitioning. Empirical evidence of division of labor in vertebrates is scarce, largely because we lack a theoretical framework to explore the conditions under which division of labor is likely to evolve. By explicitly considering alternative helping tasks with varying fitness costs, we model how individual decisions on task specialization may influence the emergence of division of labor under both direct and indirect fitness benefits. Surprisingly, we find that direct survival benefits of living in larger groups are the primary force driving the evolution of cooperation to enhance group productivity, and that indirect fitness benefits derived from related group members are only a non-essential facilitator of more stable forms of division of labor. In addition, we find that division of labor is favored by increasingly harsh environments. Ultimately, our model not only makes key predictions that are consistent with existing empirical data, but also proposes novel avenues for new empirical work in vertebrate and invertebrate systems alike.
G protein Inactivation as a Mechanism for Addiction Treatment
Authors: Neiswanger Carlie , Ruiz Micaela V. , Kimball Kandace , Lee Justin D. , Land Benjamin , Berndt Andre , Chavkin Charles
Published: December 2024

The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation. Neither nalfurafine nor nalmefene are completely selective KOR ligands, but KOR inactivation was observed at doses 10-100 fold lower than necessary for mu opioid receptor actions. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, and mitigated the aversion during acute and protracted withdrawal in fentanyl-dependent mice. Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders.
Individual Alpha Frequency Predicts the Sensitivity of Time Perception
Authors: Morrow Audrey , Wilson Montana , Geller-Montague Michaela , Soldano Sara , Hajidamji Sabah , Samaha Jason
Published: December 2024

A growing body of research links individual differences in the frequency of alpha-band oscillations to temporal aspects of perception. However, whether the human alpha rhythm is a correlate of time perception itself has remained controversial. This multi-day study combined EEG with multiple duration estimation and discrimination tasks in order to evaluate whether individual alpha frequency (IAF) is associated with sensitivity or bias in judging visual durations across a range of peri-second durations (spanning 1200 to 100ms). In a temporal estimation task, participants (n = 55) reported the duration of a single stimulus between 300-1200ms. In a temporal discrimination task, participants reported which of two stimuli was longer: a standard (100, 600, or 1200ms) or comparison (50-150% of the standard). Stimuli also varied in whether their luminance was static or dynamic (varying randomly over time). We found that IAF was significantly related to the variance of duration estimates, a measure of precision (or sensitivity), but not average duration estimates, a measure of bias. Further supporting this relationship, psychometric function slopes obtained from independent duration discrimination tasks were correlated with IAF, particularly for the static stimulus conditions. These effects were largely consistent across the range of stimulus durations tested and held when controlling for participant age. Taken together, these results suggest that IAF plays a role in shaping individual differences in the sensitivity of time perception. However, we did not observe effects of spontaneous fluctuations in single-trial alpha frequency, suggesting the effect is primarily observable at the cross-subject level.

Significance Statement

Brain waves in the 8-13 Hz range, known as alpha waves, have long been hypothesized to modulate our perception of time, yet the evidence remains unclear. This study investigates the relationship between an individual’s alpha frequency (IAF) and temporal sensitivity using a wide range of time perception tasks and stimulus durations to address gaps in the literature. We demonstrate that IAF is significantly associated with the precision of duration estimates and sensitivity in duration discrimination, particularly for static unchanging stimuli. These findings provide novel evidence that IAF shapes individual differences in time perception, emphasizing its role as a neural marker of temporal sensitivity.
Why did you use that test? Exploring speech-language pathologists clinical decision-making in bilingual language and literacy assessment
Authors: Wood Emily , Kika Mariya , Daub Olivia , Molnar Monika
Published: December 2024

Purpose

Our overarching goal is to advance our understanding of clinical decision-making processes in bilingual language and literacy assessment. When evaluating bilingual children, speech-language pathologists (SLPs) use static norm-referenced assessments (SAs) developed for English monolinguals more frequently than less biased dynamic assessments (DAs). To date, no research has considered why SLPs use SAs over DAs or examined SLPs’ conceptualization of validity beyond knowledge of psychometrics. In this study we explore factors that affect SLPs’ choice and use of assessments and how clinicians conceptualize and employ validity through the lens of modern validity frameworks.

Method

Canadian SLPs (n=21) participated in semi-structured interviews, using a guide informed by the Theoretical Domains frameworks and Kane’s Validity framework. Reflexive thematic analysis was used to generate themes.

Results

Clinicians rarely report using “dynamic assessment” but did “assess dynamically” by incorporating teaching in testing. When assessing oral language, SLPs acknowledged that using SAs with bilinguals may be inappropriate, but that they continue to do primarily because scores from these measures are necessary for diagnosis and accessing services. To contend with this friction between clinical beliefs and workplace requirements, most SLPs report caveats alongside SA scores SAs to contextualize findings. Though individual clinical knowledge of psychometrics and validity in assessment varies, systemic issues play a key role in perpetuating current assessment practices with bilinguals. Finally, bilingual literacy assessment practices differ. Clinicians use a wider variety of assessments and rely less on scores to achieve desired outcomes for students.

Conclusion

Clinical decision-making in bilingual language and literacy assessment is influenced by both individual and contextual factors. Accordingly, efforts to shift practice patterns cannot solely focus on individual clinical knowledge but must also examine and address these systemic issues.
Re-evaluating malarial retinopathy to improve its diagnostic accuracy in cerebral malaria
Authors: Wilson Kyle J , Liomba Alice Muiruri , Seydel Karl B , Moxon Christopher A , MacCormick Ian JC , Harding Simon P , Beare Nicholas AV , Taylor Terrie E
Published: December 2024

Background

Previous work has identified that malarial retinopathy (MR) has diagnostic value in cerebral malaria (CM). To improve our understanding of MR as a predictor of cerebral parasite sequestration in CM we reviewed data from the Blantyre autopsy study.

Methods

We performed a retrospective analysis of data collected from a consecutive series of patients presenting to the Pediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre, Malawi between 1996 and 2010. We determined the diagnostic accuracy of MR as a predictor of cerebral parasite sequestration in a cohort of children with fatal CM.

Results

Of 84 children included in the study, 65 met the WHO criteria for CM during life. Eighteen (28%) of 65 did not have evidence of cerebral parasite sequestration at autopsy and 17 had an alternative cause of death. MR had a sensitivity of 89% and specificity of 73% to predict sequestration. In a subset of patients with graded retinal assessments, this was improved to 94% and 88% by reclassifying patients with 1-5 hemorrhages in only one eye as retinopathy negative.

Conclusions

MR remains the most specific point-of-care test for CM in endemic areas. Its specificity can be improved, without sacrificing sensitivity, by reclassifying patients with less than 5 hemorrhages in one eye only as MR negative.
Deaminase-mediated chromatin accessibility profiling with single-allele resolution
Authors: Yu Tian , Li Zhijian , Gibbs Ellie , Iwase Reina , Francoeur Matthew J , Phan Quang vinh , Zhao Jing , Rosin Jane , Cole Phillip A , Pinello Luca , Sherwood Richard I
Published: December 2024

Binding of transcription factors (TFs) at gene regulatory elements controls cellular epigenetic state and gene expression. Current genome-wide chromatin profiling approaches have inherently limited resolution, complicating assessment of TF occupancy and co-occupancy, especially at individual alleles. In this work, we introduce Accessible Chromatin by Cytosine Editing Site Sequencing with ATAC-seq (ACCESS-ATAC), which harnesses a double-stranded DNA cytosine deaminase (Ddd) enzyme to stencil TF binding locations within accessible chromatin regions. We optimize bulk and single-cell ACCESS-ATAC protocols and develop computational methods to show that the increased resolution compared with ATAC-seq improves the accuracy of TF binding site prediction. We use ACCESS-ATAC to perform genome-wide allelic occupancy and co-occupancy imputation for 64 TFs each in HepG2 and K562, revealing that the propensity of a majority of TFs to co-occupy nearby motifs oscillates with a period approximating the helical turn of DNA. Altogether, ACCESS-ATAC expands the resolution and capabilities of bulk and single-cell epigenomic profiling.
Auditory and Visual Thalamocortical Connectivity Alterations in Unmedicated People with Schizophrenia: An Individualized Sensory Thalamic Localization and Resting-State Functional Connectivity Study
Authors: Williams John C. , Tubiolo Philip N. , Gil Roberto B. , Zheng Zu Jie , Silver-Frankel Eilon B. , Haubold Natalka K. , Abeykoon Sameera K. , Pham Dathy T. , Ojeil Najate , Bobchin Kelly , Slifstein Mark , Weinstein Jodi J. , Perlman Greg , Horga Guillermo , Abi-Dargham Anissa , Van Snellenberg Jared X.
Published: December 2024

Background

Converging evidence from clinical neuroimaging and animal models has strongly implicated dysfunction of thalamocortical circuits in the pathophysiology of schizophrenia. Preclinical models of genetic risk for schizophrenia have shown reduced synaptic transmission from auditory thalamus to primary auditory cortex, which may represent a correlate of auditory disturbances such as hallucinations. Human neuroimaging studies, however, have found a generalized increase in resting state functional connectivity (RSFC) between whole thalamus and sensorimotor cortex in people with schizophrenia (PSZ). We aimed to more directly translate preclinical findings by specifically localizing auditory and visual thalamic nuclei in unmedicated PSZ and measuring RSFC to primary sensory cortices.

Methods

In this case-control study, 82 unmedicated PSZ and 55 matched healthy controls (HC) completed RSFC functional magnetic resonance imaging (fMRI). Auditory and visual thalamic nuclei were localized for 55 unmedicated PSZ and 46 HC who additionally completed a sensory thalamic nuclei localizer fMRI task (N = 101). Using localized nuclei as RSFC seeds we assessed group differences in auditory and visual thalamocortical connectivity and associations with positive symptom severity.

Results

Auditory thalamocortical connectivity was not significantly different between PSZ and HC, but hyperconnectivity was associated with greater positive symptom severity in bilateral superior temporal gyrus. Visual thalamocortical connectivity was significantly greater in PSZ relative to HC in secondary and higher-order visual cortex, but not predictive of positive symptom severity.

Conclusion

These results indicate that visual thalamocortical hyperconnectivity is a generalized marker of schizophrenia, while hyperconnectivity in auditory thalamocortical circuits relates more specifically to positive symptom severity.
Hemodynamic Mechanisms Underlying Orthostatic Hypotension in Stroke Survivors: A Cross-Sectional Study
Authors: Oyake Kazuaki , Mochida Ayumi , Terashi Masakiyo , Hasegawa Mahiro , Saito Akari , Kondo Kunitsugu , Otaka Yohei , Momose Kimito
Published: December 2024

Background

Orthostatic hypotension is an important consideration for stroke survivors, given its association with adverse outcomes, such as cardiovascular diseases and falls. Understanding the hemodynamic mechanisms underlying orthostatic hypotension is essential for selecting the appropriate treatment based on individual hemodynamic patterns. However, the relative contribution of changes in cardiac output and total peripheral resistance to orthostatic hypotension remains unclear in stroke survivors.

Objective

To determine whether orthostatic hypotension is more strongly associated with a marked decrease in cardiac output or an impaired increase in total peripheral resistance among individuals with stroke.

Methods

This cross-sectional study included 23 individuals with stroke (13 males, mean [SD] age 63.7 [12.1] years, mean time since stroke 85.1 [34.1] days) recruited from an intensive inpatient rehabilitation ward between June 2022 and November 2023. Participants underwent a head-up tilt test to assess orthostatic hypotension and associated changes in cardiac and total peripheral resistance indices. The head-up tilt test protocol consisted of a 5-min period in the supine position followed by a 5-min period with a 70° head-up tilt. Orthostatic hypotension was defined as a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg during the test.

Results

Orthostatic hypotension was identified in five participants (22%). During the head-up tilt test, these individuals demonstrated a significantly greater increase in the cardiac index (p = 0.023) and decrease in the total peripheral resistance index (p = 0.002) than those without orthostatic hypotension.

Conclusions

Our results suggest that an impaired increase in total peripheral resistance upon standing mainly contributes to orthostatic hypotension in individuals with stroke. These findings advance the understanding of the hemodynamic mechanisms underlying orthostatic hypotension in the stroke population and may guide the implementation of targeted therapeutic strategies.

Highlights

Orthostatic hypotension is associated with a higher risk of adverse outcomes.

Mechanisms of orthostatic hypotension were examined in stroke survivors.

Orthostatic hypotension may be associated with impaired vasoconstriction.

Findings may aid in managing orthostatic hypotension during stroke rehabilitation.
Acoustic Recognition of Individual Animals in the Presence of Unknown Individuals
Authors: Huang Lifi , Clarke Rohan , Teixeira Daniella , Chiaradia André , Meyer Bernd
Published: December 2024

Passive acoustic monitoring is firmly established as an effective non-invasive technique for wildlife monitoring. The analysis of animal vocalizations recorded in their natural habitats is commonly used to monitor species occupancy, distribution mapping and community composition. The ability to distinguish between individual animals, however, remains underexplored and presents an exciting opportunity to study individual animal behavior and population demographics in more detail. In this work, we investigate bioacoustic individual-level recognition. In contrast to existing work, we focus on settings where only a subset of the existing population is known and labeled. This is crucial because wildlife populations are constantly changing so that solutions operating only within a known set of individuals are not realistically applicable in the wild. Using two novel datasets, we show that models initially trained to classify only known individuals can also be extended to detect new, previously unseen, individuals that are not part of the training set. We demonstrate that feature extractors pretrained on species classification can be successfully adapted for this task. Extending individual-level recognition to unknown individuals, so-called out-of-distribution classification, is a crucial step towards making individual recognition a realistic possibility in the wild.
The Effects of Climate Hazards on Personal Hygiene Practices among People with Disabilities in Bangladesh: A Qualitative Study
Authors: Nawaz Shahpara , Upoma Tasnia Alam , Goshami Arka , Podder Bithy , Akter Jarin , Hasan Mehedi , Shoaib Dewan Muhammad , D’Mello-Guyett Lauren , Kovats Sari , Alam Mahbub-Ul , Wilbur Jane
Published: December 2024

People with disabilities experience unique challenges in practising good hygiene, and climate hazards exacerbate those challenges. This study investigates the effects of climate hazards on personal hygiene practices (handwashing, bathing, laundry, and menstrual health) among people with disabilities and their caregivers in cyclone-affected Satkhira and flood-affected Gaibandha of Bangladesh.

A phenomenological qualitative study was conducted in rural Satkhira and Gaibandha. We applied purposive sampling to select 39 people with disabilities and 16 caregivers who experienced cyclones or floods between 2018 and 2023. Data were collected through in-depth interviews, photovoice and ranking, and observations. We thematically analysed findings using Nvivo 14.

During Cyclone Amphan in Satkhira and recurrent floods in Gaibandha, handwashing practices remained unchanged. However, water-logged muddy paths led participants to refrain from bathing for days in Satkhira, causing dissatisfaction about cleanliness. Flooded water points and surroundings in Gaibandha forced participants to bathe and do laundry in contaminated floodwaters, resulting in people reporting increased rashes, skin infections, and fevers. In both districts, the need for bathing and laundering soiled clothes and bedding among people with disabilities experiencing incontinence remained unmet. Additionally, caregivers struggled to provide dignified hygiene support. Women with disabilities could not wash menstrual materials during cyclone in Satkhira. In Gaibandha, contaminated floodwater was used to wash menstrual materials, and individuals living in temporary shelters expressed privacy concerns. Disposal practices were disrupted, with used materials stored indoors or thrown into floodwaters. These challenges adversely affected the health and well-being of people with disabilities and the emotional well-being of the caregivers.

People with disabilities face more complex challenges in maintaining personal hygiene during floods and cyclones due to impairments, gender-specific biological needs, additional health requirements, and dependency on caregivers. To prevent worsening inequalities in a changing climate, it is crucial to systematically include people with disabilities in climate-resilient hygiene initiatives.
Aberrant Neuronal Synchronization Associated with Cognitive Deficits in a Rodent Model of Childhood Cranial Irradiation
Authors: Barrientos Sebastian A. , Konradsson Elise , Ceberg Crister , Petersson Per
Published: December 2024

Cranial radiation can be a life-saving intervention in pediatric brain cancer therapy but often results in debilitating cognitive decline. To clarify the underlying mechanisms of these side-effects we have here recorded neurophysiological activity in distributed brain networks involved in decision-making and memory functions in adult rats exposed to cranial irradiation on postnatal day 21. Multi-structure local field potential (LFP) recordings revealed decreased power in irradiated animals in the 4-9 Hz frequency band. Additionally, a distinct slowing of the oscillatory activity was observed preceding erroneous choice in a decision-making task. Moreover, irradiated rats showed reduced dynamics and a fragmented pattern of inter-structural coherence across different phases of the task. Our results suggest that the cognitive deficits and reduced processing speed following irradiation of the juvenile brain arise as a consequence of changes in long-range functional connectivity, including thalamocortical circuits, causing abnormally slow and spatially fractionated patterns of coordinating LFP activity.
A Toolbox for Generating Multidimensional 3-D Objects with Fine-Controlled Feature Space: Quaddle 2.0
Authors: Wen Xuan , Malchin Leo , Womelsdorf Thilo
Published: December 2024

Multidimensional 3D-rendered objects are an important component of vision research and video- gaming applications, but it has remained challenging to parametrically control and efficiently generate those objects. Here, we describe a toolbox for controlling and efficiently generating 3D rendered objects composed of ten separate visual feature dimensions that can be fine-adjusted using python scripts. The toolbox defines objects as multi-dimensional feature vectors with primary dimensions (object body related features), secondary dimensions (head related features) and accessory dimensions (including arms, ears, or beaks). The toolkit interfaces with the freely available Blender software to create objects. The toolbox allows to gradually morph features of multiple feature dimensions, determine the desired feature similarity among objects, and automatize the generation of multiple objects in 3D object and 2D image formats. We document the use of multidimensional objects in a sequence learning task that embeds objects in a 3D- rendered augmented reality environment controlled by the gaming engine unity. Taken together, the toolbox enables the efficient generation of multidimensional objects with fine control of low- level features and higher-level object similarity useful for visual cognitive research and immersive visual environments.
Transcriptional control ofC. elegansmale tail tip morphogenesis by DMD-3
Authors: Fernandez Porfirio , Ercan Sevinç , Kiontke Karin C. , Fitch David H. A.
Published: December 2024

Sexual dimorphic morphogenesis is governed by DM-domain transcription factors (TFs) in many animals, but how these transcriptional control links to the morphogenetic mechanisms is insufficiently known. The DM-domain TF DMD-3 inC. elegansis the master regulator of a male-specific development that changes the shape of the tail tip from long and pointed in larvae to short and round in adults. This tail tip morphogenesis (TTM) requires cell-shape changes, cell migration and fusion. To understand how transcriptional regulation by DMD-3 governs TTM, we used male-specific ChIP-seq to identify its direct targets. We found 1,755 DMD-3 bound sites. We identify a DMD-3 associated binding motif and validate its function in TTM. This motif is similar to the binding motif of EOR-1, and we suggest that DMD-3 acts cooperatively with EOR-1 and possibly other TFs. DMD-3 targets 270 genes that play a role in TTM. These genes include other TFs but also effectors and components of morphogenetic mechanisms. By deleting the DMD-3 bound region endogenously and observing changes in reporter expression and tail tip phenotypes, we identify tissue specific enhancers in the cis-regulatory region offos-1, pan-1, nmy-2andhmr-1that play a role in TTM. Forfos-1, we propose that a feed-forward loop is responsible for tail-tip specific increase of gene-expression. This study provides insights into the architecture of the genetic regulatory network controlling a morphogenetic process.

Article Summary

DM domain transcription factors are often responsible for sexually dimorphic morphogenesis, but how they connect to morphogenetic mechanisms is insufficiently known. Here, we use ChIP-seq to determine the direct targets of DMD-3, which is the master regulator of male-specific tail tip morphogenesis (TTM) inC. elegans. We find that DMD-3 targets 270 TTM genes which include other transcription factors but also effectors and components of morphogenetic mechanisms. This study provides insights into the architecture of the genetic regulatory network controlling a morphogenetic process.
ScPectral: Spectrally Clustering Hypergraph Representations of Transcription Networks to Identify Developmental Pathways
Authors: Bersenev Dennis
Published: December 2024

Transcription Networks, otherwise known as Gene Regulatory Networks (GRNs), are models of biological systems centred on Transcription Factor (TF) interactions. These models equip experimentalists with a powerful computational tool to predict the effects of different genetic perturbations. GRNs are canonically modelled using a digraph, wherein the arcs indicate activation or repression between each pair of nodes to represent the relationships among the TFs. However, gene regulation is accomplished by groups of TFs working in concert, a biological reality the pairwise model neglects. In addition to the paucity of GRN representations incorporating this known TF biology, a persisting challenge to inference of the networks themselves is in accounting for the latent dynamics of gene interactions. In considering this second point, the advent of single-cell RNA sequencing technologies, provides the high resolution data needed to begin effectively inferring temporally-aware models. Despite this, utilisation of temporally-aware statistical metrics to do so has been limited. In addressing these shortcomings to GRN inference, scPectral is introduced as a method to infer a robust dynamic representation of a common GRN motif, the cascade, in the form of a hypergraph. ScPectral is applied to the identification of developmental pathways for known processes to validate its efficacy. Given scPectral’s modest success in finding key constituents of developmental pathways, and its ability to do so in a manner requiring no input or annotation of known biology, through further improvement it may develop to become a technique able to aid experimentalists exploring novel development processes. ScPectral is made available at:https://github.com/Dennis-Bersenev/scPectral.
Development of an H&E on-block staining technique for collagen detection in cryo-fluorescence tomography imaging of frozen breast tissue samples
Authors: Snoddy Erin P. , Tang Tien T. , Fowlkes Natalie , Huynh Thomas , Brewer Savannah Kari J. , Contreras Alejandro , Reece Gregory , Brock Kristy K.
Published: December 2024

Background

Hematoxylin and eosin (H&E) staining is widely considered to be the gold-standard diagnostic tool for histopathology evaluation. However, the fatty nature of some tissue types, such as breast tissue, presents challenges with cryo-sectioning, often resulting in artifacts that can make histopathologic interpretation and correlation with other imaging modalities virtually impossible. We present an optimized on-block H&E staining technique that improves contrast for identifying collagenous stroma during cryo-fluorescence tomography (CFT) sectioning.

Approach

In this prospective study, we embedded four breast specimens with confirmed ligaments from a bilateral mastopexy in an optimal cutting temperature block. Two of the samples were processed on a CFT imager and stained with our on-block staining protocol. In this protocol, hematoxylin was applied to the block face before being washed with deionized water. Eosin was then applied and washed with 95% ethanol. We then applied mounting medium and acquired images with a stereo-dissecting microscope and camera. Prior to staining, GFP fluorescence and white-light images were acquired with the CFT system to serve as a validation metric. The other two samples were sectioned on a standard cryostat and stained according to gold-standard H&E protocol. The resulting microscope slides were imaged with a digital slide scanner and viewed with Leica Imagescope software. An experienced pathologist evaluated both sets of images for qualitative comparisons.

Results

Pathologist evaluation confirmed that striations from on-block staining were qualitatively comparable with collagen tracks identified in gold-standard histology images. Furthermore, GFP images captured collagen autofluorescence, which aligned with the same structures identified by our on-block staining protocol.

Conclusion

Our on-block staining technique shows comparable visualization of collagenous structures at the mesoscopic level for fresh breast tissue samples. This technique improves tissue contrast and region of interest selection for histology during CFT imaging for analysis of the stromal architecture of the breast.
Digital Spatial Profiling identifies phospho-JNK as a biomarker for early risk stratification of aggressive prostate cancer
Authors: Eickelschulte Samaneh , Kaczorowski Adam , Janke Florian , Riediger Anja Lisa , Lazareva Olga , Böning Sarah , Kristiansen Glen , Schwab Constantin , Stenzinger Albrecht , Sültmann Holger , Duensing Stefan , Duensing Anette , Görtz Magdalena
Published: December 2024

Background

Prostate cancer (PCa) is a highly heterogeneous disease, with cases ranging from indolent to highly aggressive forms. Ongoing research focuses on identifying new biomarkers to improve early risk stratification in PCa, addressing current limitations to accurately evaluate disease progression. A promising new approach to aid PCa risk stratification is digital spatial profiling (DSP) of PCa tissue.

Methods

A total of 94 regions of interest from 38 PCa patients at first diagnosis were analyzed for the expression of 44 proteins, including components of the PI3K-AKT, MAPK, and cell death signaling pathways as well as immune cell markers. An additional validation cohort consisting of 154 PCa patients with long-term follow-up data was analyzed using immunohistochemistry (IHC) to assess the consistency of the identified biomarkers across a larger sample set.

Results

DSP identified proliferation marker Ki-67 and phospho-c-Jun N-terminal protein kinase (p-JNK), a member of the MAPK signaling pathway, as significantly upregulated proteins in aggressive PCa (Gleason scores 4 and 5) compared to indolent disease (Gleason score 3). The upregulation of p-JNK was confirmed through IHC. High p-JNK expression was associated with a shorter time to biochemical recurrence (log-rank, p=0.1).

Conclusion

Our results indicate that p-JNK may contribute to PCa progression and serve as an early biomarker for aggressive PCa stratification. Identifying this biomarker through DSP could be crucial in advancing disease management and addressing the critical unmet need for more targeted therapies in the treatment of aggressive PCa. Further studies are recommended to evaluate the role of p-JNK in PCa progression.
Quantitative risk assessment of human H5N1 infection from consumption of fluid cow’s milk
Authors: Koebel Katherine J. , Bulut Ece , Alcaine Samuel D. , Trmčić Aljoša , Nooruzzaman Mohammed , Covaleda Lina M. , Diel Diego G. , Ivanek Renata
Published: December 2024

The spillover of highly pathogenic avian influenza H5N1 into dairy cattle has raised concerns over the safety of fluid milk. While no human foodborne infection has been reported, this strain has infected dozens of people and milk from infected cows is known to be infectious by ingestion in multiple other species. Investigation into the public health threat of this outbreak is critical. This study uses quantitative risk assessment (QRA) models to represent the United States raw and pasteurized fluid milk supply chains to estimate the risk of human infection from consumption of fluid cow’s milk. These models were parameterized with literature emerging from this outbreak, then employed to estimate the H5N1 infection risk and evaluate multiple potential interventions aimed at reducing this risk. The median (5th, 95thpercentiles) probabilities of infection per 240-mL serving of pasteurized, farmstore-purchased raw, or retail-purchased raw milk were 5.68E-15 (1.77E-16, 2.98E-13), 1.13E-03 (5.16E-06, 3.82E-02), and 1.02E-03 (5.20E-06, 3.64E-02), respectively. Our results demonstrate that pasteurization is highly effective at reducing H5N1 infection risk. Scenario analysis revealed quantitative real-time reverse transcriptase-polymerase chain reaction (qrRT-PCR) testing of bulk tank milk to be an effective method for reducing risk from raw milk. Additionally, we identify knowledge gaps related to human H5N1 dose-response by ingestion and raw milk consumption patterns. These findings emphasize the importance of pasteurization in protecting public health and will inform the implementation of control strategies to reduce the risk of human H5N1 infection from raw milk.
Strain-level antigen variation facilitates immune evasion inBacteroides thetaiotaomicron
Authors: Glowacki Robert W.P. , Till Jessica M. , Brock Orion D. , Engelhart Morgan J. , Ahern Philip P.
Published: December 2024

The T cell receptor (TCR) repertoire of intestinal CD4+ T cells is enriched for specificity towards microbiome-encoded epitopes shared among many microbiome members, providing broad microbial reactivity from a limited pool of cells. These cells actively coordinate mutualistic host-microbiome interactions, yet many epitopes are shared between gut symbionts and closely related pathobionts and pathogens. Given the disparate impacts of these agents on host health, intestinal CD4+ T cells must maintain strain-level discriminatory power to ensure protective immunity while preventing inappropriate responses against symbionts. However, to date, the mechanisms by which this occurs have remained enigmatic. To interrogate this, we leveraged BθOM mice that express a transgenic TCR specific for aBT4295-encoded epitope inB. thetaiotaomicron. While manyB. thetaiotaomicronstrains potently activated BθOM CD4+ T cellsin vitro, strain dnLKV9 escaped recognition. Bioinformatic analyses uncovered twoBT4295homologs inB. thetaiotaomicron-dnLKV9, with each homolog harboring sequence modifications relative to strain VPI-5482, specifically a premature stop codon and a T548S substitution within the epitope. Reconstruction of these variants inB. thetaiotaomicron-VPI-5482ΔBT4295conferred evasion from BθOM CD4+ T cellsin vitroto this otherwise permissive strain. Adoptive transfer of BθOM CD4+ T cells to gnotobiotic RAG1-/- colonized withB. thetaiotaomicronharboring these variantBT4295forms verified the sufficiency of these antigen modifications for evasion of BθOM CD4+ T cells. Collectively, these data uncover the existence of strain-level immune evasion inB. thetaiotaomicronand reveal a mechanism whereby strains evade recognition by CD4+ T cells, facilitating strain-level discrimination in responsiveness to the microbiome.

Key Points

-

SelectB. thetastrains evade recognition by aB. theta-specific CD4+ T cell

-

Strain-specific antigen modifications rather than absence of antigen mediate evasion

-

Evasion strategies limitin vivoaccumulation ofB. theta-specific CD4+ T cells
Mitogenome Diversity and Phylogenetic Insights of Aedes albopictus in Greece
Authors: BALATSOS GEORGIOS , Karathanasi Venetia , Evangelou Vasiliki , Kapantaidaki Despoina , Tegos Nikolaos , Panagopoulou Anastasia , Bisia Marina , Karras Vasileios , Papachristos Dimitrios , Papadopoulos Nikos T , Augustinos Antonios A , Patsoula Eleni , Michaelakis Antonis
Published: December 2024

The invasive mosquito species Aedes albopictus, commonly known as the Asian Tiger Mosquito, is a significant global health concern due to its role as a vector for diseases such as Dengue, Zika, and Chikungunya. In Greece, Ae. albopictus was first detected in 2005, with subsequent widespread establishment across the country. This study investigates the genetic diversity and phylogeography of Greek Ae. albopictus populations by analyzing mitochondrial cytochrome oxidase I (COI) gene sequences. A total of 488 female individuals were analyzed, revealing six haplotypes in samples collected from 2016 to 2018 using the LCO 1490 and HCO 2198 primer pair, including instances of identical haplotypes across years, while only one haplotype was consistently detected across all 2019 to 2022 samples using the UBC6 and UBC9 primer pair. These findings underscore the importance of molecular tools in understanding invasion dynamics and informing targeted surveillance and control measures. Further research is needed to assess additional worldwide populations and expand phylogeographic comparisons to elucidate global dispersal patterns.
A Co-essentiality Network of Cancer Driver Genes Better Prioritizes Anticancer Drugs
Authors: Lee Kwanghwan , Kim Donghyo , Kim Inhae , Lee Juhee , Ha Doyeon , Lim Seongsu , Kim Eunjee , Im Sin-Hyeog , Shin Kunyoo , Kim Sanguk
Published: December 2024

Diverse molecular networks have been extensively studied to discover therapeutic targets and repurpose approved drugs. However, it is necessary to select a suitable network since the performance of network medicine relies heavily on the completeness and characteristics of the selected network. Although a network using gene essentiality from cancer cells could be an effective platform for identifying anticancer targets, efforts to apply these networks in therapeutic applications have been limited. We constructed a phenotype-level network using the co-essentiality relationship between genes in CRISPR screens across 769 cancer cells to discover therapeutic targets for diverse cancer types. Leveraging cancer driver genes and network propagation on the networks, we found that the co-essentiality network better prioritized anticancer targets and biomarkers and predicted more precise drug responses in cancer cells than other molecular networks. The co-essentiality network outperformed conventional molecular networks in drug repurposing, which were validated in silico by clinical trial records. Notably, the co-essentiality network provided 37 repurposed drugs that the other networks have yet to cover, and we showcased three approved drugs repurposed for lung adenocarcinoma (Pioglitazone hydrochloride, Atovaquone, and Eflornithine). Our study provides a novel network for precision oncology to improve the identification of therapeutic targets in specific cancers.
Engineering Adaptive Alleles forEscherichia coliGrowth on Sucrose Using the EasyGuide CRISPR System
Authors: Barreto Joneclei Alves , e Silva Matheus Victor Maso Lacôrte , Marin Danieli Canaver , Brienzo Michel , Jacobus Ana Paula , Contiero Jonas , Gross Jeferson
Published: December 2024

Adaptive Laboratory Evolution (ALE) is a powerful approach for mining genetic data to engineer industrial microorganisms. This evolution-informed design requires robust genetic tools to incorporate the discovered alleles into target strains. Here, we introduce the EasyGuide CRISPR, a five-plasmid platform that exploitsE. coli’s natural recombination system to assemble gRNA plasmids from overlapping PCR fragments. The production of gRNAs and donor DNA is further facilitated by using recombination cassettes generated through PCR with 40 to 60-mer oligos. With the new CRISPR toolkit, we constructed 22 gene edits inE. coliDH5α, most of which corresponded to alleles mapped inE. coliDH5α and E2348/69 ALE populations selected for sucrose propagation. For DH5α ALE, sucrose consumption was supported by thecscBKAoperon expression from a high-copy plasmid. During ALE, plasmid integration into the chromosome, or its copy number reduction due to thepcnBdeletion, conferred a 30–35% fitness gain, as demonstrated by CRISPR-engineered strains. A ∼5% advantage was also associated with a ∼40.4 kb deletion involvingflioperons for flagella assembly. In E2348/69 ALE, inactivation of thehflsystem suggested selection pressures for maintaining λ-prophage dormancy (lysogeny). We further enhanced our CRISPR toolkit using yeast for in vivo assembly of donors and expression cassettes, enabling the establishment of polyhydroxybutyrate synthesis from sucrose. Overall, our study highlights the importance of combining ALE with streamlined CRISPR-mediated allele editing to advance microbial production using cost-effective carbon sources.