bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of De-Epithalialized Flap for Elevating the Alar Base in Patients With Cleft Lip
Authors: Selamioğlu Engin , Eyüpoğlu Ümit , Göztepe Mehmet Berke , Eroğlu Yağiz Berk , Eroğlu Lütfi
Published: October 2024

Alar base asymmetry is a common problem in cleft lip patients. Caused by a lack of bone support and soft tissue deficiency, it is one of the problems that must be corrected during cleft lip repair. While it is encountered during primary lip repair, it can also be seen as a secondary cleft lip nasal deformity after repair. This study aimed to provide alar base symmetry with a de-epithelialized muscle-skin flap during the primary cleft lip repair of incomplete cleft lip patients and secondary cleft lip deformity repair. In incomplete cleft lip patients, the tissue under the incomplete part is de-epithelialized and elevated as a superiorly based flap. The flap is rotated and sutured under the alar base for the elevation. In secondary patients, scar tissue to be removed is de-epithelialized and elevated as a superiorly based flap. It is turned over and sutured under the alar base for augmentation. The effect of the surgery is monitored during the follow-up period. There were no complications related to the flap, and no volume loss was observed. Using a de-epithelialized musculocutaneous flap, the augmentation of the alar base and nasal sill can be achieved without additional incisions in patients undergoing primary incomplete cleft lip repair and in patients undergoing secondary cleft lip deformity repair. We think it is an effective and safe method, improving the esthetic outcomes of cleft lip patients.
Intraoperative Factors Affecting Pain Management and Postoperative Narcotic Use in Cranial Vault Remodeling: A Retrospective Review
Authors: Dominguez Elizabeth , O’Donnell Carly M. , Bacos Jonathan T. , Havlik Robert J. , Lin Kant Y. , Shakir Sameer , Klement Kristen A.
Published: October 2024

Perioperative pain control in open cranial vault reconstruction (CVR) poses significant challenges. Narcotic use may confound signs of neurological deterioration and cause medication-induced complications. Previous studies have shown improved health outcomes in CVR with reduced narcotic use. The purpose of this study was to investigate the relationship between modifiable intraoperative factors on postoperative narcotic use. A retrospective cohort study was performed on 237 patients with craniosynostosis who presented to a tertiary pediatric hospital over a 10-year period for open CVR. There was a statistically significant relationship between total fluid volume infused intraoperatively (mL/kg) and total morphine equivalents (MEs, mL/kg) given throughout hospitalization (P< 0.001). Longer operative times were associated with greater total hospitalization ME (P ≤ 0.006) and total intraoperative blood products transfused (P ≤ 0.001). Patients who received drains were given significantly higher total hospitalization ME compared with those who did not (P< 0.001). Patients who received postoperative nonsteroidal anti-inflammatory drugs required significantly fewer total ME compared with children who did not (P< 0.005) and patients who received intraoperative tranexamic acid were less likely to require postoperative blood transfusion (P< 0.001). Postoperative nonsteroidal anti-inflammatory drug use is associated with decreased narcotic requirements during the immediate postoperative period whereas increased fluid requirements intraoperatively, longer operative durations, and drain placement are associated with higher narcotic use. Modifying intraoperative factors like these may lead to decreased postoperative pain, thus limiting narcotic use for patients, and improving overall outcomes.
Surgical Treatment and Clinical Evaluation of Calvarial Metastases
Authors: Zhou Jiahua , Wu Yingxi , Feng Dayun , Wang Shoujie , Qin Huaizhou , Li Jiang , Yang Di
Published: October 2024

Background:

The aim of this study is to explore surgical treatment techniques and clinical attributes associated with calvarial metastases, while providing a comprehensive review of the treatment experiences relevant to this particular type of tumor.

Methods:

This study involves a retrospective analysis of clinical data from 12 patients diagnosed with calvarial metastatic tumors who underwent surgical intervention. Among these patients, 5 had a history of previous malignant tumor resections, while 7 presented with calvarial metastatic tumors as their initial symptom. In all cases, the surgical approach consisted of calvarial tumor resection followed by titanium mesh repair. Following the surgical intervention, all patients underwent a comprehensive course of treatment, encompassing both local radiotherapy and systemic chemotherapy.

Results:

In 1 instance, a patient presented with multiple tumors located in the central area of the frontal bone and the right temporal bone. The larger tumor situated in the middle of the frontal bone was surgically excised, while the tumor in the right temporal bone was treated using radiotherapy. In 2 cases characterized by multiple metastases within the skull, a comprehensive excision of all tumors was accomplished in a single surgical procedure. In the remaining cases featuring a solitary metastatic growth, the respective tumors were surgically removed. There were 10 instances of dura mater invasion and 3 cases involving the invasion of brain tissue. Pathologic examinations revealed 1 case of metastatic lung adenocarcinoma, 1 case of metastatic paraganglioma, 1 case of metastatic hepatocellular carcinoma, 2 cases of metastatic thyroid carcinoma, and 7 cases of metastatic clear cell renal cell carcinoma. Throughout the follow-up period, spanning from 14 to 90 months, various outcomes were noted. These included three occurrences of in situ recurrence. In addition, 1 patient required 3 distinct surgical interventions, while 2 other patients underwent 2 separate surgical procedures each. Notably, 1 of these cases involved the exposure of the titanium mesh on the scalp, necessitating the removal of the titanium mesh. Regrettably, there have been 9 recorded fatalities among the patients, while 3 individuals have survived.

Conclusion:

Solitary metastasis of calvarium region is rare, and surgical resection is effective. However, it is necessary to extend the resection range and combine with local radiotherapy to avoid local recurrence. Surgical intervention can significantly enhance the quality of life for affected patients. The prognosis of the patients mainly depends on the treatment of the primary disease and the situation of important organ dissemination and treatment.
Differences on In-hospital Outcomes in Patients with Cardiogenic Shock due to STEMI vs NSTEMI Using A Nationwide Database
Authors: Diaz-Arocutipa Carlos , Bueno Héctor , Moreno Guillermo , Olmos Víctor Juárez , Vicent Lourdes
Published: October 2024

Background

Our study aims to compare in-hospital management and outcomes in patients with cardiogenic shock due to ST-segment elevation myocardial infarction (STEMI) vs. non-ST-segment elevation myocardial infarction (NSTEMI).

Methods

We conducted a retrospective cohort study using the National Inpatient Sample database between 2016-2019, including patients with STEMI/NSTEMI complicated by cardiogenic shock. An inverse probability treatment weighting (IPTW) analysis was performed to compare in-hospital management and outcomes between patients with STEMI and NSTEMI. Adjusted relative risks (aRR) with their 95% confidence intervals (CI) were estimated.

Results

A total of 150,395 patients with cardiogenic shock due to acute myocardial infarction were included, of whom 52.8% had STEMI. The median age was 68 years (60 - 77) and 35% were female. Percutaneous coronary intervention (PCI), intra-aortic balloon counterpulsation, percutaneous ventricular assist device, extracorporeal membrane oxygenation and mechanical ventilation use were significantly higher in the STEMI group compared to NSTEMI. Coronary artery bypass grafting (CABG), renal replacement therapy, length of hospital stay, and total costs were lower in the STEMI group. Pulmonary arterial catheterization and cardiac transplantation were similar between both groups. IPTW analysis showed that in-hospital mortality was significantly higher in the STEMI group compared to NSTEMI (34.2% vs. 28.8%, aRR 1.19, 95% CI 1.14 - 1.23) and also major bleeding.

Conclusion

In conclusion, patients with cardiogenic shock due to STEMI had worse prognosis, higher use of PCI/mechanical circulatory support and major bleeding than the NSTEMI group. In contrast, patients with NSTEMI had greater use of CABG and hospital resources.
Clinical Consensus Statement: Vaginal Energy-Based Devices
Authors: Alshiek Jonia , Garcia Bobby , Minassian Vatche , Iglesia Cheryl B. , Clark Amanda , Sokol Eric R. , Murphy Miles , Malik Shazia A. , Kimble Alexis , Shobeiri S. Abbas
Published: October 2024

This clinical consensus statement on vaginal energy-based devices (EBDs) reflects an update by content experts from the American Urogynecologic Society’s EBD writing group. In 2019, the American Urogynecologic Society’s EBD writing group used a modified Delphi process to assess statements that were evaluated for consensus after a structured literature search. A total of 40 statements were assessed and divided into 5 categories: (1) patient criteria, (2) health care provider criteria, (3) efficacy, (4) safety, and (5) treatment considerations. Of the 40 statements that were assessed, 28 reached consensus and the remaining 12 did not. Lack of evidence was among the main reasons that vulvovaginal EBD treatment statements did not reach consensus. In March 2022, these statements were reassessed using the interim literature.
Surgical management of costal margin rupture associated with intercostal hernia: Evolution of techniques
Authors: Wijerathne Pradeep , Rao Jagan N. , Wijffels Mathieu M.E. , Tamburrini Alessandro , Tenconi Sara , Edwards John Gurney
Published: October 2024

INTRODUCTION

Costal margin rupture (CMR) injuries in association with intercostal hernia (IH) are rare and symptomatic and provide a significant surgical challenge. Surgical failure rates up to 60% are reported, and optimal techniques are unclear. We have characterized these injuries and describe the evolution of our surgical management techniques.

METHODS

Patients characterized by the Sheffield Classification where CMR and IH were both present, either CMR-IH or transdiaphragmatic intercostal hernia (TDIH), were identified prospectively, and injury characteristics, patient management, and follow-up data were recorded. Surgical techniques evolved according to patient outcomes from suture repair without and then with extrathoracic mesh, to three iterations of double-layer mesh repair (DLMR). The third iteration involved DLMR with biologic mesh, titanium buttress plates applied to the ribs adjacent to the IH with intercostal nerve-sparing suture placement. Associated surgical stabilization of rib fractures, or surgical stabilization of nonunited rib fractures, was performed when required, with costal margin plate fixation where possible.

RESULTS

Of 25 patients with CMR-IH and 11 with TDIH, 25 patients underwent surgery, with 6 reoperations in 5 patients. There were 8 suture repairs and 3 extrathoracic mesh repairs: DLMR was performed in 14 patients (3 Mark [Mk] 1, 5 Mk 2, and 6 Mk 3) with 2, 1, and 0 reoperations, respectively. Costal margin stabilization with titanium plates was successful twice at the level of the seventh but failed twice out of three times at the ninth costal cartilage.

Reoperation after a failed mesh repair is particularly challenging and may require the placement of titanium buttress plates, surgical stabilization of rib fractures, and the use of stainless steel wire sutures.

CONCLUSION

Repair of CMR-IH/TDIH is challenging, but experience-based evolution of techniques has led to a durable and reproducible Mk 3 repair.

LEVEL OF EVIDENCE

Observational; Level III.
Acorn ant exhibits age-dependent induced defence in response to parasitic raids
Authors: Koenig Phoebe A. , Moreau Corrie S.
Published: October 2024

When risk is unpredictable, organisms may evolve induced defenses, which are activated after an indication of increased risk. In colonies with behavioural specialization, investment in defence may not be uniformly beneficial among group members. Instead, it should depend on the individual’s likelihood of participating in defence. The ant
Temnothorax longispinosus
uses venom to defend against raids by the social parasite
Temnothorax americanus
. We tested whether
T. longispinosus
upregulate investment in venom after experiencing a raid, investigating the relationship between venom volume and worker behavioural caste. Overall, raided colonies had more venom per capita than unraided colonies. When divided into behavioural castes, foragers had more venom after experiencing a raid, while nurses did not. These results demonstrate that
T. longispinosus
have an induced chemical defence against parasitic raids. However, instead of this defence being deployed uniformly among all workers, the induction of the defence depends on the behavioural caste, and therefore age, of the worker, implying that plasticity in venom production increases with age. Since older social insect workers tend to perform riskier tasks, inducibility may align with an increase in expected risk of death, especially if foragers are more likely to defend the colony against parasites than younger workers.
Himatiichnus mangano
igen. et isp. nov., a scalidophoran trace fossil from the late Ediacaran of Namibia
Authors: Turk Katherine A. , Pulsipher Mikaela A. , Mocke Helke , Laflamme Marc , Darroch Simon A. F.
Published: October 2024

Himatiichnus mangano
igen. et isp. nov., a new trace fossil from the late Ediacaran Huns Member of the Urusis Formation, southern Namibia, comprises intertwining tubes exhibiting dual lineation patterns and reminiscent of both modern and early Cambrian examples of priapulid worm burrows. These similarities support the interpretation of a total-group scalidophoran tracemaker for
H. mangano
, thus providing direct evidence for the first appearance date of Scalidophora in the late Ediacaran
ca
539 Ma. This new material is thus indicative of the presence of total-group scalidophorans below the Cambrian boundary and supports inference of a lengthy Precambrian fuse for the Cambrian explosion.
Online landmark replacement for out-of-sample dimensionality reduction methods
Authors: Thongprayoon Chanon , Masuda Naoki
Published: October 2024

A strategy to assist visualization and analysis of large and complex datasets is dimensionality reduction, with which one maps each data point into a low-dimensional manifold. However, various dimensionality reduction techniques are computationally infeasible for large data. Out-of-sample techniques aim to resolve this difficulty; they only apply the dimensionality reduction technique on a small portion of data, referred to as landmarks, and determine the embedding coordinates of the other points using landmarks as references. Out-of-sample techniques have been applied to online settings, or when data arrive as time series. However, existing online out-of-sample techniques use either all the previous data points as landmarks or the fixed set of landmarks and therefore are potentially not good at capturing the geometry of the entire dataset when the time series is non-stationary. To address this problem, we propose an online landmark replacement algorithm for out-of-sample techniques using geometric graphs and the minimal dominating set on them. We mathematically analyse some properties of the proposed algorithm, particularly focusing on the case of landmark multi-dimensional scaling as the out-of-sample technique, and test its performance on synthetic and empirical time-series data.
Kin recognition for incest avoidance in Damaraland mole-rats,
Fukomys damarensis
Authors: Leedale Amy E. , Vullioud Philippe , Seager David , Zöttl Markus , Glauser Gaétan , Clutton-Brock Tim
Published: October 2024

Across taxa, breeding among close relatives is usually avoided because it incurs fitness costs to offspring. Incest is often averted through the dispersal of either sex from the natal area to breed. In some philopatric species, association among relatives extends into adulthood, and an ability to discriminate kin may be required for individuals to reduce inbreeding risk. Here, we aim to determine the mechanism of kin recognition for incest avoidance in the Damaraland mole-rat
Fukomys damarensis
, a cooperative breeder characterized by extreme reproductive skew. Pairs of opposite-sex adults were formed in the laboratory and, within pairs, genetic relatedness and degree of familiarity were manipulated through cross-fostering experiments. We found that unfamiliar pairs were more likely to engage in sexual behaviours and bred more successfully than familiar pairs, regardless of their genetic similarity. Females paired with unfamiliar males were also more likely to exhibit reproductive activation, characterized by increased levels of oestradiol and progesterone. This study shows that in Damaraland mole-rats, inbreeding avoidance can be achieved through a discrimination mechanism that relies on association during rearing, and that ovulation is induced by mating. This study advances our understanding of incest avoidance in species with constrained dispersal.
Supergenes are not necessary to explain the maintenance of complex alternative phenotypes
Authors: Flanagan Sarah P. , Alonzo Suzanne H.
Published: October 2024

Evolutionary biology aims to explain the diversity seen in nature. Evolutionary theory provides frameworks to understand how simple polymorphisms or continuous variation are maintained, but phenotypes inherited as discrete suites of quantitative traits are difficult to fit into this framework. Supergenes have been proposed as a solution to this problem—if causal genes are co-located, they can be inherited as if a single gene, thus bridging the gap between simple polymorphisms and continuous traits. We develop models to ask: how are critical supergenes for maintaining phenotypic diversity? In our simplest model, without explicit genetic architectures, three alternative reproductive morphs are maintained in many of the parameter combinations we evaluated. For these same parameter values, models with demographic stochasticity, recombination and mutation (but without explicit genetic architecture) maintained only two of these three morphs, with stochasticity determining which morphs persisted. With explicit genetic architectures, regardless of whether causal loci were co-located in a supergene or distributed randomly, this stochasticity in which morphs are maintained was reduced. Even when phenotypic variation was lost, genetic diversity was maintained. Altogether, categorical traits with polygenic bases exhibited similar evolutionary dynamics to those determined by supergenes. Our work suggests that supergenes are not the only answer to the puzzle of how discrete polygenic phenotypic variation is maintained.
DO NOT LOSE SLEEP OVER IT: IMPLANTED BRAIN-COMPUTER INTERFACE FUNCTIONALITY DURING NIGHTTIME IN LATE-STAGE AMYOTROPHIC LATERAL SCLEROSIS
Authors: Leinders Sacha , Aarnoutse Erik J. , Branco Mariana P. , Freudenburg Zac V. , Geukes Simon H. , Schippers Anouck , Verberne Malinda S.W. , van den Boom Max , van der Vijgh Benny , Crone Nathan E. , Denison Timothy , Ramsey Nick F. , Vansteensel Mariska J.
Published: October 2024

Background and objectives

Brain-computer interfaces (BCIs) hold promise as augmentative and alternative communication technology for people with severe motor and speech impairment (locked-in syndrome) due to neural disease or injury. Although such BCIs should be available 24/7, to enable communication at all times, feasibility of nocturnal BCI use has not been investigated. Here, we addressed this question using data from an individual with amyotrophic lateral sclerosis (ALS) who was implanted with an electrocorticography-based BCI that enabled the generation of click-commands for spelling words and call-caregiver signals.

Methods

We investigated nocturnal dynamics of neural signal features used for BCI control, namely low (LFB: 10–30Hz) and high frequency band power (HFB: 65-95Hz). Additionally, we assessed the nocturnal performance of a BCI decoder that was trained on daytime data by quantifying the number of unintentional BCI activations at night. Finally, we developed and implemented a nightmode decoder that allowed the participant to call a caregiver at night, and assessed its performance.

Results

Power and variance in HFB and LFB were significantly higher at night than during the day in the majority of the nights, with HFB variance being higher in 88% of nights. Daytime decoders caused 245 unintended selection-clicks and 13 unintended caregiver-calls per hour when applied to night data. The developed nightmode decoder functioned error-free in 79% of nights over a period of ±1.5 years, allowing the user to reliably call the caregiver, with unintended activations occurring only once every 12 nights.

Discussion

Reliable nighttime use of a BCI requires decoders that are adjusted to sleep-related signal changes. This demonstration of a reliable BCI nightmode and its long-term use by an individual with advanced ALS underscores the importance of 24/7 BCI reliability.

Trial registration

This trial is registered inclinicaltrials.govunder numberNCT02224469(https://clinicaltrials.gov/study/NCT02224469?term=NCT02224469&rank=1). Date of submission to registry: August 21, 2014. Enrollment of first participant: September 7, 2015.
VIDEO BASED DETECTION OF EPILEPTIC SEIZURES USING A THREE-DIMENSIONAL CONVOLUTIONAL NEURAL NETWORK
Authors: Boyne Aidan , Yeh Hsiang J. , Allam Anthony K. , Brown Brandon M. , Tabaeizadeh Mohammad , Stern John M. , Cotton R. James , Haneef Zulfi
Published: October 2024

Objective

Seizure detection in epilepsy monitoring units (EMU) is essential for the clinical assessment of drug-resistant epilepsy. Automated video analysis using machine learning provides a promising aid for seizure detection with resultant reduction in the resources required for diagnostic monitoring. We employ a 3D convolutional neural network with fully fine-tuned backbone layers to identify seizures from EMU videos.

Methods

A two-stream inflated 3D-ConvNet architecture (I3D) classified video clips as a seizure or not a seizure. A pretrained action classification model was fine-tuned on 11 hours of video data containing 49 tonic-clonic seizures from 25 patients monitored at a large academic hospital (site A) using leave-one-patient-out cross-validation. Performance was evaluated by comparing model predictions to ground-truth annotations obtained from video-EEG review by an epileptologist on videos from site A and a separate dataset from a second large academic hospital (site B).

Results

The model achieved leave-one subject out cross-validation F1-score of 0.960 ± 0.007 and area under the receiver operating curve (AUC) score of 0.988 ± 0.004 at site A. Evaluation on full videos successfully detected all seizures with median detection latency of 0.0 (0.0, 3.0) seconds from seizure onset. The site A model had an average false alarm rate of 1.81 alarms per hour, though 33 of the 49 videos (67%) had no false alarms. Evaluation at site B demonstrated generalizability of the model architecture and training strategy, though cross-site evaluation (site A model tested on site B data and vice versa) resulted in diminished performance.

Significance

Our model demonstrates high performance in the detection of epileptic seizures from video data using a fine-tuned I3D model and outperforms prior similar models identified in the literature. This study provides a foundation for future work in real-time EMU seizure monitoring and possibly for reliable and cost-effective at-home detection of tonic-clonic seizures.

KEY POINTS

We evaluate a video-based 3-D CNN for seizure detection in patients undergoing evaluation in an EMU at 2 large academic hospitals.

Our video-only model provides highly accurate detection of tonic-clonic seizures with low detection latency.

The underlying model architecture requires no video preprocessing and is generalizable across two EMUs.
Diagnostic performance of Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy for detecting osteoarthritis and rheumatoid arthritis from blood serum
Authors: Mannerkorpi Minna , Das Gupta Shuvashis , Rieppo Lassi , Saarakkala Simo
Published: October 2024

Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common rheumatic diseases worldwide, causing pain and disability. Both conditions are highly heterogeneous, and their onset occurs insidiously with non-specific symptoms, so they are not always distinguishable from other arthritis during the initial stages. This makes early diagnosis difficult and resource-demanding in clinical environments. Here, we estimated its diagnostic performance in classifying ATR-FTIR spectra obtained from serum samples from OA patients, RA patients, and healthy controls. Altogether, 334 serum samples were obtained from 100 OA patients, 134 RA patients, and 100 healthy controls. The infrared spectral acquisition was performed on air-dried 1µl of serum with a diamond-ATR-FTIR spectrometer. Machine learning models combining Partial Least Squares Discriminant Analysis (PLS-DA) and Support Vector Machine (SVM) were trained to binary classify preprocessed ATR-FTIR spectra as follows: controls vs. OA, controls vs. RA, and OA vs. RA. For a separated test dataset and the validation dataset, the overall model performance was better in classifying OA and RA patients, followed by the RA and controls, and lastly, between OA and controls, with corresponding AUC-ROC values: 0.84, 0.76, 0.72 (test dataset) and 0.94, 0.92, 79 (validation dataset). In conclusion, this study reports robust binary classifier models to differentiate blood serum from the two most common rheumatic diseases, showing the potential of ATR-FTIR as an effective aid in rheumatic disease classification.
Subtle methodological variations substantially impact correlation test results in ecological time series
Authors: Cannistra Caroline , Hoang Linh , Yuan Alex E. , Shou Wenying
Published: October 2024

Correlation analyses using ecological time series can indicate phenomena such as interspecific interactions or an environmental factor that affects several populations. However, methodological choices in these analyses can significantly impact the results, potentially leading to spurious correlations or missed true associations. In this study, we explore how different decisions affect the performance of statistical tests for correlations between pairs of time series in simulated two-species ecosystems. We show that when performing nonparametric “surrogate data” tests, both the choice of statistic and the method of generating the null distribution can affect true positive and false positive rates. We also show how seemingly closely related methods of accounting for lagged correlation produce vastly different false positive rates. For methods that establish a null model by simulating the dynamics of one of the two species, we show that the choice of species simulated can influence test behavior. Additionally, we identify scenarios where the outcomes of analyses can be highly sensitive to the initial conditions of an ecosystem, even under simple mathematical models. Our results indicate the importance of thoughtful consideration and documentation of the statistical choices investigated here. To make this work broadly accessible, we include visual explanations of most methods tested in an appendix.
Synthesis and Evaluation of Carmofur Analogs as Antiproliferative Agents, Inhibitors to the Main Protease (Mpro) of SARS-CoV-2, and Membrane Rupture-Inducing Agents
Authors: Gu Tiffany , Lu Amber , Wang Xina , Brahan Natalie , Xu Lexi , Zhang Leyuan , Su Kaitlyn , Seow Kody , Vu Julia , Luk Charissa , Lee Yunseo , Raman Anirudh , Pazzi Joseph , Njoo Edward
Published: October 2024

Initially developed as a derivatized analog of 5-fluorouracil for the treatment of colorectal cancer, carmofur has more recently demonstrated potent covalent inhibition of the main protease (Mpro) of SARS-CoV-2. Harnessing our previously described workflow for the optimized preparation of carmofur using benchtop19F NMR spectroscopy, here, we prepared and evaluated a synthetic library of nine carmofur analogs with a selection of side chain motifs or single-atom substitution to explore the diversifiability of these compounds as Mproinhibitors, where we discovered that a hexyl carbamate analog outperformed carmofur, and as antiproliferative agents in model human cell lines to identify differences in potency when the carbonyl electrophilicity and/or alkyl side chains are modified. Finally, we describe a novel workflow for the evaluation of membrane-rupturing small molecules through imaging of fluorescently labeled giant unilamellar vesicles (GUVs), and through this, we identified two lipophilic urethane analogs of carmofur bearing dodecyl urethane and octadecyl urethane side chains that have potent membrane-rupturing capability in the nanomolar range, providing insight into a potential mechanism for thein vitroactivities of lipidated 5-fluorouracil analogs.
Toward Automatic Variant Interpretation: Discordant Genetic Interpretation Across Variant Annotations for ClinVar Pathogenic Variants
Authors: Chen Yu-An , Yuan Tzu-Hang , Huang Jia-Hsing , Wang Yu-Bin , Hung Tzu-Mao , Chen Chien-Yu , Chen Pei-Lung , Hsu Jacob Shujui
Published: October 2024

Purpose

High-throughput sequencing has revolutionized genetic disorder diagnosis, but variant pathogenicity interpretation is still challenging. Even though the Human Genome Variation Society (HGVS) provides recommendations for variant nomenclature, discrepancies in annotation remain a significant hurdle.

Methods

This study evaluated the annotation concordance between three tools— ANNOVAR, SnpEff, and Variant Effect Predictor (VEP)—using 164,549 two-star variants from ClinVar. The analysis used HGVS nomenclature string-match comparisons to assess annotation consistency from each tool, corresponding coding impacts, and associated ACMG criteria inferred from the annotations.

Results

The analysis revealed variable concordance rates, with 58.52% agreement for HGVSc, 84.04% for HGVSp, and 85.58% for the coding impact. SnpEff showed the highest match for HGVSc (0.988), while VEP bettered for HGVSp (0.977). The substantial discrepancies were noted in the Loss-of-Function (LoF) category. Incorrect PVS1 interpretations affected the final pathogenicity and downgraded PLP variants (ANNOVAR 55.9%, SnpEff 66.5%, VEP 67.3%), risking false negatives of clinically relevant variants in reports.

Conclusions

These findings highlight the critical challenges in accurately interpreting variant pathogenicity due to discrepancies in annotations. To enhance the reliability of genetic variant interpretation in clinical practice, standardizing transcript sets and systematically cross-validating results across multiple annotation tools is essential.

Graphic abstract

This study examined the consistency of variant annotations produced by three widely used open-source tools—ANNOVAR, SnpEff, and VEP—against 164,549 ClinVar two starts variants. The investigation covers HGVS-based transcript, protein nomenclature and coding impact annotation. The results showed that none of the tools were fully consistent with ClinVar across all coding impact categories, particularly in the LoF category, which exhibited the poorest consistency. This inconsistency may lead to discrepancies in PVS1 interpretation, affecting the final pathogenicity assessment. PVS1 loss resulted in a significant downgrading of PLP variants, potentially leading to the omission of clinically relevant variants in reports.
Cholesterol sulfate prevents maternal–fetal conflict by locally modulating immune reactivity
Authors: Hirotani Kenichiro , Kunimura Kazufumi , Maeda Rae , Sugiura Yuki , Nakata Keisuke , Takahashi Masatomo , Izumi Yoshihiro , Akiyoshi Sayaka , Matsubara Keisuke , Morino Kenji , Iwasaki Takeshi , Tanaka Kaori , Aulia Fadlina , Miyata Kanjiro , Hosokawa Takanatsu , Mori Takeshi , Ohkawa Yasuyuki , Bamba Takeshi , Toh Hidehiro , Sasaki Hiroyuki , Oda Yoshinao , Uruno Takehito , Kato Kiyoko , Fukui Yoshinori
Published: October 2024

Although placental mammals are at high risk of maternal–fetal immune conflict, it is unclear how the semi-allogeneic fetus avoids rejection. Cholesterol sulfate (CS) is a bioactive metabolite that inhibits leukocyte migration and activation. This study investigated the roles and cells associated with CS in pregnant mice and humans. CS was sequentially produced by maternal-derived endometrial cells and fetal-derived placental trophoblasts before and after placentation. When mated with allogeneic males, CS-deficient mice showed increased fetal resorption rates under induced placental inflammation. This phenotype disappeared when the activity of the CS-producing enzyme was restored in the placenta. Placental CS levels were reduced in patients with “villitis of unknown etiology.” Thus, we uncovered the spatiotemporal control of CS production and its relevance to local immunosuppression during pregnancy.
Leveraging zebrafish embryo phenotypic observations to advance data-driven analyses in toxicology
Authors: Michaelis Paul , Klüver Nils , Aulhorn Silke , Bohring Hannes , Bumberger Jan , Haase Kristina , Kuhnert Tobias , Küster Eberhard , Krüger Janet , Luckenbach Till , Massei Riccardo , Nerlich Lukas , Petruschke Sven , Schnicke Thomas , Schnurpel Anton , Scholz Stefan , Schweiger Nicole , Sielaff Daniel , Busch Wibke
Published: October 2024

Zebrafish have emerged as a central model organism in toxicological research. Zebrafish embryos are exempt from certain animal testing regulations which facilitates their use in toxicological testing. Next to the zebrafish embryo acute toxicity test (ZFET) according to the OECD TG 236, fish embryos are used in mechanistic investigations, chemical screenings, in ecotoxicology, and drug development. However, inconsistencies in the applied test protocols and the monitored endpoints in addition to a lack of standardized data formats, impede comprehensive meta-analyses and cross-study comparisons. To address these challenges, we developed the Integrated Effect Database for Toxicological Observations (INTOB), a comprehensive data management tool that standardizes collection of metadata and phenotypic observations using a controlled vocabulary. By incorporating data from more than 600 experiments into the database and subsequent comprehensive data analyses, we demonstrate its utility in improving the comparability and interoperability of toxicity data. Our results show that the ZFET can detect toxicity spanning seven orders of magnitude at the scale of effect concentrations. We also highlight the potential of read-across analyses based on morphological fingerprints and their connection to chemical modes of action, provide information on control variability of the ZFET, and highlight the importance of time for mechanistic understanding in chemical exposure-effect assessments. We provide the full FAIR dataset as well as the analysis workflow and demonstrate how professional data management, as enabled with INTOB, marks a significant advancement by offering a comprehensive framework for the systematic use of zebrafish embryo toxicity data, thus paving the way for more reliable, data-driven chemical risk assessment.

Synopsis

This article shows how a novel data management tool for zebrafish embryo toxicity data advances comparative chemical risk assessment by enhancing data and metadata standardization, comparability, and cross-study analyses.
Structure-Guided Loop Grafting Improves Expression and Stability of Influenza Neuraminidase for Vaccine Development
Authors: Rijal Pramila , Wei Leiyan , Paesen Guido C , Stuart David I , Howarth Mark R , Huang Kuan-Ying A , Bowden Thomas A , Townsend Alain RM
Published: October 2024

Influenza neuraminidase is a crucial target for protective antibodies, yet the development of recombinant neuraminidase protein as a vaccine has been held back by instability and variable expression. We have taken a pragmatic approach to improving expression and stability of neuraminidase by grafting antigenic surface loops from low-expressing neuraminidase proteins onto the scaffold of high-expressing counterparts. The resulting hybrid proteins retained the antigenic properties of the loop donor while benefiting from the high-yield expression, stability, and tetrameric structure of the loop recipient. These hybrid proteins were recognised by a broad set of human monoclonal antibodies elicited by influenza infection or vaccination, with X-ray structures validating the accurate structural conformation of the grafted loops and the enzymatic cavity. Immunisation of mice with neuraminidase hybrids induced inhibitory antibodies to the loop donor and conferred protected against lethal influenza challenge. This pragmatic technique offers a robust solution for improving the expression and stability of influenza neuraminidase proteins for vaccine development.

Graphical Abstract
Pre-exposure to stress reduces loss of community and genetic diversity following severe environmental disturbance
Authors: Xu Charles C.Y. , Fugère Vincent , Barbosa da Costa Naíla , Beisner Beatrix E. , Bell Graham , Cristescu Melania E. , Fussmann Gregor F. , Gonzalez Andrew , Shapiro B. Jesse , Barrett Rowan D.H.
Published: October 2024

Environmental stress caused by anthropogenic impacts is increasing worldwide. Understanding the ecological and evolutionary consequences for biodiversity will be crucial for our ability to respond effectively. Historical exposure to environmental stress is expected to select for resistant species, shifting community composition towards more stress-tolerant taxa. Concurrent with this species sorting process, genotypes within resistant taxa that have the highest relative fitness under severe stress are expected to increase in frequency, leading to evolutionary adaptation. However, empirical demonstrations of these dual ecological and evolutionary processes in natural communities are lacking. Here, we provide the first evidence for simultaneous species sorting and evolutionary adaptation across multiple species within a natural freshwater bacterial community. Using a two-phase stressor experimental design (acidification pre-exposure followed by severe acidification) in aquatic mesocosms, we show that pre-exposed communities were more resistant than naïve communities to taxonomic loss when faced with severe acid stress. However, after sustained severe acidification, taxonomic richness of both pre-exposed and naïve communities eventually converged. All communities experiencing severe acidification became dominated by an acidophilic bacterium,Acidiphilium rubrum, but this species retained greater genetic diversity and followed distinct evolutionary trajectories in pre-exposed relative to naïve communities. These patterns were shared across other acidophilic species, providing repeated evidence for the impact of pre-exposure on evolutionary outcomes despite the convergence of community profiles. Our results underscore the need to consider both ecological and evolutionary processes to accurately predict the responses of natural communities to environmental change.
The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8⁺ T-cell revitalization
Authors: Gramatica Andrea , Miller Itzayana G. , Ward Adam R. , Khan Farzana , Kemmer Tyler J. , Weiler Jared , Huynh Tan Thinh , Zumbo Paul , Kurland Andrew P. , Leyre Louise , Ren Yanqin , Klevorn Thais , Copertino Dennis C. , Chukwukere Uchenna , Levinger Callie , Dilling Thomas R. , Linden Noemi , Board Nathan L. , Iversen Emma Falling , Terry Sandra , Mota Talia M. , Bedir Seden , Clayton Kiera L. , Bosque Alberto , Ehui Lynsay MacLaren , Kovacs Colin , Betel Doron , Johnson Jeffry R. , Paiardini Mirko , Danesh Ali , Jones R. Brad
Published: October 2024

Persistent HIV reservoirs in CD4⁺ T-cells pose a barrier to curing HIV infection. We identified overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4⁺ T- cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the FDA-approved drug tazemetostat increased surface expression of major histocompatibility complex class I (MHC-I) on CD4⁺ T-cells, counterbalancing HIV Nef–mediated MHC-I downregulation. This improved CTL-mediated elimination of HIV-infected cells and suppressed viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevated MHC-I and the pro-apoptotic protein BIM in CD4⁺ T-cells, facilitating CD8⁺ T-cell–mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promoted sustained skewing of CD8⁺ T-cells toward less differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a novel mechanism of CTL resistance and support the clinical evaluation of tazemetostat to enhance clearance of HIV reservoirs and improve CD8+ T-cell function.
Texture profile analysis and rheology of plant-based and animal meat
Authors: Dunne Reese A. , Darwin Ethan C. , Perez Medina Valerie A. , Levenston Marc E. , St. Pierre Skyler R. , Kuhl Ellen
Published: October 2024

Plant-based meat can help combat climate change and health risks associated with high meat consumption. To create adequate mimics of animal meats, plant-based meats must match in mouthfeel, taste, and texture. The gold standard to characterize the texture of meat is the double compression test, but this test suffers from a lack of standardization and reporting inconsistencies. Here we characterize the texture of five plant-based and three animal meats using texture profile analysis and rheology, and report ten mechanical features associated with each product’s elasticity, viscosity, and loss of integrity. Our findings suggest that, of all ten features, the stiffness, storage, and loss moduli are the most meaningful and consistent parameter to report, while other parameters suffer from a lack of interpretability and inconsistent definitions. We find that the sample stiffness varies by an order of magnitude, from 418.9±41.7kPa for plant-based turkey to 56.7±14.1kPa for tofu. Similarly, the storage and loss moduli vary from 50.4±4.1kPa and 25.3±3.0kPa for plant-based turkey to 5.7±0.5kPa and 1.3±0.1kPa for tofu. All three animal products, animal turkey, sausage, and hotdog, consistently rank in between these two extremes. Our results suggest that–with the right ingredients, additives, and formulation–modern food fabrication techniques can create plant-based meats that successfully replicate the full viscoelastic texture spectrum of processed animal meat.
Ecological and socioeconomic factors associated with globally reported tick-borne viruses
Authors: Sambado Samantha , Ryan Sadie J
Published: October 2024

Background

Public health resources are often allocated based on reported disease cases. However, for lesser-known infectious diseases, such as tick-borne viruses, disease risk reporting should account for more than just the biology of the disease and include mediating factors such as socioeconomics which can determine if an infection gets reported.

Objectives

We aim to identify country-level ecological and socioeconomic factors important to reporting tick-borne viruses and examine whether countries with more economic resources have a higher likelihood of reporting resource intensive incidences. Our study goals are to determine potential country-level interventions that could enhance recognition of and reduce the health burden associated with tick-borne viruses.

Methods

We apply machine learning to the most comprehensive tick-borne virus database, ZOVER, with a curated global trait matrix of 23 environmental and socioeconomic predictors.

Results

We identified socioeconomic factors driving reported tick-borne viruses captured in the database at a country level. Countries that were more likely to report tick-borne viruses had a lower Gini Index (i.e., countries with less inequalities such as Nordic countries), increased dollars spent on pesticide imports, and had institutions (i.e., IVSA chapter) or individuals with agricultural, forestry, or veterinary knowledge (i.e., % of tertiary grads) present. Additional characteristics included countries with a lower percent of population exposed to conflict also had a higher probability of reporting a tick-borne virus. As expected, broad environmental factors such as the Köeppen-Geiger climate classification zone was important and identified Mediterranean climate or humid subtropical climate as environmentally suitable zones for reported tick-borne viruses.

Discussion

For environmentally persistent pathogens, the role of ancillary factors mediating reporting must be considered for allocating resources to interventions. In addition, while direct interruption of transmission is important, socioeconomic interventions may be the greatest tool to reduce local disease burden.
ABI5 Binding Proteins are substrates of key components in the ABA core signaling pathway
Authors: Lynch Tim J , Erickson McNally B. Joy , Losic Teodora , Lindquist Jonas , Finkelstein Ruth
Published: October 2024

The central components of the ABA core signaling pathway are families of receptors, clade A type 2C protein phosphatases (PP2Cs), SNF1-Related Protein Kinases (SnRK2s), and diverse sets of proteins regulated by phosphorylation via these kinases, including bZIP transcription factors such as ABA-INSENSITIVE(ABI)5. The larger network of ABA signaling factors includes additional kinases and E3 ligases that modify these components to affect their activity and stability. The ABI5-Binding Proteins (AFPs) are negative regulators of ABA response. This study shows that the AFPs interact with specific family members of all components of this pathway and are substrates for SnRK2s and PP2Cs. AFPs also interact with subsets of MAP kinases (MPKs) and 14-3-3 proteins previously found to regulate activity of the ABI5-related clade of transcription factors. Residues predicted to be phosphorylated are conserved between AFPs, but are located within regions predicted to be unstructured. ABA promotes phosphorylation of AFP2, but conditions that prevent phosphorylation of AFP2 result in decreased stability, a shift in localization toward dispersed foci, and reduced effectiveness for inhibiting ABA response at germination. Thus, AFP2 appears to be an important hub in the ABA core signaling pathway.