bluuebunny/crossref_metadata_2025 huggingface dataset:
KIRREL3-related disorders: a case report confirming the radiological features and expanding the clinical spectrum to a less severe phenotype
Authors: Querzani Andrea , Sirchia Fabio , Rustioni Gianluca , Rossi Alessandra , Orsini Alessandro , Marseglia Gian Luigi , Savasta Salvatore , Chiapparini Luisa , Foiadelli Thomas
Published: August 2023

Background

Neurodevelopmental disorders have a multifactorial etiology, since biological, genetic, psychosocial and environmental risk factors are involved. Recent studies have been linking neurodevelopmental disorders and intellectual disability with a variety of genes, some of which encoding neuronal cell-adhesion molecules. Among these, KIRREL3 is known to play a role in CNS development, and his variants have recently been related to intellectual disability, autism spectrum disorder, childhood apraxia of speech, cerebellar hypoplasia and mild dysmorphic features.

Case presentation

In this study, we describe a young Caucasian boy with mild intellectual disability, cerebellar anomalies (cerebellar hypoplasia and mega cisterna magna) and minor dysmorphic features associated to a novel KIRREL3 variant.

Conclusions

Aim of the present case report is to expand the clinical spectrum of KIRREL3-related diseases towards a milder phenotype than what is already described in the literature. We speculate that the interaction between KIRREL3 and CASK might play a major role in promoting cognitive and cerebellar development, contributing to a variety of clinical manifestations.
Association of the controlling nutritional status score with all-cause mortality and cancer mortality risk in patients with type 2 diabetes: NHANES 1999–2018
Authors: Pan Dikang , Guo Julong , Su Zhixiang , Wang Jingyu , Wu Sensen , Guo Jianming , Gu Yongquan
Published: August 2023

Objective

There are studies on the nutritional status of type 2 diabetes (T2D), but there are no large cohort studies on the prognosis of Controlling Nutritional Status (CONUT) score for T2D. The aim of this study was to examine the association between CONUT score and all-cause mortality as well as cancer mortality in adults with T2D.

Methods

For this study, we analyzed a total of 3763 adult patients with T2D who were part of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Mortality outcomes were determined by linking to the National Death Index records as of December 31, 2019. Cox proportional risk models were used to estimate risk ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cancer deaths.

Results

During the mean follow-up of 8.17 years, there were 823 deaths from all causes and 155 deaths from cancer. After adjusting for multiple variables, the risk of all-cause mortality was higher in patients with a Mild (CONUT score ≥ 2), compared with patients with a Normal (CONUT score of 0–1). All-cause mortality risk was 39% higher, and cancer mortality risk was 45% higher. Consistent results were observed when stratified by age, sex, race, BMI, smoking status, and glycated hemoglobin levels.

Conclusions

In a nationally representative sample of American adults with T2D, we found an association between CONUT score and all-cause mortality and cancer mortality.
Sound touch elastography of Achilles tendons in patients with type 2 diabetes mellitus versus healthy adults
Authors: Huang Xinxin , Chen Xingyu , Chen Xiu , Chi Ping , Wang Pengfei , Zhan Xiaomei , Zou Chunpeng , Wang Liang , Dong Yanyan
Published: August 2023

Background

The studies of the effect of diabetes on the stiffness of Achilles tendon (AT) tissue remain inconclusive, we believe it is necessary to find a reliable method which can be used to detect the stiffness changes of the AT in the diabetic state. The objective of the present study was to investigate the effectiveness of sound touch elastography (STE) as a tool for detecting diabetic Achilles tendinopathy.

Methods

We conducted a retrospective review of 180 participants, consisting of 82 patients with type 2 diabetes mellitus (T2DM) and 98 healthy adults, who had undergone AT ultrasonography. Young ‘s modulus (E) values of the distal, middle, and proximal segments of bilateral ATs of all participants were measured using STE technique. The E values of each AT segment between the case and control group were compared.

Results

The E values of the three segments of ATs in T2DM patients were lower than the healthy controls (P < 0.05). In both groups, the E values of the distal segments were lower than those of the middle segments, and the latter were lower than those of the proximal segments (P < 0.05). The E value of each segment of AT was inversely related to FPG, HbA1c, and diabetes duration (P < 0.05). The best cut-off points for the E values of the three segments of the AT for detecting diabetic tendinopathy were 347.44 kPa (AUC, 0.779), 441.57 kPa (AUC, 0.692), and 484.35 kPa (AUC, 0.676), respectively.

Conclusion

STE can be used as a complementary diagnostic tool for the diagnosis of diabetic Achilles tendinopathy.
Late gadolinium enhancement entropy as a new measure of myocardial tissue heterogeneity for prediction of adverse cardiac events in patients with hypertrophic cardiomyopathy
Authors: Gu Zi-Yi , Qian Yu-Fan , Chen Bing-Hua , Wu Chong-Wen , Zhao Lei , Xue Song , Zhao Lei , Wu Lian-Ming , Wang Yong-Yi
Published: August 2023

Objectives

Entropy is a new late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR)–derived parameter that is independent of signal intensity thresholds. Entropy can be used to measure myocardial tissue heterogeneity by comparing full pixel points of tissue images. This study investigated the incremental prognostic value of left ventricular (LV) entropy in patients with hypertrophic cardiomyopathy (HCM).

Methods

This study enrolled 337 participants with HCM who underwent 3.0-T CMR. The LV entropy was obtained by calculating the probability distribution of the LV myocardial pixel signal intensities of the LGE sequence. Patients who underwent CMR imaging were followed up for endpoints. The primary endpoint was defined as readmission to the hospital owing to heart failure. The secondary endpoint was the composite of the primary endpoint, sudden cardiac death and non-cardiovascular death.

Results

During the median follow-up of 24 months ± 13 (standard deviation), 43 patients who reached the primary and secondary endpoints had a higher entropy (6.20 ± 0.45, p < 0.001). The patients with increased entropy (≥ 5.587) had a higher risk of the primary and secondary endpoints, compared with HCM patients with low entropy (p < 0.001 for both). In addition, Cox analysis showed that LV entropy provided significant prognostic value for predicting both primary and secondary endpoints (HR: 1.291 and 1.273, all p < 0.001). Addition of LV entropy to the multivariable model improved model performance and risk reclassification (p < 0.05).

Conclusion

LV entropy assessed by CMR was an independent predictor of primary and secondary endpoints. LV entropy assessment contributes to improved risk stratification in patients with HCM.

Critical relevance statement

Myocardial heterogeneity reflected by entropy the derived parameter of LGE has prognostic value for adverse events in HCM. The measurement of LV entropy helped to identify patients with HCM who were at risk for heart failure and sudden cardiac death.

Key points

• Left ventricular entropy can reflect myocardial heterogeneity in HCM patients.

• Left ventricular entropy was significantly higher in HCM patients who reached endpoint events.

• Left ventricular entropy helps to predict the occurrence of heart failure and death in HCM patients.

Graphical Abstract
Soluble CX3CL1-expressing retinal pigment epithelium cells protect rod photoreceptors in a mouse model of retinitis pigmentosa
Authors: Jong Eric D. , Hacibekiroglu Sabiha , Guo Lily , Sawula Evan , Li Biao , Li Chengjin , Ho Margaret T. , Shoichet Molly S. , Wallace Valerie A. , Nagy Andras
Published: August 2023

Background

Retinitis pigmentosa (RP) is an inherited retinal disease that results in photoreceptor degeneration, leading to severe vision loss or blindness. Due to its genetic heterogeneity, developing a new gene therapy to correct every genetic mutation contributing to its progression is infeasible. Photoreceptor transplantation can be harnessed to restore vision; however, this approach is limited by poor cell survival and synaptic integration into the neural retina. Thus, we developed a combined cell and gene therapy that is expected to protect photoreceptors in most, if not all, cases of RP.

Methods

Human embryonic stem cells (hESCs) modified with our FailSafe™ system were genetically engineered to overexpress sCX3CL1, an inhibitor of microglia activation that has been shown to preserve photoreceptor survival and function in mouse models of RP, independent of the genetic cause. These cells were differentiated into human retinal pigment epithelium (hRPE) cells and used as therapeutic cells due to their longevity and safety, both of which have been demonstrated in preclinical and clinical studies. Transgenic hRPE were delivered into the subretinal space of immunodeficient mice and the rd10 mouse model of RP to evaluate donor cell survival and retention of transgene expression. The outer nuclear layer was quantified to assess photoreceptor protection.

Results

Transgenic FailSafe™ hRPE (FS-hRPE) cells can survive for at least four months in the retina of immunodeficient mice and retain transgene expression. However, these cells do not persist beyond two weeks post-injection in the retina of immunocompetent rd10 recipients, despite Cyclosporine A treatment. Nevertheless, sCX3CL1-expressing FailSafe™ hRPE cells prevented photoreceptor degeneration in a local acting manner during the duration of their presence in the subretinal space.

Conclusions

Transgenic hESCs differentiate into hRPE cells and retain sCX3CL1 transgene expression both in vitro and in vivo. Moreover, hRPE cells delivered to the subretinal space of rd10 mice prevented photoreceptor degeneration in a local-acting manner, suggesting that this approach could have applications for preserving photoreceptors in specific subregions of the retina, such as the macula. Overall, our study not only reveals the potential of a combined cell and gene therapy for the treatment of RP, but also the possibility of using hRPE cells to deliver therapeutic biologics in situ to treat diseases over long-term.
Substrate topographies modulate the secretory activity of human bone marrow mesenchymal stem cells
Authors: Rosado-Galindo Heizel , Domenech Maribella
Published: August 2023

Background

Mesenchymal stem cells (MSCs) secrete a diversity of factors with broad therapeutic potential, yet current culture methods limit potency outcomes. In this study, we used topographical cues on polystyrene films to investigate their impact on the secretory profile and potency of bone marrow-derived MSCs (hBM-MSCs). hBM-MSCs from four donors were cultured on topographic substrates depicting defined roughness, curvature, grooves and various levels of wettability.

Methods

The topographical PS-based array was developed using razor printing, polishing and plasma treatment methods. hBM-MSCs from four donors were purchased from RoosterBio and used in co-culture with peripheral blood mononuclear cells (PBMCs) from Cell Applications Inc. in an immunopotency assay to measure immunosuppressive capacity. Cells were cultured on low serum (2%) for 24–48 h prior to analysis. Image-based analysis was used for cell quantification and morphology assessment. Metabolic activity of BM-hMSCs was measured as the mitochondrial oxygen consumption rate using an extracellular flux analyzer. Conditioned media samples of BM-hMSCs were used to quantify secreted factors, and the data were analyzed using R statistics. Enriched bioprocesses were identify using the Gene Ontology tool enrichGO from the clusterprofiler. One-way and two-way ANOVAs were carried out to identify significant changes between the conditions. Results were deemed statistically significant for combined P < 0.05 for at least three independent experiments.

Results

Cell viability was not significantly affected in the topographical substrates, and cell elongation was enhanced at least twofold in microgrooves and surfaces with a low contact angle. Increased cell elongation correlated with a metabolic shift from oxidative phosphorylation to a glycolytic state which is indicative of a high-energy state. Differential protein expression and gene ontology analyses identified bioprocesses enriched across donors associated with immune modulation and tissue regeneration. The growth of peripheral blood mononuclear cells (PBMCs) was suppressed in hBM-MSCs co-cultures, confirming enhanced immunosuppressive potency. YAP/TAZ levels were found to be reduced on these topographies confirming a mechanosensing effect on cells and suggesting a potential role in the immunomodulatory function of hMSCs.

Conclusions

This work demonstrates the potential of topographical cues as a culture strategy to improve the secretory capacity and enrich for an immunomodulatory phenotype in hBM-MSCs.
More than 100 years of a mistake: on the anatomy of the atlas of the enigmatic Macrauchenia patachonica
Authors: Püschel Hans P. , Martinelli Agustín G.
Published: August 2023

Ever since the discovery of the first remains of Macrauchenia patachonica by Charles Darwin in 1834, this taxon has puzzled researchers with its peculiar anatomy. Being the best-known member of the family Macraucheniidae and with fossil records in extensive areas of South America between the Middle to Late Pleistocene/earliest Holocene, M. patachonica has been extensively studied over decades, and recently even included in molecular studies. However, there are some elements of its skeleton that have been inadvertently unstudied. One of these elements is the atlas of M. patachonica that due to a misidentification made 159 years ago by the prominent zoologist Hermann Burmeister, was not examined or illustrated by later researchers even with access to excellent specimens. Here, we describe and illustrate the atlas of M. patachonica for the first time, correcting Burmeister’s mistake. Overall, the anatomy of the atlas of M. patachonica is consistent with the anatomy of older macraucheniids. The atlas described by Burmeister as being M. patachonica probably corresponds to that of a bovid. It is noteworthy that most mounted skeletons of M. patachonica present today in museum exhibitions, display a correct atlas derived from a more complete specimen discovered ca. 1904 by the prominent palaeontologist Santiago Roth.
The relationship between different levels of facial attractiveness and malocclusion perception: an eye tracking and survey study
Authors: Zorlu Merve , Camcı Hasan
Published: August 2023

Introduction

The aim of this study was to investigate the relationship between levels of facial attractiveness and the perception of different types of malocclusion.

Methods

A preliminary questionnaire was used to assign photographs of three female patients to low, moderate, and high facial attractiveness designations. Seven modified photographs for each smile photograph of each of these three patients were created. The evaluated photographs were as follows: P0: at rest position, P1: ideal smile, P2: − 2-mm (low) smile line, P3: + 4-mm gummy smile, P4: + 6-mm gummy smile, P5: maxillary anterior crowding, P6: median diastema, P7: polydiastema. An eye tracking device and a questionnaire were used to collect data from orthodontists, dentists, orthodontic patients, and laypeople.

Results

Total fixation duration varied depending on the type of malocclusion, the level of facial attraction, and the participants’ occupations. In general, orthodontists and dentists had higher total fixation duration scores than orthodontic patients and laypersons. The maxillary anterior crowding photograph had the lowest visual analysis scale score at each attractiveness level (low, medium, and high). Visual analysis scale scores became similar at each attractiveness level only in the P4 photographs, and thus the difference in facial attractiveness disappeared.

Conclusion

While a worsening of the ideal smile had a smaller impact on aesthetic perceptions in an individual with low facial attractiveness, it had a significant negative impact on a person with high facial attractiveness. Anterior crowding and diastema had a more negative impact on facial attractiveness than low or high smile lines.
Variations of precipitable water vapor in sandstorm season determined from GNSS data: the case of China’s Wuhai
Authors: Han Shihao , Liu Xin , Jin Xin , Zhang Fangzhao , Zhou Maosheng , Guo Jinyun
Published: August 2023

In recent years, the Global Navigation Satellite System (GNSS) has witnessed rapid development. However, during the sandstorm season, the precipitable water vapor (PWVGNSS) determined from the GNSS data produces large fluctuations due to the influence of particulate matter, which can indirectly reflect the change in particulate matter concentration. To study the variations of PWVGNSS during the sandstorm season, daily data of PWVGNSS, particulate matter (PM10), and precipitation in Wuhai from 2017 to 2021 were used in this study. The principal components of PWV residual (PWVRPC) were obtained by using the least-squares linear fitting, singular spectrum analysis, and least-squares spectral analysis on PWVGNSS. The principal components of PM10 (PM10PC) were obtained by using least squares linear fitting and singular spectrum analysis for PM10. This study performed a correlation analysis of PWVRPC with PM10PC and precipitation data. The results showed a strong correlation between PWVRPC and PM10PC, with a correlation coefficient greater than 0.6. However, it was found that the correlation between PWVRPC and precipitation was not significant. This indicates that during the sandstorm season, PM10 affects PWV determined from GNSS data.

Graphical Abstract
Anatomical ablation for small hepatocellular carcinomas using multiple applicators: a preliminary study
Authors: Kim Jae Hyun , Kim Hee Soo , Yoon Jeong Hee , Joo Ijin , Yoon Jung-Hwan , Kim Yoon Jun , Yu Su Jong , Lee Jeong Min
Published: August 2023

Background

Anatomical ablation, defined as thermal ablation of tumor-bearing small portal territories, may provide excellent local tumor control in peripherally-located small hepatocellular carcinomas (HCC), which has been a major concern with percutaneous ablation alone.

Purpose

To evaluate the technical feasibility and therapeutic outcomes of anatomical ablation using multiple radiofrequency (RF) applicators for the ablation of tumor-bearing small portal territories of peripherally-located small (≤ 4 cm) HCCs.

Materials and methods

Patients with peripherally-located single HCCs (≤ 4 cm) to be treated with anatomical ablation using multiple RF applicators between January 2020 and March 2022 were enrolled in this prospective study. Anatomical ablation was performed for the index tumor under real-time US-CT/MR fusion imaging guidance, with one or two clustered electrode needles placed across the tumor-bearing portal vein branches. Technical success and complications of anatomical ablations were assessed. Cumulative incidence of local tumor progression (LTP) and recurrence-free survival were estimated using the Kaplan–Meier method.

Results

Fifty-five HCCs (mean size, 1.77 ± 0.59 cm) in 55 participants (mean age, 66.4 ± 7.7 years; 39 men, 16 women) were treated with anatomical ablation; 98.2% (54/55) technical success was achieved. No major complications were noted. Among the 55 participants, LTP occurred in only one patient who had experienced technical failure of anatomical ablation. Estimated 1- and 2-year cumulative incidences of LTP were 0% and 3.7%, respectively. Five patients developed intrahepatic remote recurrence during the median follow-up period of 19.2 months (range, 3.7–28.8 months); therefore, estimated 1- and 2-year recurrence-free survival was 91.7% and 85.0%, respectively.

Conclusion

Anatomical ablation using multiple RF applicators provided the excellent results of local tumor control in patients with peripherally-located small (≤ 4 cm) HCCs.

Trial registration

clinicaltrial.gov identifier: NCT05397860.
Local digital lending development and the incidence of deprivation in Kenya
Authors: Tetteh Godsway Korku
Published: August 2023

In the developing world, vulnerable communities often lack access to regular income sources to cope with unforeseen events. Recent advancements in financial technology have enabled microcredit to be delivered via digital platforms. Although digital credit may quicken remote access to consumer credit without the need for collateral, little is known about its contribution to the welfare of underserved communities. This study examines the effects of local digital lending development on deprivation and explores the implications of these effects on rural inhabitants. The results show a negative association between local digital lending development and food deprivation on one hand and health deprivation on the other. The evidence suggests that local digital lending development can reduce the probability of food and health deprivation. Furthermore, the evidence reveals that inhabitants of rural communities benefit more from digital lending development. This study recommends the decentralization of financial inclusion policies as a pathway to promote digital lending at the local level.
Machine learning-assisted optimal schedule of underground water pipe inspection
Authors: Fan Xudong , Yu Xiong
Published: August 2023

There are over 2.2 million miles of underground water pipes serving the cities in the United States. Many are in poor conditions and deteriorate rapidly. Failures of these pipes could cause enormous financial losses to the customers and communities. Inspection provides crucial information for pipe condition assessment and maintenance plan; it, however, is very expensive for underground pipes due to accessibility issues. Therefore, water agencies commonly face the challenge to 1) decide whether it is worthwhile to schedule expensive water pipe inspections under financial constraints, and 2) if so, how to optimize the inspection schedule to maximize its value. This study leverages the physical model and data-based ML (ML) models for underground water pipe failure prediction to shed light on these two important questions for decision making. Analyses are firstly conducted to assess the value of water pipe inspection. Results by use of a physical-based failure model and Monte Carlo simulations indicate that by inspecting pipe’s condition, i.e., assessment of pipe’s erosion depth, the uncertainty of water pipe failure prediction can be narrowed down by 51%. For optimal inspection schedule, an artificial neural network (ANN) model, trained with historical inspection data, is evaluated for its performance in forecasting the future pipe failure probability. The results showed that a biased pipe failure prediction can occur under limited rounds of inspection. However, incorporating more rounds of inspection allows to predict the pipe failure conditions over its life cycle. From this, an optimal inspection plan can be proposed to achieve the maximum benefits of inspection in uncertainty reduction. A few salient results from the analyses include 1) the optimal schedule for inspection is not necessarily equal in the time interval, 2) by setting the goal of uncertainty reduction, an optimal inspection schedule can be obtained, where ML (ML) model augmented by continuously training with inspection data allows to reliably predict water pipe failure conditions over its life cycle. While this study focuses on underground pipe inspection, the general observations and methodology are applicable to optimize the inspection of other types of infrastructure as well.
Phase II Trial of Atezolizumab Combined With Carboplatin and Pemetrexed for Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Untreated Brain Metastases (Atezo-Brain, GECP17/05)
Authors: Nadal Ernest , Rodríguez-Abreu Delvys , Simó Marta , Massutí Bartomeu , Juan Oscar , Huidobro Gerardo , López Rafael , De Castro Javier , Estival Anna , Mosquera Joaquín , Sullivan Ivana , Felip Enriqueta , Blasco Ana , Guirado Maria , Pereira Eva , Vilariño Noelia , Navarro Valentín , Bruna Jordi
Published: August 2023

PURPOSE

The Atezo-Brain study evaluated atezolizumab combined with chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC) with untreated brain metastases, a population traditionally excluded from trials.

METHODS

This single-arm phase II clinical trial enrolled patients with advanced nonsquamous NSCLC with untreated brain metastases without neurologic symptoms or asymptomatic with medical treatment. Dexamethasone was allowed up to 4 mg once daily. Atezolizumab plus carboplatin and pemetrexed was given for four to six cycles followed by atezolizumab plus pemetrexed until progression for a maximum of 2 years. The primary end points were to determine the progression-free survival (PFS) rate at 12 weeks and the incidence of grade ≥3 adverse events during the first 9 weeks. Intracranial outcomes were assessed using response assessment in neuro-oncology brain metastases criteria.

RESULTS

Forty patients were enrolled and 22 (55%) were receiving corticosteroids at baseline. The overall 12-week PFS rate was 62.2% (95% credibility interval [CrI], 47.1 to 76.2). The rate of grade 3/4 adverse events during the first 9 weeks was 27.5%. Most neurologic events were grade 1 and 2 but five patients (12.5%) experienced grade 3-4 neurologic events. With a median follow-up of 31 months, intracranial median PFS was 6.9 months and response rate was 42.7% (95% CrI, 28.1 to 57.9). Systemic median PFS was 8.9 months and response rate was 45% (95% CrI, 28.1 to 57.9). The median overall survival (OS) was 11.8 months (95% CI, 7.6 to 16.9) and the 2-year OS rate was 27.5% (95% CI, 16.6 to 45.5).

CONCLUSION

Atezolizumab plus carboplatin and pemetrexed demonstrates activity in patients with advanced nonsquamous NSCLC with untreated brain metastases with an acceptable safety profile.
Metformin, Cognitive Function, and Changes in the Gut Microbiome
Authors: Rosell-Díaz Marisel , Fernández-Real José Manuel
Published: August 2023

The decline in cognitive function and the prevalence of neurodegenerative disorders are among the most serious threats to health in old age. The prevalence of dementia has reached 50 million people worldwide and has become a major public health problem. The causes of age-related cognitive impairment are multiple, complex, and difficult to determine. However, type 2 diabetes (T2D) is linked to an enhanced risk of cognitive impairment and dementia. Human studies have shown that patients with T2D exhibit dysbiosis of the gut microbiota. This dysbiosis may contribute to the development of insulin resistance and increased plasma lipopolysaccharide concentrations. Metformin medication mimics some of the benefits of calorie restriction and physical activity, such as greater insulin sensitivity and decreased cholesterol levels, and hence may also have a positive impact on aging in humans. According to recent human investigations, metformin might partially restore gut dysbiosis related to T2D. Likewise, some studies showed that metformin reduced the risk of dementia and improved cognition, although not all studies are concordant. Therefore, this review focused on those human studies describing the effects of metformin on the gut microbiome (specifically the changes in taxonomy, function, and circulating metabolomics), the changes in cognitive function, and their possible bidirectional implications.
Frizzled2 receives WntA signaling during butterfly wing pattern formation
Authors: Hanly Joseph J. , Loh Ling S. , Mazo-Vargas Anyi , Rivera-Miranda Teomie S. , Livraghi Luca , Tendolkar Amruta , Day Christopher R. , Liutikaite Neringa , Earls Emily A. , Corning Olaf B. W. H. , D'Souza Natalie , Hermina-Perez José J. , Mehta Caroline , Ainsworth Julia A. , Rossi Matteo , Papa Riccardo , McMillan W. Owen , Perry Michael W. , Martin Arnaud
Published: August 2023

Butterfly color patterns provide visible and biodiverse phenotypic readouts of the patterning processes. Although the secreted ligand WntA has been shown to instruct the color pattern formation in butterflies, its mode of reception remains elusive. Butterfly genomes encode four homologs of the Frizzled-family of Wnt receptors. Here, we show that CRISPR mosaic knockouts of frizzled2 (fz2) phenocopy the color pattern effects of WntA loss of function in multiple nymphalids. Whereas WntA mosaic clones result in intermediate patterns of reduced size, fz2 clones are cell-autonomous, consistent with a morphogen function. Shifts in expression of WntA and fz2 in WntA crispant pupae show that they are under positive and negative feedback, respectively. Fz1 is required for Wnt-independent planar cell polarity in the wing epithelium. Fz3 and Fz4 show phenotypes consistent with Wnt competitive-antagonist functions in vein formation (Fz3 and Fz4), wing margin specification (Fz3), and color patterning in the Discalis and Marginal Band Systems (Fz4). Overall, these data show that the WntA/Frizzled2 morphogen-receptor pair forms a signaling axis that instructs butterfly color patterning and shed light on the functional diversity of insect Frizzled receptors.
Disability and developmental biology
Authors: Morgan Jack Darius
Published: August 2023

Disabled scientists face tremendous barriers to entry into, and progression within, a scientific career, remaining immensely under-represented at every career stage. Disability inclusivity drives in science are increasingly prevalent, but few data are available from the developmental biology community specifically. The Young Embryologist Network sought to draw attention to this by platforming disability inclusivity as a key theme at the 2022 conference. Here, I review literature exploring disabled scientists' experiences in academia, report findings from the conference attendee survey and spotlight a new disability support grant from the British Society for Developmental Biology. I also highlight specific unmet needs and suggest educational resources and actionable measures in the hope of improving the experiences of disabled scientists in our community.
A Novel Injection Protocol Using Voluven®-Assisted Indocyanine Green with Improved Near-Infrared Fluorescence Guidance in Breast Cancer Sentinel Lymph Node Mapping—A Translational Study
Authors: Hsieh Yung-Chun , Guo Kai-Wei , Wang Man-Wen , Su Shih-Po , Syu Yu-Han , Huang Chiun-Sheng , Chan Yang-Hsiang
Published: August 2023

Background

Near-infrared (NIR) fluorescence-guided surgery with indocyanine green (ICG) has been demonstrated to provide high sensitivity in sentinel lymph node biopsy (SLNB) for breast cancer but has several limitations, such as unstable pharmacokinetics, limited fluorescence brightness, and undesired diffusion to neighboring tissues. This paper investigates the use of Voluven® as the solvent for ICG fluorescence-guided SLNB (ICG-SLNB).

Methods

The photophysical properties of ICG in water and Voluven® were evaluated in laboratory experiments and in a mouse model. Nine patients with early breast cancer underwent subareolar injection of diluted ICG (0.25 mg/ml) for ICG-SLNB. Six of the nine patients received ICG dissolved in Voluven® (ICG:Voluven®), while three were administered ICG dissolved in water (ICG:water); a repetitive injection-observation protocol was followed for all patients. The mapping image quality was evaluated.

Results

Laboratory experiments and in vivo mouse study showed improved fluorescence and better targeting using Voluven® as the solvent. ICG-SLNB with a repetitive injection-observation protocol was successfully performed in all nine patients. ICG:Voluven® administration had an overall better signal-to-background ratio (SBR) in sequential sentinel lymph nodes. The rates of transportation within the lymphatics were also improved using ICG:Voluven® compared with ICG:water.

Conclusions

From basic research to animal models to in-human trial, our study proposes a repetitive injection-observation technique with ICG:Voluven®, which is characterized by better transportation and more stable mapping quality for ICG-SLNB in breast cancer patients.
Neuropsychological and emotional characteristics of patients with parasomnia
Authors: Νταφούλη Μαρία
Published: August 2023

Αν και οι παραϋπνίες είναι νυχτερινά φαινόμενα που συμβαίνουν κατά τη διάρκεια του ύπνου ή κατά τη διάρκεια της αφύπνισης από τον ύπνο, υπάρχουν αυξανόμενες ενδείξεις ότι σχετίζονται και με ημερήσια συμπτώματα. Ωστόσο, οι συστηματικές μελέτες σε αυτό το πεδίο είναι σπάνιες. Σκοπός της παρούσας μελέτης ήταν η διερεύνηση του ύπνου-εγρήγορσης, του νευροψυχολογικού και συναισθηματικού προφίλ των ασθενών με παραϋπνίες. Στην συγκεκριμένη εργασία συμπεριελήφθησαν 30 ασθενείς με παραϋπνία (13 NREM, 17 REM) και 30 υγιή άτομα αντίστοιχα ως προς την ηλικία, το φύλο και την εκπαιδευτική κατάσταση. Όλοι οι συμμετέχοντες υποβλήθηκαν σε ολοκληρωμένη νευροψυχολογική, και συμπεριφορική αξιολόγηση. Βρέθηκε ότι οι ασθενείς με παραϋπνία σημείωσαν χειρότερη επίδοση σε όλες τις κλίμακες νευροψυχολογίας, συναισθηματικής κατάστασης, ύπνου-εγρήγορσης και ποιότητας ζωής σε σύγκριση με τα υγιή άτομα. Η παρουσία της παραϋπνίας συσχετίστηκε με σημαντικό αντίκτυπο στην ημερήσια λειτουργία σε διάφορους τομείς, συγκεκριμένα με αυξημένα επίπεδα κόπωσης (FSS>4) στο 56%, υπνηλία (ESS>10) στο 47%, καταθλιπτικά συμπτώματα (BDI>20) στο 17%, άγχος (PSWQ>52) στο 17%, εξωτερίκευση της έκφρασης θυμού (STAXI A>16) στο 27%, εσωτερίκευση έκφρασης θυμού (STAXI B>16) στο 23%, καθώς και με μειωμένη μέση βαθμολογία ποιότητας ζωής (κλίμακα RAND, προερχόμενη από το ερωτηματολόγιο SF-36). Οι διαταραχές ύπνου-εγρήγορσης βρέθηκε να συσχετίζονται σημαντικά με τις βαθμολογίες ποιότητας ζωής. Αυτά τα ευρήματα υποδηλώνουν ότι η παραϋπνία σχετίζεται με δυσκολίες σε διάφορες πτυχές της ημερήσιας λειτουργικότητας (νοητική, συναισθηματική και σωματική) και, ως εκ τούτου, η διαγνωστική εξέταση της παραϋπνίας δεν πρέπει να περιορίζεται μόνο στην διερεύνηση των νυχτερινών συμπτωμάτων και εκδηλώσεων.
Implementing ai-driven methodologies for cyberattack detection
Authors: Μπουντάκας Παναγιώτης
Published: August 2023

Η ευρεία επέκταση των ψηφιακών τεχνολογιών και των διαδικτυακών εφαρμογών έχει κάνει τις καθημερινές δραστηριότητες ευκολότερες και πιο διασκεδαστικές. Ωστόσο, οδήγησε στη δημιουργία νέων κυβερνοεγκληματικών ενεργειών καθώς και στην ανάπτυξη εξελιγμένων κυβερνοεπιθέσεων. Αυτό το νέο παράδειγμα έχει κάνει τις παραδοσιακές αμυντικές λύσεις ανίκανες να αντιμετωπίσουν την ανάπτυξη των κυβερνοεπιθέσεων και έτσι έχουν εμφανιστεί νέες άμυνες που εκμεταλλεύονται την αποτελεσματικότητα των συστημάτων Τεχνητής Νοημοσύνης. Παρόλο που η Μηχανική Μάθηση έχει χρησιμοποιηθεί συχνά για τον εντοπισμό και τον μετριασμό των επιθέσεων στον κυβερνοχώρο, η βιβλιογραφία έχει αρκετά κενά και περιορισμούς που είτε καθιστούν τις τρέχουσες λύσεις αναξιόπιστες είτε δύσκολες στην εφαρμογή τους στην πραγματική ζωή. Προς αυτή την κατεύθυνση και προκειμένου να αντιμετωπιστούν οι περιορισμοί των υφιστάμενων ερευνών, η παρούσα διατριβή έχει μελετήσει την ασφάλεια των συστημάτων Τεχνητής Νοημοσύνης, ερευνώντας τις τρέχουσες αμυντικές λύσεις έναντι των επιθέσεων Adversarial Machine Learning και έχει δημιουργήσει μια ταξινόμηση των προσδιορισμένων αμυντικών λύσεων για να διευκολύνει τους ερευνητές να προτείνουν στο μέλλον νέες ισχυρές άμυνες. Αφού αναγνωρίσαμε ότι τα συστήματα Τεχνητής Νοημοσύνης μπορούν να προστατευτούν, αυτή η διατριβή επικεντρώθηκε στο σχεδιασμό και την ανάπτυξη αμυντικών μεθοδολογιών Μηχανικής Μάθησης έναντι δύο γνωστών κυβερνοεπιθέσεων, γνωστών ως phishing και exploit kit. Τα πειραματικά αποτελέσματα έδειξαν ότι οι προτεινόμενες μεθοδολογίες, συνολικά, βελτίωσαν την απόδοση ανίχνευσης επιθέσεων phishing και exploit kit, καταλήγοντας στο συμπέρασμα ότι η Μηχανική Μάθηση μπορεί να χρησιμοποιηθεί για να σταματήσει τη συνεχιζόμενη απειλή των κυβερνοεπιθέσεων. Επιπλέον, η παρούσα διατριβή μελετά μια επίθεση code injection που εισήχθη πρόσφατα, η οποία ονομάζεται Server-side JavaScript Injection και προτείνει μια μεθοδολογία που έχει δημιουργηθεί επίσης ως εργαλείο λογισμικού που εντοπίζει και εκμεταλλεύεται αυτόματα ευπάθειες που σχετίζονται με τις επιθέσεις Server-side JavaScript Injection. Τέλος, αυτή η διατριβή έχει εντοπίσει διάφορες κατευθύνσεις για μελλοντική έρευνα που ελπίζουμε ότι θα διευκολύνουν τους ερευνητές στο μέλλον να δημιουργήσουν ισχυρές αμυντικές λύσεις και να αντιμετωπίσουν αποτελεσματικά εξελιγμένες κυβερνοεπιθέσεις.
Τα ποιήματα ποιητικής του Αντώνη Φωστιέρη
Authors: Μακρίδου Παρασκευή
Published: August 2023

Οι σύγχρονες προσεγγίσεις στον χώρο της Κριτικής θεωρίας στο δεύτερο μισό του 20ού αιώνα, και ιδιαίτερα η ανάπτυξη του Δομισμού, έφεραν στο προσκήνιο νέους τρόπους προσέγγισης του λογοτεχνικού κειμένου. Ειδικότερα, σε ό,τι αφορά στον ποιητικό λόγο, το ποίημα αντιμετωπίστηκε ως μήνυμα που εκπέμπεται από τον πομπό-ποιητή προς τον δέκτη-αναγνώστη, ενώ ιδιαίτερη έμφαση δόθηκε στον τρόπο γλωσσικής «κωδικοποίησης» του ποιητικού λόγου. Μέσα σε αυτό το γενικότερο πλαίσιο κινήθηκαν οι δομιστικές αντιλήψεις για την ανάλυση της ποίησης με κύριο εκφραστή τον R. Jakobson (1926-1948), από τον Γλωσσολογικό Κύκλο της Πράγας, ο οποίος αναγνώρισε το ποιητικό έργο ως «λειτουργική δομή» και έστρεψε την προσοχή στη μελέτη δύο ρητορικών τρόπων: της μεταφοράς και της μετωνυμίας.Μέσα σε αυτό το θεωρητικό πλαίσιο η παρούσα διδακτορική διατριβή επιχειρεί την εξέταση των ποιημάτων ποιητικής του Αντώνη Φωστιέρη (1953), ο οποίος συγκαταλέγεται ανάμεσα στους πλέον αναγνωρισμένους ποιητές της γενιάς του ’70. Ως ερευνητικό δείγμα της διατριβής ορίζονται τα «ποιήματα ποιητικής» ή «ποιήματα για την ποίηση», τα ποιήματα δηλαδή που η θεματική τους περιστρέφεται τόσο γύρω από την έννοια της ποίησης όσο και γύρω από επιμέρους στοιχεία, πτυχές και εκφάνσεις της ποιητικής τέχνης, ως ιδιαίτερης γλωσσικής έκφρασης της ποιητικής ιδέας. Η εν λόγω κατηγορία ποιημάτων είναι ιδιαιτέρως ορατή στο έργο του ποιητή, από τις πρώτες μέχρι τις τελευταίες του συλλογές, και εξετάζεται, στη βάση μιας τριμερούς δομής: ο πομπός-ποιητής και οι ιδεολογικές του αντιλήψεις που αφορούν την ποιητική τέχνη, το ποίημα, ως το μήνυμα της επικοινωνίας και ο αναγνώστης, ως παραλήπτης του ποιητικού μηνύματος. Το ερευνητικό υλικό εξετάζεται και ως προς τον άξονα της ομοιότητας (μεταφορά) και της συνάφειας (μετωνυμία). Μέσα από αυτήν την οπτική μελετώνται οι ιδιότητες που λαμβάνουν το ποίημα και τα ποιήματα, ο αναγνώστης αλλά και ο ίδιος ο ποιητής, ως δημιουργός του συγγραφικού του εαυτού. Η έρευνα δομείται σε τρία μέρη και σε δεκατρία(13) κεφάλαια. Στο πρώτο μέρος περιέχονται τα κεφάλαια που αφορούν σε θεωρητικά ζητήματα και εργογραφικά στοιχεία του ποιητή, στο δεύτερο μέρος εξετάζονται ξεχωριστά οι τρεις παράγοντες επικοινωνίας (το ποίημα/ποιήματα, ο αναγνώστης/ες και ο ποιητής), στο τρίτο μέρος της διατριβής επιχειρείται η μελέτη της ποιητικής λειτουργίας, στον άξονα της ομοιότητας, με την εξέταση των κυριότερων υφολογικών-γλωσσικών επιλογών, ενώ στα συμπεράσματα κατατίθενται οι τελικές διαπιστώσεις. Η εργασία πλαισιώνεται από παράρτημα στο οποίο υπάρχουν οι πίνακες καταγοριοποίησης των ποιημάτων ποιητικής και αδημοσίευτη συνέντευξη της γράφουσας με τον ποιητή.
Αδικοπρακτική ευθύνη του παρέχοντος ιατρικές υπηρεσίες
Authors: Νταριϊτσούκ Ειρήνη
Published: August 2023

Με τη μελέτη αυτή επιχειρείται εμβάθυνση στην έρευνα της αδικοπρακτικής ευθύνης των παρεχόντων ιατρικές υπηρεσίες μέσω της συγκριτικής για το ζήτημα αυτό επισκόπησης του ελληνικού, του ουκρανικού και του ρωσικού δικαίου. Η αποδοκιμασία της δράσης και στάσης του ζημιώσαντος, ως θεμέλιο της αδικοπρακτικής ευθύνης των παρεχόντων ιατρικές υπηρεσίες και τα κρίσιμα γι’ αυτήν κριτήρια, ο επιδιωκόμενος με αυτήν σκοπός, η θεμελίωση και η ανάλυση του δύσκολου ζητήματος της παραβίασης των υποχρεώσεων πρόνοιας και ασφάλειας τόσο στο αντικειμενικό όσο και στο υποκειμενικό επίπεδο της αδικοπρακτικής ευθύνης, είναι κάποια από τα πιο βασικά ζητήματα τα οποία πραγματεύεται η συγγραφέας με τη μελέτη αυτή.
Σύνθεση και μελέτη βιοδραστικών λιπιδίων
Authors: Μουντανέα Όλγα
Published: August 2023

Στο πλαίσιο της παρούσας διδακτορικής διατριβής επετεύχθη η ανάπτυξη συνθετικών μεθοδολογιών με στόχο τη σύνθεση βιοδραστικών λιπιδίων. Πιο συγκεκριμένα, ολοκληρώθηκε η σύνθεση εστέρων λιπαρών οξέων με υδρόξυ λιπαρά οξέα (ή FAHFAs), ενώσεων με αντιδιαβητική αλλά και αντιφλεγμονώδη και αντικαρκινική δράση. Η συνθετική μέθοδος επέτρεψε την παραλαβή διαφορετικών εναντιομερών και τοποϊσομερών, ενώ μικρές αλλαγές στη συνθετική πορεία επέτρεψαν την απομόνωση αναλόγων FAHFAs με αμιδικό δεσμό ή αρωματικό δακτύλιο. Παράλληλα, πραγματοποιήθηκε σύνθεση χειρόμορφων κορεσμένων και ακόρεστων υδρόξυ λιπαρών οξέων (ΗFAs), τα οποία μελετήθηκαν στη συνέχεια για την αντικαρκινική και αντιδιαβητική τους δράση παρουσιάζοντας θετικά αποτελέσματα. Για την περαιτέρω κατανόηση της ενδογενούς σύνθεσης των FAHFAs, σκόπιμη κρίθηκε η σύνθεση ενός δευτεριωμένου HFA. Ακόμα, κατά τη διάρκεια της παρούσας διδακτορικής διατριβής αναπτύχθηκαν εναλλακτικές συνθετικές μεθοδολογίες για την παραλαβή των FAHFAs τόσο με χρήση διασταυρούμενης σύζευξης με χρήση καταλύτη Hoveyda-Grubbs δεύτερης γενιάς αλλά και μέσω φωτοκαταλυτικού πρωτοκόλλου. Επιπροσθέτως, πραγματοποιήθηκε μελέτη φωτοεπαγόμενης αντίδρασης σύζευξης μεταξύ ενός οξέος και μιας αμίνης, όπου με τη χρήση πηγής φωτός, μιας βάσης αλλά και ενός αλογονοδότη, επετεύχθη η σύνθεση ενώσεων τόσο βιολογικού όσο και συνθετικού ενδιαφέροντος, όπως είναι τα προστατευμένα υδροξαμικά οξέα και τα αμίδια Weinreb. Η ανακάλυψη και μελέτη του σχηματισμού ενός συμπλόκου μεταφοράς φορτίου (Charge Transfer Complex) μεταξύ της βάσης και του δότη αλογόνου οδήγησε στην ανάπτυξη μιας νέας φωτοχημικής αντίδρασης σύζευξης μεταξύ ενός οξέος και μιας αμίνης προς τον σχηματισμό αμιδικού δεσμού για την παραλαβή αμιδίων και διπεπτιδίων.
The genome sequence of the Soprano Pipistrelle, Pipistrellus pygmaeus (Leach, 1825)
Authors: Ruedi Manuel , Vernes Sonja C. , Teeling Emma C. , Mai Meike ,   Wellcome Sanger Institute Tree of Life programme,   Wellcome Sanger Institute Scientific Operations: DNA Pipelines collective,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2023

We present a genome assembly from an individual male Pipistrellus pygmaeus (the Soprano Pipistrelle; Chordata; Mammalia; Chiroptera; Vespertilionidae). The genome sequence is 1,895.1 megabases in span. Most of the assembly is scaffolded into 23 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 17.18 kilobases in length.
The genome sequence of a conopid fly, Thecophora atra (Fabricius, 1775)
Authors: Mitchell Ryan , Falk Steven , Thomas Sam , Sivell Olga , Sivell Duncan ,   Natural History Museum Genome Acquisition Lab,   University of Oxford and Wytham Woods Genome Acquisition Lab,   Darwin Tree of Life Barcoding collective,   Wellcome Sanger Institute Tree of Life programme,   Wellcome Sanger Institute Scientific Operations: DNA Pipelines collective,   Tree of Life Core Informatics collective,   Darwin Tree of Life Consortium
Published: August 2023

We present a genome assembly from an individual male Thecophora atra (a conopid fly; Arthropoda; Insecta; Diptera; Conopidae). The genome sequence is 354.2 megabases in span. Most of the assembly is scaffolded into 5 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 17.3 kilobases in length. Gene annotation of this assembly on Ensembl identified 30,620 protein coding genes.
The Use of Descriptive Geometry Methods for Graphical Study of the Parameters of the Cutting Part of a Spiral Drill
Authors: Paliy N.
Published: August 2023

The article presents examples of practical application of descriptive geometry methods for solving engineering problems of determining and studying the parameters of the cutting part of a spiral drill. The necessity of graphical constructions is noted, which is due to the fact that it is impossible to measure the rear angle by a direct measurement method using a universal measuring instrument due to the complex geometric shape of the measuring object. The analysis of the geometric shape of the working part of the spiral drill, which includes the main rear conical surface of the drill tooth, the front screw surface of the drill groove, the cylindrical surface of the tooth back, the main and transverse cutting edges are presented. Using the double contact theorem, a projection of the tooth profile of a spiral drill is constructed on a plane parallel to the drill axis with a given profile projection on a plane perpendicular to the drill axis. The tooth profile is determined by the lines of intersection of the conical surface with the cylindrical surface and with the helical surface of the drill groove. The shape of the drill groove is considered to be set. Projections of the transverse cutting edge of the drill are constructed as lines of intersection of two conical surfaces with intersecting axes. The problem is solved using a bundle of auxiliary planes. The tendency of an increase in the angle of inclination of the transverse cutting edge to the drill axis with a decrease in the distance between the intersecting axes of conical surfaces is shown. Graphically, at an arbitrary point of the drill blade, the value of one of the main geometric parameters of the drill - the rear angle is determined. It is shown that the closer the point of the blade is to the center of the drill, the greater the value of the rear angle. The constructions are made in the 2D Compass-Graph design system. The paper used alternative methods for solving geometric problems, which, unlike traditional ones, provide a simpler and more visual graphical solution.
Medical confidentiality in the Polish legal system: a real or illusory instrument of patient privacy protection?
Authors: Pudlo Robert , Pudlo Małgorzata , Burdzik Marcin
Published: August 2023

Informacje o stanie zdrowia przekazywane przez pacjentów w gabinecie lekarskim należą do sfery ich życia prywatnego. Tajemnica lekarska ma zapobiegać nieuzasadnionej ingerencji w treść tych informacji, zarówno przez organy państwa jak i podmioty prywatne. Tajemnica lekarska jest zarazem narzędziem ochrony konstytucyjnego prawa do prywatności jednostki jak i gwarancją skutecznego procesu diagnostyczno-terapeutycznego. Z tych względów dostęp do informacji objętych tajemnicą lekarską powinien mieć charakter wyjątkowy, zwłaszcza, że dane te mają wysoce sensytywny charakter. Dotyczy to zwłaszcza tajemnicy psychiatrycznej. Wbrew tym, wydawałoby się oczywistym założeniom, polski prawodawca wprowadza do systemu prawa coraz więcej rozwiązań prawnych, które poważnie ingerują w sferę informacji o stanie zdrowia jednostki. Taki stan czyni z tajemnicy lekarskiej (psychiatrycznej) instytucję o charakterze iluzorycznym i godzi w konstytucyjne prawo do prywatności pacjenta. Wpływa też negatywnie na skuteczność procesu diagnostyczno-terapeutycznego, który wymaga pełnego zaufania w relacji lekarz-pacjent, a co za tym idzie zagwarantowania poufności. W artykule omówiono ratio legis tajemnicy lekarskiej oraz wzajemną relację tajemnicy psychiatrycznej i tajemnicy lekarskiej, a także przesłanki pozwalające na uchylenie tych sekretów. Następnie omówiono też relację jaka zachodzi pomiędzy tajemnicą lekarską a innymi obowiązkami prawnymi spoczywającymi na lekarzach. Na kanwie tych rozważań poddano analizie rozwiązania prawne, które są wyrazem tendencji do osłabiania ochrony prawnej tajemnicy lekarskiej, a tym samym stanowią realne zagrożenie dla informacji nią objętych.